S. Sundar, D. More, and M. Singh, Clin. Infect. Dis, vol.31, pp.1104-1107, 2000.

M. Loiseau and C. Bories, Curr. Top. Med. Chem, vol.6, pp.539-550, 2006.

Y. Zhou, N. Messier, and M. Ouelette, J. Biol. Chem, vol.279, pp.37445-37451, 2004.

H. Denton, J. C. Mcgregor, and G. H. Coobs, Biochem. J, vol.381, pp.405-412, 2004.

C. S. Ferreira, P. S. Martins, and C. Demicheli, Biometals, vol.16, pp.441-446, 2003.

A. Ponte-sucre, F. Gamarro, and J. Dujardin, PLoS Negl. Trop. Dis, p.6052, 2017.

D. Sereno, P. Holzmuller, and I. Mangot, Antimicrob. Agents Chemother, vol.45, pp.2064-2069, 2001.

M. L. Cunningham and A. H. Fairlamb, Eur. J. Biochem, vol.230, pp.460-468, 1995.

S. Mandal, M. Maharjan, and S. Singh, J. Antimicrob. Chemother, vol.65, pp.496-507, 2010.

W. Yorke, Trans. R. Soc. Trop. Med. Hyg, p.463, 1940.

J. Willinsky, Emerg. Infect. Dis, p.1473, 2006.

M. P. Barrett, Lancet, vol.353, pp.1113-1114, 1999.

D. Mumba, E. Bohorquez, and J. Messina, PLoS Negl. Trop. Dis, 1246.

F. N. Wamwiri and R. E. Changasi, Biomed. Res. Int, p.8, 2016.

J. S. Franco, P. P. Simarro, and A. Diarra, Clin. Epidemiol, vol.6, pp.257-275, 2014.

D. H. Molyneux, Insect Science and its Application, vol.1, pp.39-46, 1980.

C. Schmid, M. Richer, and C. M. Bilenge, J. Infect. Dis, 1922.

J. Keiser, O. Ericsson, and C. Burri, Clin. Pharmacol. Ther, vol.67, pp.478-488, 2000.

M. L. Cunningham, M. J. Zvelebil, and A. H. Fairlamb, Eur. J. Biochem, vol.221, pp.285-295, 1994.

A. H. Fairlamb and D. Horn, Trends Parasitol, vol.34, pp.481-492, 2018.

N. Carter and A. H. Fairlamb, Nature, vol.361, pp.173-176, 1993.

M. R. Perry, S. Wyllie, and A. Raab, Proc. Natl. Acad. Sci. USA, vol.110, 2013.

D. Steverding, Parasit. Vectors, vol.3, pp.15-159, 2010.

P. G. Janssens and A. Demuynck, Ann. Soc. Belg. Med. Trop, vol.57, pp.475-480, 1977.

M. Kaiser, M. A. Bray, and M. , Antimicrob. Agents Chemother, vol.55, pp.5602-5608, 2011.

J. Pépin, F. Milord, and F. Meurice, Trans. R. Soc. Trop. Med. Hyg, vol.86, pp.254-256, 1992.

G. Eperon, M. Balasegaram, and J. Potet, Expert Rev. Anti Infect., Ther, vol.12, pp.1407-1417, 2014.

A. Buschini, L. Ferrarini, and S. Franzoni, J. Parasitol. Res, 2009.

B. S. Hall, C. Bot, and S. R. Wilkinson, J. Biol. Chem, vol.286, pp.13088-13095, 2011.

S. Patterson and S. Wyllie, Trends Parasitol, vol.30, pp.289-298, 2014.

G. Priotto, C. Fogg, and M. Balasegaram, Br. J. Pharmacol, 2006.

C. Schmid, A. Kuemmerle, and J. Blum, PLoS Negl. Trop. Dis, 1920.

J. C. Rodriques and S. L. De-castro, Mem. Inst. Oswaldo Cruz, vol.97, pp.3-24, 2002.

S. H. Wilkinson, M. C. Taylor, and D. Horn, Proc. Natl. Acad. Sci. USA, vol.105, pp.5022-5027, 2008.

S. M. Murta, R. T. Gazzinelli, and Z. Brener, Mol. Biochem. Parasitol, vol.93, pp.203-214, 1998.

A. Mahalingam, A. R. Geonnotti, and J. Balzarini, Mol. Pharm, vol.8, pp.2465-2475, 2011.

A. Markham, Drugs, vol.74, pp.1555-1558, 2014.

E. J. Goldstein, D. M. Citron, and K. L. Tyrrell, Antimicrob. Agents Chemother, vol.57, pp.4872-4876, 2013.

Y. K. Zhang, J. J. Plattner, and E. E. Easom, Bioorg. Med. Chem. Lett, vol.25, pp.5589-5593, 2015.

R. T. Jacobs, J. J. Plattner, and B. Nare, Future Med. Chem, vol.3, pp.1259-1278, 2011.

R. T. Jacobs, B. Nare, and S. A. Wring, PLoS Negl. Trop. Dis, 1151.

. Dndi,

E. Beveridge, L. G. Goodwin, and L. P. Walls, Nature, vol.182, pp.316-317, 1958.

K. E. Kinnamon, E. A. Steck, and P. S. Loizeaux, Am. J. Trop. Med. Hyg, vol.27, pp.751-757, 1978.

K. E. Kinnamon, E. A. Steck, and P. S. Loizeaux, Am. J. Trop. Med. Hyg, vol.27, pp.751-757, 1978.

J. A. Sherwood, G. S. Gachihi, and R. K. Muigai, Clin. Infect. Dis, vol.19, pp.1034-1039, 1994.

R. Dietze, S. F. Carvalho, and L. C. Valli, Am. J. Trop. Med. Hyg, vol.65, pp.685-689, 2001.

M. K. Wasunna, J. R. Rashid, and J. Mbui, Am. J. Trop. Med. Hyg, vol.73, pp.871-876, 2005.

S. Sundar, P. K. Sinha, and S. A. Dixon, Am. J. Trop. Med. Hyg, vol.84, pp.892-900, 2011.

P. M. Loiseau, S. Cojean, and J. Schrével, Parasite, vol.18, pp.115-119, 2011.

. Dndi,

S. Patterson and A. H. Fairlamb, Curr. Med. Chem, 2018.

J. A. Urbina, J. Eukaryot. Microbiol, vol.62, pp.149-156, 2015.

L. F. Diniz, A. L. Mazzeti, and I. S. Caldas, Antimicrob. Agents Chemother, vol.62, pp.401-00418, 2018.

C. E. Mowbray, Drug Discovery for Leishmaniasis édité par L. Rivas et C. Gil, vol.2, pp.24-36, 2017.

M. Van-den, D. Kerkhof, E. Mabille, and . Chatelain, Drugs and Drug resistance, vol.8, pp.81-86, 2018.

A. M. Thompson, P. D. O'connor, and A. Blaser, J. Med. Chem, vol.59, pp.2530-2550, 2016.

A. M. Thompson, P. D. O'connor, and A. J. Marshall, J. Med. Chem, vol.61, pp.2329-2352, 2018.

S. Lofmark, C. Edlund, and C. Nord, Clin. Infect. Dis, vol.50, pp.16-23, 2010.

J. Samuelson, Antimicrob. Agents Chemother, vol.43, pp.1533-1541, 1999.

M. Skold, H. Gnarpe, and L. Hillstrom, Br. J. Vener. Dis, vol.53, pp.44-48, 1977.

D. Videau, G. Niel, and A. Siboulet, Br. J. Vener. Dis, vol.54, pp.77-80, 1978.

F. Nesslany, S. Brugier, and M. Mouriès, Mutat. Res. Genet. Toxicol. Environ. Mutagen, vol.560, pp.147-158, 2004.

G. C. Lancini and L. Lazzari, Experientia, p.83, 1965.

B. Cavalleri, R. Ballotta, and V. Arioli, J. Med. Chem, vol.16, pp.557-560, 1973.

R. Sharma, Curr. Radiopharm, vol.4, pp.379-393, 2011.

J. Williamson, Exp. Parasitol, vol.12, pp.323-367, 1962.

S. Patterson and S. Wyllie, Trends Parasitol, vol.30, pp.289-298, 2014.

A. Huttner, E. M. Verhaegh, and S. Harbarth, Antimicrob Agents Chemother, vol.70, pp.2456-2564, 2015.

C. Brevet and . Ernest, , p.3290213, 1961.

B. Begovic, S. Ahmedtagic, and L. Calkic, , vol.28, pp.454-458, 2016.

J. F. Rossignol and R. Cavier, Chem. Abstr, p.28216, 1975.

J. F. Rossignol, H. Maisonneuve, and Y. W. Cho, Int. J. Clin. Pharmacol. Ther. Toxicol, vol.22, pp.63-72, 1984.

C. S. Mcvay and R. D. Rolee, Antimicrob. Agents Chemother, vol.44, pp.2254-2258, 2000.

K. Tatsumi, T. Doi, and H. Yoshimura, J. Pharmacobiodyn, vol.5, pp.423-429, 1982.

Y. Yanto, M. Hall, and A. S. Bommarius, Org. Biomol. Chem, vol.8, pp.1826-1832, 2010.

W. T. Speck, J. L. Blumer, and E. J. Rosenkranz, Cancer Res, vol.41, pp.2305-2307, 1981.

E. J. Rosenkranz, E. C. Mccoy, and R. Mermelstein, Carcinogenesis, vol.3, pp.121-123, 1982.

O. Ostling and K. Johanson, Biochem. Biophys. Res. Commun, vol.123, pp.291-298, 1984.

N. Singh, M. Mccoy, and R. Tice, Exp. Cell. Res, vol.175, pp.184-191, 1988.

R. Araldi, T. Melo, and N. Diniz, Biomed. Res. Int, pp.1-7, 2013.

A. Azqueta and A. Collins, Arch. Toxicol, vol.87, pp.949-968, 2013.

A. R. Collins, Biochim. Biophys. Acta, vol.1840, pp.794-800, 2014.

D. Pace and L. , J. Infect, vol.69, 2014.

P. Büscher, G. Cecchi, V. Jamonneau, and G. Priotto, Human African trypanosomiasis, Lancet, vol.390, issue.17, pp.31510-31516, 2017.

B. Zulfiqar, T. B. Shelper, and V. M. Avery, Leishmaniasis drug discovery: recent progress and challenges in assay development, Drug Discov. Today, vol.22, pp.1516-1531, 2017.

A. Ponte-sucre, A. Gamarro, J. C. Dujardin, M. P. Barrett, R. Lopez-v-elez et al., Drug resistance and treatment failure in leishmaniasis: a 21st century challenge, PLoS Neglected Trop. Dis, vol.11, 2017.

M. C. Field, D. Horn, A. H. Fairlamb, M. A. Ferguson, D. W. Gray et al., Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need, Nat. Rev. Microbiol, vol.15, pp.217-231, 2017.

S. Patterson, S. Wyllie, S. Norval, L. Stojanovski, F. R. Simeons et al., The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis, p.9744, 2016.

W. C. Ang, A. M. Jarrad, M. A. Cooper, and M. A. Blaskovich, Nitroimidazoles: molecular fireworks that combat a broad spectrum of infectious diseases, J. Med. Chem, vol.60, pp.7636-7657, 2017.

. Dndi,

V. K. Mesu, W. M. Kalonji, C. Bardonneau, O. V. Mordt, S. Blesson et al., Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial, Lancet, issue.17, pp.32758-32765, 2018.

S. Patterson and S. Wyllie, Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects, Trends Parasitol, vol.30, pp.289-298, 2014.

S. Wyllie, S. Patterson, L. Stojanovski, F. R. Simeons, S. Norval et al., The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis, Sci. Transl. Med, vol.4, 2012.

P. Verhaeghe, P. Rathelot, S. Rault, and P. Vanelle, Convenient preparation of original vinylic chlorides with antiparasitic potential in quinoline series, Lett. Org. Chem, vol.3, 2006.

L. Paloque, P. Verhaeghe, M. Casanova, C. Castera-ducros, A. Dum-etre et al., Discovery of a new antileishmanial hit in 8-nitroquinoline series, Eur. J. Med. Chem, vol.54, pp.75-86, 2012.
URL : https://hal.archives-ouvertes.fr/hal-02049707

C. Kieffer, A. Cohen, P. Verhaeghe, S. Hutter, C. Castera-ducros et al., Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series, Eur. J. Med. Chem, vol.92, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01460569

C. Kieffer, A. Cohen, P. Verhaeghe, L. Paloque, S. Hutter et al., Antileishmanial pharmacomodulation in 8-nitroquinolin-2(1H)-one series, Bioorg. Med. Chem, vol.23, pp.2377-2386, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01460646

V. P. Andreev and Y. P. Nizhnik, Reaction of 2,4-dibromoquinoline with hydrogen chloride, Russ. J. Org. Chem, vol.38, pp.137-138, 2002.

N. J. O'brien, M. Brzozowski, D. J. Wilson, L. W. Deady, and B. M. Abbott, Synthesis and biological evaluation of substituted 3-anilinoquinolin-2(1H)-ones as PDK1 inhibitors, Bioorg. Med. Chem, vol.22, pp.3781-3790, 2014.

F. Zaragoza, H. Stephensen, B. Peschke, and K. , 2-(4-Alkylpiperazin-1-yl) quinolines as a new class of Imidazole-free Histamine H 3 Receptor Antagonists, J. Med. Chem, vol.48, pp.306-311, 2005.

R. I. Zubatyuk, L. Gorb, O. V. Shishkin, M. Qasim, and J. Leszczynski, Exploration of density functional methods for one-electron reduction potential of nitrobenzenes, J. Comput. Chem, vol.31, pp.144-150, 2010.

M. Uchimiya, L. Gorb, O. Isayev, M. M. Qasim, and J. Leszczynski, One-electron standard reduction potentials of nitroaromatic and cyclic nitramine explosives, Environ. Pollut, vol.158, pp.3048-3053, 2010.

E. Torreele, B. Bourdin-trunz, D. Tweats, M. Kaiser, R. Brun et al., Fexinidazole e a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness, PLoS Neglected Trop. Dis, vol.4, p.923, 2010.

S. Wyllie, S. Patterson, and A. H. Fairlamb, Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation, Antimicrob. Agents Chemother, vol.57, pp.901-906, 2013.

S. Wyllie, A. J. Roberts, S. Norval, S. Patterson, B. J. Foth et al., Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania, PLoS Pathog, vol.12, p.1005971, 2016.

V. Purohit and A. K. Basu, Mutagenicity of nitroaromatic compounds, Chem. Res. Toxicol, vol.13, pp.673-692, 2000.

E. J. Rosenkranz, E. C. Mccoy, R. Mermelstein, and H. S. Rosenkranz, Evidence for the existence of distinct nitroreductases in Salmonella typhimurium: roles in mutagenesis, Carcinogenesis, vol.3, pp.121-123, 1982.

A. Buschini, L. Ferrarini, S. Franzoni, S. Galati, M. Lazzaretti et al., Genotoxicity revaluation of three commercial nitroheterocyclic drugs: nifurtimox, benznidazole and metronidazole, J. Parasitol. Res, 2009.

F. Misani and N. T. Bogert, The search for superior drugs for tropical diseases; further experiments in the quinolone group, J. Org. Chem, vol.10, pp.458-463, 1945.

I. G. Moores, R. K. Smalley, and H. Suschitzky, Alkaline Hydrolysis of 2-(Trifluoromethyl)imidazo, J. Fluorine Chem, vol.4, pp.573-580, 1982.

M. Ishikawa and I. Kikkawa, Studies on quinoline derivatives. IV, vol.75, pp.36-39, 1955.

V. V. Patil and G. S. Shankarling, Steric-hindrance-induced Regio-and Chemoselective Oxydation of Aromatic amines, J. Org. Chem, vol.80, pp.7876-7883, 2015.

O. H. Johnson and C. S. Hamilton, Syntheses in the quinoline series. III. The nitration of 2-chloro-4-methylquinoline and the preparation of some 2-hydroxy-4-methyl-8-(dialkylaminoalkyl)-aminoquinolines, J. Am. Chem. Soc, vol.63, pp.2867-2869, 1941.

A. R. Todorov, T. Wirtanen, and J. Helaja, Photoreductive removal of O-Benzyl groups from Oxyarene N-Heterocycles assisted by O-Pyridine-pyridone Tautomerism, J. Org. Chem, vol.82, pp.13756-13767, 2017.

E. Rosenhauer, Über Reaktionen von N-Alkyl-a-methylen-chinolanen, I.: Diazo-Kupplung der Methylenbase in neutraler L? osung, Eur. J. Inorg. Chem, vol.57, 1924.

T. Hashimoto, Amyostatic poisons. VIII. Syntheses of alkyl derivatives of 3-amino-3,4-dihydrocarbostyril and diamino-3,4-dihydrocarbostyril, Yakugaku Zasshi, vol.75, pp.340-342, 1955.

K. Mislow and J. B. Koepfli, The synthesis of potential Antimalarials. Some 2-substituted 8-(3-Diethylaminopropylamino)-quinolines, J. Am. Chem. Soc, vol.68, pp.1553-1556, 1946.

M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb et al., , 2013.

Y. Zhao and D. G. Truhlar, The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals, Thero. Chem. Acc, vol.120, pp.215-241, 2008.

J. Tomasi, B. Mennucci, and R. Cammi, Quantum mechanical continuum solvation models, Chem. Rev, vol.105, pp.2999-3093, 2005.

C. P. Kelly, C. J. Cramer, and D. G. Truhlar, Aqueous solvation free energies of Ions and Ion-water Clusters based on an accurate value for the absolute aqueous solvation free energy of the Proton, J. Phys. Chem. B, vol.110, pp.16066-16081, 2006.

C. Zhang, S. Bourgeade-delmas, A. F. Alvarez, A. Valentin, C. Hemmert et al., Synthesis, characterization, and antileishmanial activity of neutral N-heterocyclic carbenes gold(I) complexes, Eur. J. Med. Chem, vol.143, pp.1635-1643, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01963517

T. J. Mosman, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, J. Immunol. Meth, vol.65, issue.83, pp.90303-90307, 1983.

R. I. Da-luz, M. Vermeersch, J. C. Dujardin, P. Cos, and L. Maes, Vitro sensitivity testing of Leishmania clinical field Isolates: Preconditioning of promastigotes Enhances Infectivity for macrophage host cells, Antimicrob. Agents Chemother, vol.53, pp.5197-5203, 2009.

S. Goyard, H. Segawa, J. Gordon, M. Showalter, R. Duncan et al., An in vitro system for developmental and genetic studies of Leishmania donovani phosphoglycans, Mol. Biochem. Parasitol, vol.130, pp.142-149, 2003.

S. Wyllie, S. Patterson, and A. H. Fairlamb, Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation, Antimicrob. Agents Chemother, vol.57, pp.901-906, 2013.

S. Wyllie, A. J. Roberts, S. Norval, S. Patterson, B. J. Foth et al., Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania, PLoS Pathog, vol.12, p.1005971, 2016.

S. Wyllie, S. Patterson, L. Stojanovski, F. R. Simeons, S. Norval et al., The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis, Sci. Transl. Med, vol.4, 2012.

T. Baltz, D. Baltz, C. Giroud, and J. Crockett, Cultivation in a semi-defined medium of animal infective forms of, EMBO J, vol.4, pp.1273-1277, 1985.

B. , M. Iten, Y. Grether-bühler, and R. Kaminsky, The AlamarBlue ® Blue assay to determine drug sensitive of African trypanosome (T. brucei rhodesiense and T. brucei gambiense) in vitro, Acta Trop, vol.68, 1997.

J. Guillon, A. Cohen, R. Das, C. Boudot, N. Gueddouda et al., Sonnet, Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives, Chem. Biol. Drug Des, pp.1-22, 2018.

N. Greig, S. Wyllie, S. Patterson, and A. H. Fairlamb, FEBS J, vol.276, pp.376-386, 2009.

S. Wyllie, B. J. Foth, A. Kelner, A. Y. Sokolova, M. Berriman et al., J. Antimicrob. Chemother, vol.71, pp.625-634, 2016.

D. C. Jones, I. Hallyburton, L. Stojanovski, K. D. Read, J. A. Frearson et al., Biochem. Pharmacol, vol.80, pp.1478-1486, 2010.

M. De-m-eo, M. Laget, C. D. Giorgio, H. Guiraud, A. Botta et al., Dum enil, Optimization of the Salmonella/mammalian microsome assay for urine mutagenesis by experimental designs, Mutat. Res, vol.340, pp.51-65, 1996.

H. Perdry, K. B. Gutzkow, M. Chevalier, L. Huc, G. Brunborg et al., Validation of Gelbond® high-throughput alkaline and Fpg-modified comet assay using a linear mixed model, Environ. Mol. Mutagen, 2018.

, Etude des couplages pallado-catalysés de Suzuki-Miyaura et de Sonogashira sur la 3-bromo-8-nitroquinoléin-2(1H)-one

, Mécanisme de la réaction de Suzuki-Miyaura

, Le mécanisme réactionnel de la réaction de Suzuki-Miyaura fait intervenir trois étapes successives : une addition oxydante, une transmétallation et une élimination réductrice, vol.87

M. S. Tremblay, M. Halim, and D. Sames, JACS, vol.129, pp.7570-7577, 2007.

Z. Zhao, W. H. Leister, and R. G. Robinson, Bioorg. Med. Chem. Lett, vol.15, pp.905-909, 2005.

P. R. Likhar, S. S. Racharlawar, and M. V. Karkhelikar, Synthesis, vol.15, pp.2407-2414, 2011.

J. Reisch and A. Bathe, Liebigs Annalen Der Chemie, vol.1, pp.69-73, 1988.

J. Reisch and P. Nordhaus, J. Heterocycl. Chem, vol.28, pp.167-171, 1991.

, Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using PalladiumCatalysed Cross-Coupling Reactions Julien Pedron +

S. Bourgeade-delmas,

, Alix Sournia-Saquet

L. Paloque,

M. Rastegari,

M. Abdoulaye,

H. El-kashef,

C. Bonduelle, Genevive Pratviel

A. H. Fairlamb,

B. Courtioux,

P. Verhaeghe,

P. Capewell, N. J. Veitch, C. M. Turner, C. M. Turner, J. Raper et al., PLoS Neglected Trop. Dis, 1287.

P. Büscher, G. Cecchi, V. Jamonneau, and G. Priotto, Lancet, vol.390, pp.2397-2405, 2017.

D. Pace, J. Infect, vol.69, pp.10-18, 2014.

M. M. Ashkan and K. M. Rahim, 186 -188; b) Neglected Tropical Diseases, Trop. Doct, vol.38, 2008.

. Leishmaniasis, . Who-fact, and . Sheet, , 2018.

H. Trypanosomiasis and . African, updated February 16, 2018.

M. C. Field, D. Horn, A. H. Fairlamb, M. A. Ferguson, D. W. Gray et al., Nat. Rev. Microbiol, vol.15, pp.217-231, 2017.

G. Eperon, M. Balasegaram, J. Potet, C. Mowbray, O. Valverde et al., Chappuis, Expert Rev. Anti-Infect. Ther, vol.12, pp.1407-1417, 2014.

B. Zulfiqar, T. B. Shelper, and V. M. Avery, Drug Discovery Today, vol.22, pp.1516-1531, 2017.

S. Patterson and A. H. Fairlamb, Curr. Med. Chem, 2018.

R. T. Jacobs, B. Nare, S. A. Wring, M. D. Orr, D. Chen et al., PLoS Neglected Trop. Dis, 1151.

S. Wyllie, S. Patterson, L. Stojanovski, F. R. Simeons, S. Norval et al., Sci. Transl. Med, 2012.

V. K. Mesu, W. M. Kalonji, C. Bardonneau, O. V. Mordt, S. Blesson et al., Lancet, vol.391, pp.144-154, 2018.

S. Patterson and S. Wyllie, Trends Parasitol, vol.30, pp.289-298, 2014.

S. Wyllie, S. Patterson, and A. H. Fairlamb, Antimicrob. Agents Chemother, vol.57, pp.901-906, 2013.

S. Wyllie, A. J. Roberts, S. Norval, S. Patterson, B. Foth et al., PLoS Pathog, vol.12, pp.1005971-1005993, 2016.

B. S. Hall, X. Wu, L. Hu, and S. R. Wilkinson, Antimicrob. Agents Chemother, vol.54, pp.1193-1199, 2010.

P. Verhaeghe, P. Rathelot, S. Rault, and P. Vanelle, Lett. Org. Chem, vol.3, pp.891-897, 2006.

L. Paloque, P. Verhaeghe, M. Casanova, C. Castera-ducros, A. Dumtre et al., Eur. J. Med. Chem, vol.54, pp.75-86, 2012.

C. Kieffer, A. Cohen, P. Verhaeghe, S. Hutter, C. Castera-ducros et al., Eur. J. Med. Chem, vol.92, pp.282-294, 2015.

C. Kieffer, A. Cohen, P. Verhaeghe, L. Paloque, S. Hutter et al., Bioorg. Med. Chem, vol.23, pp.2377-2386, 2015.

J. Pedron, C. Boudot, S. Hutter, S. Bourgeade-delmas, J. Stigliani et al., Eur. J. Med. Chem, vol.155, pp.135-152, 2018.

V. P. Andreev and Y. P. Nizhnnik, Russ. J. Org. Chem, vol.38, pp.137-138, 2002.

N. J. O'brien, M. Brzozowski, D. J. Wilson, L. W. Deady, and B. M. Abbott, Bioorg. Med. Chem, vol.22, pp.3781-3790, 2014.

M. S. Tremblay, M. Halim, and D. Sames, J. Am. Chem. Soc, vol.129, pp.7570-7577, 2007.

E. Chong and L. L. Schafer, Org. Lett, vol.15, pp.6002-6005, 2013.

S. D. Kuduk, J. W. Skudlarek, C. N. Di-marco, J. G. Bruno, M. A. Pausch et al., Bioorg. Med. Chem. Lett, vol.24, pp.1784-1789, 2014.

R. Zhou, W. Wang, Z. Jiang, K. Wang, X. Zheng et al., Chem. Commun, vol.50, pp.6023-6026, 2014.

H. Van-de-pol, G. Guillaumet, and M. C. Viaux-massuard, Heterocycles, vol.57, pp.55-71, 2002.

O. A. Volkov, C. C. Cosner, A. J. Brockway, M. Kramer, M. Booker et al., , vol.3, pp.512-526, 2017.

C. Zhang, S. Bourgeade-delmas, A. F. Alvarez, A. Valentin, C. Hemmert et al., Eur. J. Med. Chem, vol.143, pp.1635-1643, 2018.

T. Baltz, D. Baltz, C. Giroud, J. Crockett, and E. J. , , vol.4, pp.1273-1277, 1985.

B. Räz, M. Iten, Y. Grether-bühler, and R. Kaminsky, Acta. Trop, vol.68, pp.139-147, 1997.

J. Guillon, A. Cohen, R. N. Das, C. Boudot, N. M. Gueddouda et al.,

C. Mergny, P. Mulliø, and . Sonnet, Chem. Biol. Drug Des, vol.91, pp.974-995, 2018.

N. Greig, S. Wyllie, S. Patterson, and A. H. Fairlamb, FEBS J, vol.276, pp.376-386, 2009.

S. Wyllie, B. J. Foth, A. Kelner, A. Y. Sokolova, M. Berriman et al., Antimicrob. Agents Chemother, vol.71, pp.625-634, 2016.

D. C. Jones, I. Hallyburton, L. Stojanovski, K. D. Read, J. A. Frearson et al., Biochem. Pharmacol, vol.80, pp.1478-1486, 2010.

T. Mosmann, J. Immunol. Methods, vol.65, pp.55-63, 1983.

, ChemMedChem, vol.13, pp.2217-2228, 2018.

, Étude de pharmacomodulation anti-kinétoplastidés en position 6 de la 8-nitroquinoléin-2(1H)-one. 2.1.2. Fonctionnalisation de la 6-trifluorométhylquinoléin-2(1H)-one. 2.1.2.1, Chapitre, vol.5

, Afin d'halogéner sélectivement la 6-trifluorométhylquinoléin-2(1H)-one, nous avons adapté le protocole décrit par O'Brien 339 en utilisant du chlorate de sodium (NaClO3) dans de l'acide

. Chlorhydrique-À-reflux, La 3-chloro-6-trifluorométhylquinoléin-2(1H)-one 63 et la 3,8-dichloro-6-trifluorométhylquinoléin-2(1H)-one 64 ont ainsi été isolées avec des rendements respectifs de 48 %

, La 3-bromo-6-trifluorométhylquinoléin-2(1H)-one 65 a été synthétisée selon un protocole adapté de Glasnov en série 4-arylquinoléin-2(1H)-one

, La molécule 65 a ainsi été obtenue avec un rendement de 54 %

, RMN 2D : les signaux de l'atome de carbone C6 lié à un atome de brome couplent avec le signal de deux atomes d'hydrogène. En effet, si le couplage s'était réalisé en position 6, le signal de l'atome de carbone C3 lié à un atome de brome n

, Si la molécule 73 a permis la synthèse du dérivé monocouplé en position 3 du pharmacophore, cette dernière permet également l'introduction de deux groupements aryle sur le cycle nitroquinoléin-2(1H)-one, en position 3 et 6, via un dicouplage pallado-catalysé. Pour cela, nous avons appliqué les mêmes conditions réactionnelles que lors du monocouplage mais en doublant les quantités de base

. Ainsi, cette nouvelle méthodologie de synthèse ouvre la voie à la préparation de nouvelles séries de molécules via des dicouplages symétriques de Suzuki-Miyaura comme pour la molécule 80

, L'introduction de deux groupements aryles différents lors de deux couplages de Suzuki-Miyaura successifs est également envisageable et ouvre la porte à un nouveau travail de pharmacochimie, PARTIE EXPERIMENTALE DU CHAPITRE, vol.5

P. Dans-une, 3'-diéthoxyacryloyle (33,4 mmol, 1,2 équiv.), préparés depuis l'acide 3,3'-diéthoxypropionique par réaction avec du SOCl2, ont été ajoutés au goutte à goutte à t.a. à une solution de 3,5 mL de p-trifluorométhylaniline (27,8 mmol, 1 équiv, vol.3

, La phase organique résultante a été lavée avec du brine, séchée sur Na2SO4 anhydre et évaporée sous pression réduite pour donner une huile noire. Dans une seconde étape, 25 mL de H2SO4 à 98% ont été ajoutés au brut réactionnel et le milieu agité à t.a. pendant 2 h. Le mélange réactionnel a ensuite été versé dans un bain de glace, alcalinisé par du K2CO3, extrait deux fois avec du dichlorométhane (2 fois 50 mL) et une fois avec de l'acétate d'éthyle (50 mL). La phase organique résultante a été lavée, séchée sur Na2SO4 anhydre et évaporée sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec de l'acétate d'éthyle, solubilisés dans 50 mL de dichlorométhane dans un ballon bicol de 250 mL. Après 6 h, le milieu réactionnel a été versé dans un bécher d'eau, alcalinisé par du HCl à 37% et extrait trois fois avec du dichlorométhane

, Formule brute : C10H6F3NO Apparence : Poudre blanche

, Masse Molaire : 213,16 g/mol

F. Zaragoza, H. Stephensen, and B. Peschke, J. Med. Chem, vol.48, pp.306-311, 2005.

, Hz, CH), vol.123, issue.7, p.3

C. H. Hz, , vol.128, p.3

, Formule brute : C10H4Cl2F3NO Apparence : Poudre blanche

, Masse Molaire : 282,04 g/mol

, HRMS (DCI CH4) calculée pour C10H5Cl2F3NO [M+H] + 281,9700, trouvée 281,9696. RMN 1 H (400 MHz, CDCl3) ?: 7,74 (d, J= 1,9 Hz, 1 H, H5), vol.7, p.81

, 5 (C), vol.123, issue.4, p.9

, Dans un tube scellé de 25 mL, 400 mg de 6-trifluorométhylquinoléin-2(1H)-one 62 (1,87 mmol, p.400

, 69 mmol, 2,5 équiv.) ont été ajoutés. Après l'ajout de 10 mL d'acétonitrile, le milieu réactionnel a été chauffé à 140°C dans un réacteur micro-onde pendant 2 h. Le mélange réactionnel a été versé dans un bécher d, 835 mg de N-bromosuccinimide

, Le composé 65 a été isolé et recristallisé dans l'acétonitrile sous forme de poudre blanche avec un rendement de 54% (1,0 mmol, 293 mg)

T. N. Glasnov, W. Stadlbauer, and C. O. Kappe, Formule brute : C10H5BrF3NO Apparence : Poudre blanche, vol.70, pp.3864-3870, 2005.

, Masse Molaire : 294,07 g/mol

, HRMS (ESI-) calculée pour C10H4BrF3NO [M-H] -289.9428, trouvée 289.9433. RMN 1 H (400 MHz, CDCl3) ?: 7,58 (d, J= 8,7 Hz, 1 H, H8), vol.7, p.6

, Hz, C), vol.119, issue.7, p.5

, Préparation de la 8-nitro-6-trifluorométhylquinoléin-2(1H)-one 66

, Une solution de 0,96 mL de HNO3 à 65% (14,1 mmol, 5 équiv.) a ensuite été ajoutée au goutte à goutte à 0°C et le milieu réactionnel a été agité à t.a. pendant 2 h. Le mélange réactionnel a été successivement versé dans un bain de glace, alcalinisé par du K2CO3, extrait trois fois avec du dichlorométhane (3 fois 50 mL) et une fois avec de l'acétate d'éthyle (50 mL). La phase organique résultante a été lavée, séchée sur MgSO4 anhydre et évaporée sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec de l'acétate d'éthyle, Dans un ballon bicol de 50 mL refroidi par un bain de glace, 10 mL de H2SO4 (98%) ont été ajoutés sur 500 mg de 6-trifluorométhylquinoléin-2(1H)-one 62

, Formule brute : C10H5F3N2O3 Apparence : Poudre jaune pâle, p.177

, Masse Molaire : 258,16 g/mol

, HRMS (ESI+) calculée pour C10H6F3N2O3 [M+H] + 259,0331 trouvée 259,0333. RMN 1 H (400 MHz, CDCl3) ?: 6,86 (dd, J= 9, vol.7, p.5

, Préparation de la 3-chloro-8-nitro-6-trifluorométhylquinoléin-2(1H)-one 67

, fois 50 mL) et une fois avec de l'acétate d'éthyle (50 mL). La phase organique résultante a été lavée, séchée sur MgSO4 anhydre et évaporée sous pression réduite. Le composé 67 a été isolé et recristallisé dans l, Dans un ballon bicol de 100 mL, 25 mL de HCl à 37% ont été ajoutés sur 150 mg de 8-nitro-6-trifluorométhylquinoléin-2(1H)-one 66 (0,58 mmol, 1 équiv

, Formule brute : C10H4ClF3N2O3 Apparence : Poudre jaune pâle

, Masse Molaire : 294,61 g/mol

, HRMS (DCI CH4) calculée pour C10H5ClF3N2O3, vol.292, p.1

H. , 55 (sl, 1 H, NH). RMN 13 C (CDCl3, 100 MHz) ?: 122,1 (C), vol.11

C. and Q. , Hz), vol.124, issue.6, p.9

, Préparation de la 3-bromo-8-nitro-6-trifluorométhylquinoléin-2(1H)-one 68

, Après 4 h à reflux, le milieu réactionnel a été laissé pendant 1 h sous sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec du dichlorométhane. Le composé 68 a été isolé et recristallisé dans l'acétonitrile sous forme de poudre jaune pâle avec un rendement de 94% (1,27 mmol, 430 mg), Formule brute : C10H4BrF3N2O3 Apparence : Poudre jaune pâle

, Masse Molaire : 337,05 g/mol

, HRMS (DCI CH4) calculée pour C10H5BrF3N2O3, vol.336, p.1

H. , 51 (sl, 1 H, NH). RMN 13 C (150 MHz, CDCl3) ?: 121,6 (C), vol.11

, 6 Hz, CH), CH), vol.124, issue.7, p.9

, Préparation de la 2-méthoxy-8-nitro-6-trifluorométhylquinoléine 69

, Sous atmosphère inerte (Argon), 250 mg de 8-nitro-6-trifluorométhylquinoléin-2(1H)-one 66, p.97

, 1 équiv.) ont été solubilisés dans 5 mL de DMF anhydre et ont été ajoutés sur une solution de 77

N. J. O'brien, M. Brzozowski, and D. J. Wilson, Bioorg. Med. Chem, vol.22, pp.3781-3790, 2014.

M. Naik, V. Humnabadkar, and S. J. Tantry, J. Med. Chem, vol.57, pp.5419-5434, 2014.

, Après 10 min d'agitation à t.a., 120 µL d'iodure de méthyle (1,93 mmol, 2 équiv.) ont été ajoutés au goutte à goutte. Le milieu réactionnel a été agité à t.a. pendant 3 h, avant d'être versé dans un bain de glace et extrait quatre fois avec de l'acétate d'éthyle (4 fois 50 mL). La phase organique résultante a été successivement lavée deux fois avec du brine, séchée sur MgSO4 anhydre et évaporée sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec du dichlorométhane. Le composé 69 a été isolé et recristallisé dans l'isopropanol sous forme de poudre blanche avec un rendement de 69% (0,66 mmol, 181 mg), mg d'hydrure de sodium à 60% (1,93 mmol, 2 équiv.) également solubilisés dans 5 mL de DMF anhydre, dans un tube scellé de 25 mL

, Masse Molaire : 272,18 g/mol

, HRMS (DCI CH4) calculée pour C11H8N2O3F3, vol.273, p.474

. H-(cdcl3, MHz) ?: 4,10 (s, 3H, CH3), vol.7, p.13

, CH), vol.128, issue.6, p.1

, Préparation de la 3-bromo-2-méthoxy-8-nitro-6-trifluorométhylquinoléine 70

I. Sous-atmosphère, -bromo-8-nitro-6-trifluorométhylquinoléin-2(1H)-one 68 (0,18 mmol, 1 équiv.) ont été solubilisés dans 5 mL de DMF anhydre et ajoutés à une solution de 14 mg d'hydrure de sodium à 60% (0,36 mmol, 2 équiv.) solubilisés dans 5 mL de DMF anhydre, vol.60

, 22 µL d'iodure de méthyle (0,36 mmol, 2 équiv.) ont été ajoutés au goutte à goutte. Le milieu réactionnel a été agité à t.a. pendant 24 h, avant d'être versé dans un bain de glace et extrait trois fois avec du dichlorométhane (3 fois 25 mL), La phase organique résultante a été

M. Naik, V. Humnabadkar, and S. J. Tantry, Formule brute : C9H4Br3NO Apparence : Poudre blanche, vol.57, pp.5419-5434, 2014.

, Point de fusion, pp.230-231

, Masse Molaire : 381,85 g/mol

, CDCl3) ?: 7,65 (d, J= 2,0 Hz, 1 H, H5), HRMS (DCI CH4) calculée pour C9H5Br3NO, vol.379, p.89

, Préparation, vol.3

, 25 mL de HBr à 48% ont été ajoutés sur 103 mg de 8-nitroquinoléin-2(1H)-one 22 (0,54 mmol, 1 équiv, Le milieu réactionnel a ensuite été chauffé à 100°C avant que, p.408

, mg de bromate de sodium (2,71 mmol, 5 équiv.) soient ajoutés avec précaution

, Le mélange réactionnel a ensuite été successivement versé dans un bain de glace, alcalinisé par du K2CO3 et extrait trois fois avec du dichlorométhane (3 fois 50 mL). La phase organique résultante a été lavée, séchée sur Na2SO4 anhydre et évaporée sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec de l'éther diéthylique. Le composé 73 a été isolé et recristallisé dans l'acétonitrile sous forme de poudre jaune avec un, Après 48 h à reflux, le milieu réactionnel a été laissé pendant 1 h sous la hotte aspirante pour évacuer les vapeurs de Br2 restantes

, Formule brute : C9H4Br2N2O3 Apparence : Poudre jaune, p.202

, Masse Molaire : 347,95 g/mol

M. Fernandez, E. De-la-cuesta, and C. Avendano, Synthesis, pp.1362-1364, 1995.

N. J. O'brien, M. Brzozowski, and D. J. Wilson, Bioorg. Med. Chem, vol.22, pp.3781-3790, 2014.

, HRMS (ESI-) calculée pour C9H3Br2N2O3, vol.344, p.1

H. , 38 (sl, 1 H, NH). RMN 13 C (150 MHz, CDCl3) ?: 114,1 (C), vol.11, p.4

, Par la suite, 8 µL de dibrome (1,58 mmol, 2 équiv.) ont été ajoutés au goutte à goutte et le milieu réactionnel a été porté à reflux avant d'être saturé en acétate de sodium et agité pendant 24 h. Le mélange réactionnel a alors été successivement versé dans un bain de glace, alcalinisé par du K2CO3, extrait trois fois avec du dichlorométhane (3 fois 50 mL) et une fois avec de l'acétate d'éthyle (50 mL). La phase organique résultante a été lavée, séchée sur MgSO4 anhydre et évaporée sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec un mélange dichlorométhane/acétate d'éthyle (80/20), Dans un ballon bicol de 100 mL, 25 mL d'acide acétique ont été ajoutés sur 150 mg de 8-nitroquinolin-2(1H)-one 22 (0,79 mmol, 1 équiv.)

, Formule brute : C9H5BrN2O3 Apparence : Poudre jaune

, Masse Molaire : 269,05 g/mol

, HRMS (ESI-) calculée pour C9H4BrN2O3 [M-H] -266,9405, trouvée 266,9402. RMN 1 H (400 MHz, CDCl3) ?: 6,79 (dd, J= 9, vol.7, p.19

, 5 (C), vol.123, issue.C, p.0

O. S. Tee and M. Paventi, JACS, vol.14, pp.4142-4146, 1982.

, Préparation, vol.3

, 15 mL de HCl à 37% ont été ajoutés sur 100 mg de 8-nitroquinolin-2(1H)-one 22 (0,53 mmol, 1 équiv.). Le milieu réactionnel a été chauffé à 100°C avant que 280 mg de chlorate de sodium (2,63 mmol, 5 équiv.) ne soient ajoutés avec précaution (Dégagement de Cl2), Après 24 h à reflux, le milieu réactionnel a été laissé pendant 1 h sous la hotte aspirante pour évacuer les vapeurs de Cl2

, fois 25 mL). La phase organique résultante a été lavée, séchée sur Na2SO4 anhydre et évaporée sous pression réduite. Le brut réactionnel a été purifié par chromatographie sur colonne de gel de silice en éluant avec de l'éther diéthylique. Le composé 75 a été isolé et recristallisé dans l'acétonitrile sous forme de poudre jaune avec un, Le mélange réactionnel a ensuite été versé dans un bain de glace, alcalinisé par du K2CO3 et extrait trois fois avec du dichlorométhane

, Formule brute : C9H4Cl2N2O3 Apparence : Poudre jaune, pp.197-198

, Masse Molaire : 259,04 g/mol

, HRMS (DCI CH4) calculée pour C9H5Cl2N2O3, vol.258, p.1

H. , RMN 13 C (100 MHz, CDCl3) ?: 122,8 (C), vol.11, p.6

, Préparation de la 6-bromo-3-chloro-8-nitroquinoléin-2(1H)-one 76

, 20 mL de HBr à 48% ont été ajoutés sur 250 mg de 3-chloro-8-nitroquinoléin-2(1H)-one 25 (1,11 mmol, 1 équiv.). Le milieu réactionnel a été chauffé à 100°C avant que 700 mg de bromate de sodium (4,4 mmol, 4 équiv.) soient ajoutés avec précaution

N. J. O'brien, M. Brzozowski, and D. J. Wilson, Après 24 h à reflux, le milieu réactionnel a été laissé pendant 1 h sous la hotte aspirante pour évacuer les vapeurs de Br2. Le mélange réactionnel a ensuite été versé dans un bain de glace, vol.22, pp.3781-3790, 2014.

, Masse Molaire : 403,18 g/mol

, HRMS

, RMN 1 H (400 MHz, CDCl3) ?: En cours. RMN 13 C (CDCl3, 100 MHz) ?: En cours

, Préparation de la 6-bromo-3-(4-carboxyphényl

, 23 mmol, 1 équiv.). Par la suite, 47 mg de NaOH (1,18 mmol, 5 équiv.) ont été ajoutés et le milieu réactionnel a été agité à 60°C pendant 2 h. Le milieu réactionnel a ensuite été versé dans un bécher d'eau, neutralisé par du HCl à 37% et extrait trois fois avec de l'acétate d'éthyle (3 fois 25 mL). La phase organique résultante a été lavée avec de l'eau à pH=1, séchée sur MgSO4 anhydre et évaporée sous pression réduite, Dans un ballon bicol de 100 mL, 40 mL d'un mélange H2O/Ethanol (2/8) ont été ajoutés à 95 mg de la 6-bromo-3-(4-carboxymethylphenyl

, Formule brute : C16H9BrN2O5 Apparence : Poudre orange. Tdec : 300 °C Masse Molaire : 389,16 g/mol

, DMSO-d6) ?: 7,90-8,06 (m, 4 H, H2', H3', H5' et H6'), HRMS (ESI-) calculée pour C16H8BrN2O5, vol.8

, C), vol.124, issue.2xCH, p.0

, Préparation, vol.3, pp.6-10

, Dans un tube scellé de 25 mL, vol.200, p.1

, 750 mg de carbonate de césium (3,45 mmol, 6 équiv, 131 mg de Pd, vol.0

, 259 mg d'acide 4-carboxyméthylphenylboronique (1,44 mmol, 2,5 équiv.) ont été ajoutés

I. Sous-atmosphère, 10 mL de diméthoxyéthane et 2 mL d'eau ont ensuite été ajoutés. Le milieu réactionnel a été chauffé à 95°C dans un réacteur micro-ondes pendant 2 h avant d'être versé dans un bécher d'eau et extrait trois fois avec du dichlorométhane (3 fois 50 mL). La phase organique résultante a été lavée, séchée sur MgSO4 anhydre et évaporée sous pression réduite

, Formule brute : C25H18N2O7 Apparence : Poudre jaune

, Masse Molaire : 458,43 g/mol

, HRMS (DCI CH4) calculée pour C25H19N2O7, vol.459

, 89 (m, 2 H, H2' et H6'), vol.8, p.3

H. and H. , J= 2,0 Hz, 1 H, H7) ; 11,42 (sl, 1H, NH). RMN 13 C (100 MHz, CDCl3) ?: 52,3 (CH3), vol.8, p.3

, Préparation, vol.3, pp.6-10

, 25 mL d'un mélange H2O/Ethanol (2/8) ont été ajoutés à 150 mg de la 3,6-(4-carboxyméthylphényl)-8-nitroquinoléin-2(1H)-one 79 (0,33 mmol, 1 équiv.) ont été ajoutés. Par la suite, 65 mg de soude (1,63 mmol, 5 équiv.) ont été ajoutés et le milieu réactionnel a été agité à 60°C pendant 2 h

, et extrait trois fois avec de l'acétate d'éthyle (3 fois 50 mL). La phase organique résultante a été lavée

, Masse Molaire : 430,37 g/mol

, 429,0723, trouvée 429,0726. RMN 1 H (400 MHz, DMSO-d6) ?: 7,94-7,99

. H3'', 53 (s, 1H, H4), RMN 13 C (400 MHz, DMSO-d6) ?: 123,0 (C), vol.8, p.9

, Au cours de ce travail de thèse, il est apparu que l'introduction de substituants en positions 3 et 6 du pharmacophore permet de concevoir de puissantes molécules anti-Trypanosoma

, Sur la base de ces résultats, afin de remplacer cet atome de brome en position 6 avec pour objectif d'améliorer le profil de cytotoxicité des dérivés de cette série, il serait possible d'y introduire un groupement (hétero)aryle via un double couplage de Suzuki-Miyaura dissymétrique (molécule D). Par ailleurs, la 6-bromo-8-nitro-3-(4-carboxyphényl)quinoléin-2(1H)-one 78 fait partie des molécules les plus actives sur Trypanosoma dans cette série. Le remplacement de l'atome de brome par un groupement trifluorométhyle (molécule E) ou par un atome de chlore (molécule F), Cependant, la présence notamment d'un atome de brome en position 6 de la structure mène à des dérivés sensiblement plus cytotoxiques

. Enfin, une dernière possibilité visant à tenter de réduire la cytotoxicité de ces molécules pourrait être l'introduction de groupements (hétéro)aryles (molécule G) ou alcynyles (molécule H) en position 6 du pharmacophore via des réactions pallado-catalysées de Suzuki-Miyaura et

. Sonogashira and . Cependant, ce nouveau travail de pharmacochimie doit également être guidé par la volonté de synthétiser des molécules aux faibles poids moléculaires, préférablement inférieurs à 400 g/mol, conditionnant le bon passage à travers la barrière hémato-éncéphalique, vol.397, p.391

D. , Pour synthétiser ces molécules et introduire une aniline en position 3 du cycle via un couplage de Buchwald-Hartwig, la protection de l'atome d'azote du motif lactame apparaît indispensable à la lumière des données bibliographiques sur la

, Pour finir, l'évaluation biologique de toutes ces molécules sera réalisée prochainement sur Trypanosoma cruzi par Mr Jean-Yves Brossas au centre d'Immunologie et des Maladies infectieuses

P. Naik and L. Cucullo, J. Pharm. Sci, vol.101, pp.1337-1354, 2012.

H. Van-de-waterbeemd, G. Camenisch, and G. Folkers, J. Drug Target, vol.6, pp.151-165, 1998.

J. Smith and E. M. Taylor, What Is Next for NTDs in the Era of the Sustainable Development Goals?, PLOS Neglected Tropical Diseases, vol.10, issue.7, p.4719, 2016.

P. Trouiller, P. Olliaro, E. Torreele, J. Orbinski, R. Laing et al., Drug Development for Neglected Diseases: A Deficient Market and a Public-Health Policy Failure, The Lancet, vol.359, issue.9324, pp.2188-2194, 2002.

Y. Jackson and N. Stephenson, Neglected Tropical Disease and Emerging Infectious Disease: An Analysis of the History, Promise and Constraints of Two Worldviews, Global Public Health, vol.9, issue.9, pp.995-1007, 2014.

M. Baker, E. Mathieu, F. Fleming, M. Deming, J. King et al., Mapping, Monitoring, and Surveillance of Neglected Tropical Diseases: Towards a Policy Framework, The Lancet, vol.375, issue.9710, pp.231-238, 2010.

L. Conteh, T. Engels, and D. H. Molyneux, Socioeconomic Aspects of Neglected Tropical Diseases. The Lancet, vol.375, pp.239-247, 2010.

, Sustaining the drive to overcome the global impact of neglected tropical diseases, Rapport OMS, 2013.

O. Conférence, Interagency meeting on planning the prevention and control of neglected and zoonotic diseases (NZDs, Juillet, pp.5-6, 2011.

C. J. Murray, T. Vos, R. Lozano, M. Naghavi, A. D. Flaxman et al., Disability-Adjusted Life Years (DALYs) for 291 Diseases and Injuries in 21 Regions, 1990-2010: A Systematic Analysis for the Global Burden of Disease Study, The Lancet, vol.380, issue.9859, pp.2197-2223, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00827610

P. J. Hotez, M. Alvarado, M. Basáñez, I. Bolliger, R. Bourne et al., The Global Burden of Disease Study 2010: Interpretation and Implications for the Neglected Tropical Diseases, PLoS Neglected Tropical Diseases, vol.8, issue.7, p.2865, 2014.

A. S. Winkler, K. Klohe, V. Schmidt, I. Haavardsson, A. Abraham et al., Neglected Tropical Diseases -the Present and the Future, 2018.

P. Hotez and S. Aksoy, PLOS Neglected Tropical Diseases: Ten Years of Progress in Neglected Tropical Disease Control and Elimination ? More or Less, PLOS Neglected Tropical Diseases, vol.11, issue.4, p.5355, 2017.

, Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases, a Road Map for Implantation, Rapport OMS, 2012.

, Report of the first global partner's meeting on neglected tropical diseases: a turning point, OMS, 2007.

C. A. Buscaglia, J. C. Kissinger, and F. Agüero, Neglected Tropical Diseases in the Post-Genomic Era, Trends in Genetics, vol.31, issue.10, pp.539-555, 2015.

D. H. Molyneux and . The, Neglected Tropical Diseases": Now a Brand Identity; Responsibilities, Context and Promise, Parasites & Vectors, vol.2012, issue.1, p.23

S. Bush and A. D. Hopkins, Public-Private Partnerships in Neglected Tropical Disease Control: The Role of Nongovernmental Organisations, Acta Tropica, vol.120, pp.169-172, 2011.

T. K. Mackey, B. A. Liang, R. Cuomo, R. Hafen, K. C. Brouwer et al., Emerging and Reemerging Neglected Tropical Diseases: A Review of Key Characteristics, Risk Factors, and the Policy and Innovation Environment, Clinical Microbiology Reviews, vol.27, issue.4, pp.949-979, 2014.

D. H. Molyneux, Neglected Tropical Diseases: Now More than Just 'Other Diseases

, Agenda. International Health, vol.6, issue.3, pp.172-180, 2014.

J. P. Webster, D. H. Molyneux, P. J. Hotez, and A. Fenwick, The Contribution of Mass Drug Administration to Global Health: Past, Present and Future, Philosophical Transactions of the Royal Society B: Biological Sciences, pp.20130434-20130434, 1645.

D. H. Molyneux, Neglected Tropical Diseases: Now More than Just 'Other Diseases

, Agenda. International Health, vol.6, issue.3, pp.172-180, 2014.

G. M. Nayyar, J. G. Breman, P. N. Newton, and J. Herrington, Poor-Quality Antimalarial Drugs in Southeast Asia and Sub-Saharan Africa. The Lancet Infectious Diseases, vol.12, pp.488-496, 2012.

D. H. Molyneux, L. Dean, O. Adekeye, J. R. Stothard, and S. Theobald, The Changing Global Landscape of Health and Disease: Addressing Challenges and Opportunities for Sustaining Progress towards Control and Elimination of Neglected Tropical Diseases (NTDs), Parasitology, vol.2018, pp.1-8

, Integrating neglected tropical diseases in global health and development

M. Coleman, G. M. Foster, R. Deb, R. Singh, H. M. Ismail et al., DDT-Based Indoor Residual Spraying Suboptimal for Visceral Leishmaniasis Elimination in India, Proceedings of the National Academy of Sciences, issue.28, pp.8573-8578, 2015.

I. Tirados, J. Esterhuizen, V. Kovacic, T. N. Mangwiro, G. A. Vale et al., Tsetse Control and Gambian Sleeping Sickness; Implications for Control Strategy, PLOS Neglected Tropical Diseases, vol.2015, issue.8, p.3822

K. Rosecrans, G. Cruz-martin, A. King, and E. Dumonteil, Opportunities for Improved Chagas Disease Vector Control Based on Knowledge, Attitudes and Practices of Communities in the Yucatan Peninsula, PLoS Neglected Tropical Diseases, vol.8, issue.3, p.2763, 2014.

J. Hemingway, H. Ranson, A. Magill, J. Kolaczinski, C. Fornadel et al., Averting a Malaria Disaster: Will Insecticide Resistance Derail Malaria Control? The Lancet, vol.387, pp.1785-1788, 2016.

, Global Vector Control Response, OMS, 2017.

, One health: A new professional imperative, AVMA, 2009.

S. C. Welburn, I. Beange, M. J. Ducrotoy, and A. L. Okello, The Neglected Zoonoses-the Case for Integrated Control and Advocacy, Clinical Microbiology and Infection, vol.21, issue.5, pp.433-443, 2015.

P. J. Hotez, Human Parasitology and Parasitic Diseases: Heading Towards 2050, Advances in Parasitology

D. H. Molyneux, L. Savioli, and D. Engels, Neglected Tropical Diseases: Progress towards Addressing the Chronic Pandemic. The Lancet, vol.389, pp.312-325, 2017.

P. J. Hotez, Neglected Tropical Diseases in the Anthropocene: The Cases of Zika, Ebola, and Other Infections, PLOS Neglected Tropical Diseases, vol.10, issue.4, p.4648, 2016.

E. E. Conners, J. M. Vinetz, J. R. Weeks, and K. C. Brouwer, A Global Systematic Review of Chagas Disease Prevalence among Migrants, Acta Tropica, vol.156, issue.35, pp.14-0928, 2016.

, Investing to Overcome the Global Impact of Neglected Tropical Diseases: Third WHO Report on Neglected Tropical Diseases; World Health Organization, 2015.

M. Booth and A. Clements, Neglected Tropical Disease Control -The Case for Adaptive, Location-Specific Solutions, Trends in Parasitology, vol.34, issue.4, pp.272-282, 2018.

, Research Priorities for Chagas Disease, Human African Trypanosomiasis and Leishmaniasis: Technical Report of the TDR Disease Reference Group on Chagas Disease, Human African Trypanosomiasis and Leishmaniasis; TDR Disease Reference Group on Chagas Disease, Human African Trypanosomiasis and Leishmaniasis, 2012.

J. M. Bethony, R. N. Cole, X. Guo, S. Kamhawi, M. W. Lightowlers et al., Vaccines to Combat the Neglected Tropical Diseases: NTD Vaccines, Immunological Reviews, vol.239, issue.1, pp.237-270, 2011.

J. Alvar, I. D. Vélez, C. Bern, M. Herrero, P. Desjeux et al., Boer, M. den; the WHO Leishmaniasis Control Team. Leishmaniasis Worldwide and Global Estimates of Its Incidence, PLoS ONE, vol.2012, issue.5, p.35671

E. Torres-guerrero, M. R. Quintanilla-cedillo, J. Ruiz-esmenjaud, and R. Arenas, Leishmaniasis: A Review, vol.6, p.750, 2017.

D. Pace and . Leishmaniasis, Journal of Infection, vol.69, pp.10-18, 2014.

M. Maroli, M. D. Feliciangeli, L. Bichaud, R. N. Charrel, and L. Gradoni, Phlebotomine Sandflies and the Spreading of Leishmaniases and Other Diseases of Public Health Concern, Medical and Veterinary Entomology, vol.27, issue.2, pp.123-147, 2013.

H. Aspöck, T. Gerersdorfer, H. Formayer, and J. Walochnik, Sandflies and Sandfly-Borne Infections of Humans in Central Europe in the Light of Climate Change, Wiener klinische Wochenschrift, vol.120, issue.S4, pp.24-29, 2008.

B. Zulfiqar, T. B. Shelper, and V. M. Avery, Leishmaniasis Drug Discovery: Recent Progress and Challenges in Assay Development, Drug Discovery Today, vol.22, issue.10, pp.1516-1531, 2017.

M. Akhoundi, K. Kuhls, A. Cannet, J. Votýpka, P. Marty et al., A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies, PLOS Neglected Tropical Diseases, vol.10, issue.3, p.4349, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01947736

F. Pratlong, L. Floeter-winter, E. Ishikawa, F. El-baidouri, C. Ravel et al., Kinetoplastida: Trypanosomatidae), the Parasite Responsible for Diffuse Cutaneous Leishmaniasis in the Dominican Republic, J. Characterization of Leishmania (Leishmania) Waltoni n.Sp, vol.93, issue.3, pp.552-558, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01978074

D. Steverding, The History of Leishmaniasis, Parasites & Vectors, vol.2017, issue.1

I. Kaszak, M. Planellas, and B. Dworecka-kaszak, Canine Leishmaniosis -an Emerging Disease, Ann. Parasitol, vol.2015, issue.2, p.61

R. R. Ribeiro, M. S. Michalick, M. E. Da-silva, C. C. Santos, F. J. Frézard et al., Canine Leishmaniasis: An Overview of the Current Status and Strategies for Control, BioMed Research International, pp.1-12, 2018.

C. Bern, J. H. Maguire, and J. Alvar, Complexities of Assessing the Disease Burden Attributable to Leishmaniasis, PLoS Neglected Tropical Diseases, vol.2, issue.10, p.313, 2008.

P. A. Bates and . Leishmania, Sand Fly Interaction: Progress and Challenges, Current Opinion in Microbiology, vol.11, issue.4, pp.340-344, 2008.

S. Kamhawi, Phlebotomine Sand Flies and Leishmania Parasites: Friends or Foes?, Trends in Parasitology, vol.22, issue.9, pp.439-445, 2006.

M. Hommel, Visceral Leishmaniasis: Biology of the Parasite, Journal of Infection, vol.39, issue.2, pp.101-111, 1999.

S. Gupta and . Leishmaniasis, Experimental Models for Drug Discovery, INDIAN J MED RES, p.13, 2011.

A. J. Showler and A. K. Boggild, Cutaneous Leishmaniasis in Travellers: A Focus on Epidemiology and Treatment in 2015, Current Infectious Disease Reports, issue.7, p.17, 2015.

P. R. Machado, M. E. Rosa, L. H. Guimarães, F. V. Prates, A. Queiroz et al., Treatment of Disseminated Leishmaniasis With Liposomal Amphotericin B, Clinical Infectious Diseases, issue.6, pp.945-949, 2015.

R. Reithinger, J. Dujardin, H. Louzir, C. Pirmez, B. Alexander et al., Lancet Infectious Disease, vol.7, pp.581-596, 2007.

J. A. Guerra, O. De, S. R. Prestes, H. Silveira, L. I. Coelho et al., Mucosal Leishmaniasis Caused by Leishmania (Viannia) Braziliensis and Leishmania (Viannia) Guyanensis in the Brazilian Amazon, PLoS Neglected Tropical Diseases, vol.5, issue.3, p.980, 2011.

P. D. Marsden, R. R. Nonata, and . Mucocutaneous-leishmaniasis, A Review of Clinical Aspects. Revista da Sociedade Brasileira de Medicina Tropical, vol.9, issue.6, pp.309-326, 1975.

M. M. Ashkan and K. M. Rahim, Visceral Leishmanisis in Paediatrics: A Study of 367 Cases in Southwest Iran, Tropical Doctor, vol.38, issue.3, pp.186-188, 2008.

S. Collin, R. Davidson, K. Ritmeijer, K. Keus, Y. Melaku et al., Determinants of Adverse Outcomes of Kala-Azar among Patients in Southern Sudan, Clinical Infectious Diseases, vol.38, issue.5, pp.612-619, 2004.

S. Burza, R. Mahajan, M. G. Sanz, T. Sunyoto, R. Kumar et al., HIV and Visceral Leishmaniasis Coinfection in Bihar, India: An Underrecognized and Underdiagnosed Threat Against Elimination, Clinical Infectious Diseases, vol.59, issue.4, pp.552-555, 2014.

V. Ramesh, R. Singh, and P. Salotra, Short Communication: Post-Kala-Azar Dermal Leishmaniasis -an Appraisal: Post-Kala-Azar Dermal Leishmaniasis. Tropical Medicine & International Health, vol.12, pp.848-851, 2007.

P. Desjeux, R. Ghosh, P. Dhalaria, N. Strub-wourgaft, and E. E. Zijlstra, Report of the Post Kala-Azar Dermal Leishmaniasis (PKDL) Consortium Meeting, vol.6, p.196, 2012.

U. Brahmachari, A New Form of Cutaneous Leishmaniasis-Dermal Leishmanoid. The Indian Medical Gazette, vol.57, pp.125-127, 1922.

S. Sundar and A. Singh, Recent Developments and Future Prospects in the Treatment of Visceral Leishmaniasis. Therapeutic Advances in Infectious Disease, vol.3, pp.98-109, 2016.

S. Sundar, D. K. More, M. K. Singh, V. P. Singh, S. Sharma et al., Failure of Pentavalent Antimony in Visceral Leishmaniasis in India: Report from the Center of the Indian Epidemic, vol.31, pp.1104-1107, 2000.

P. Loiseau and C. Bories, Mechanisms of Drug Action and Drug Resistance in Leishmania as Basis for Therapeutic Target Identification and Design of Antileishmanial Modulators, Current Topics in Medicinal Chemistry, vol.6, issue.5, pp.539-550, 2006.

Y. Zhou, N. Messier, M. Ouellette, B. P. Rosen, and R. Mukhopadhyay, Leishmania Major LmACR2 Is a Pentavalent Antimony Reductase That Confers Sensitivity to the Drug Pentostam, Journal of Biological Chemistry, vol.279, issue.36, pp.37445-37451, 2004.

H. Denton, J. C. Mcgregor, and G. H. Coombs, Reduction of Anti-Leishmanial Pentavalent Antimonial Drugs by a Parasite-Specific Thiol-Dependent Reductase, TDR1. Biochemical Journal, vol.381, issue.2, pp.405-412, 2004.

C. Dos-santos-ferreira, P. Silveira-martins, C. Demicheli, C. Brochu, M. Ouellette et al., ThiolInduced Reduction of Antimony(V) into Antimony(III): A Comparative Study with Trypanothione, Cysteinyl-Glycine, Cysteine and Glutathione, Biometals, vol.16, issue.3, pp.441-446, 2003.

A. Ponte-sucre, F. Gamarro, J. Dujardin, M. P. Barrett, R. López-vélez et al., Drug Resistance and Treatment Failure in Leishmaniasis: A 21st Century Challenge, PLOS Neglected Tropical Diseases, vol.2017, issue.12, p.6052

D. Sereno, P. Holzmuller, I. Mangot, G. Cuny, A. Ouaissi et al., Antimonial-Mediated DNA Fragmentation in Leishmania Infantum Amastigotes, Antimicrobial Agents and Chemotherapy, vol.45, issue.7, pp.2064-2069, 2001.

M. L. Cunningham and A. H. Fairlamb, Trypanothione Reductase from Leishmania Donovani. Purification, Characterisation and Inhibition by Trivalent Antimonials, European Journal of Biochemistry, vol.230, issue.2, pp.460-468, 1995.

S. Mandal, M. Maharjan, S. Singh, M. Chatterjee, and R. Madhubala, Assessing Aquaglyceroporin Gene Status and Expression Profile in Antimony-Susceptible and -Resistant Clinical Isolates of Leishmania Donovani from India, Journal of Antimicrobial Chemotherapy, vol.65, issue.3, pp.496-507, 2010.

W. Yorke, Recent Work on the Chemotherapy of Protozoal Infections, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol.33, issue.5, pp.463-476, 1940.

E. Diro, K. Ritmeijer, M. Boelaert, F. Alves, R. Mohammed et al., Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study, PLOS Neglected Tropical Diseases, vol.2015, issue.10, p.4087

M. Sands, M. Kron, and R. Brown, Pentamidine: A Review, Rev. Infect. Dis, vol.7, issue.5, pp.625-634, 1985.

M. Basselin, F. Lawrence, and M. Robert-gero, Pentamidine Uptake in Leishmania Donovani and Leishmania Amazonensis Promastigotes and Axenic Amastigotes, Biochemical Journal, vol.315, issue.2, pp.631-634, 1996.

G. Kaur and B. Rajput, Comparative Analysis of the Omics Technologies Used to Study Antimonial, Amphotericin B, and Pentamidine Resistance in Leishmania, Journal of Parasitology Research, pp.1-11, 2014.

V. Wiwanitkit, Interest in Paromomycin for the Treatment of Visceral Leishmaniasis (Kala-Azar). Therapeutics and Clinical Risk Management, p.323, 2012.

R. N. Davidson, M. Boer, K. Ritmeijer, and . Paromomycin, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol.103, issue.7, pp.653-660, 2009.

M. Maarouf, F. Lawrence, S. Brown, and M. Robert-gero, Biochemical Alterations in ParomomycinTreated Leishmania Donovani Promastigotes, Parasitology Research, vol.83, issue.2, pp.198-202, 1997.

M. Maarouf, M. T. Adeline, M. Solignac, D. Vautrin, and M. Robert-gero, Development and Characterization of Paromomycin-Resistant Leishmania Donovani Promastigotes, Parasite, vol.5, issue.2, pp.167-173, 1998.

A. Musa, E. Khalil, A. Hailu, J. Olobo, M. Balasegaram et al., Sodium Stibogluconate (SSG) & Paromomycin Combination Compared to SSG for Visceral Leishmaniasis in East Africa: A Randomised Controlled Trial, PLoS Neglected Tropical Diseases, vol.2012, issue.6, p.1674

J. Alvar, S. Croft, and P. Olliaro, Chemotherapy in the Treatment and Control of Leishmaniasis, In Advances in Parasitology

H. Ramos, E. Valdivieso, M. Gamargo, F. Dagger, and B. E. Cohen, Amphotericin B Kills Unicellular Leishmanias by Forming Aqueous Pores Permeable to Small Cations and Anions, Journal of Membrane Biology, vol.152, issue.1, pp.65-75, 1996.

N. Mbongo, P. M. Loiseau, M. A. Billion, and M. Robert-gero, Mechanism of Amphotericin B Resistance in Leishmania Donovani Promastigotes, vol.42, p.6, 1998.

D. S. Palacios, I. Dailey, D. M. Siebert, B. C. Wilcock, and M. D. Burke, Synthesis-Enabled Functional Group Deletions Reveal Key Underpinnings of Amphotericin B Ion Channel and Antifungal Activities, Proceedings of the National Academy of Sciences, issue.17, pp.6733-6738, 2011.

A. Szebesczyk, E. Olshvang, A. Shanzer, P. L. Carver, and E. Gumienna-kontecka, Harnessing the Power of Fungal Siderophores for the Imaging and Treatment of Human Diseases, Coordination Chemistry Reviews, pp.84-109, 2016.

S. Rijal, B. Ostyn, S. Uranw, K. Rai, N. R. Bhattarai et al., Increasing Failure of Miltefosine in the Treatment of Kala-Azar in Nepal and the Potential Role of Parasite Drug Resistance, Reinfection, or Noncompliance, Clinical Infectious Diseases, vol.56, issue.11, pp.1530-1538, 2013.

G. Barratt, M. Saint-pierre-chazalet, and P. Loiseau, Cellular Transport and Lipid Interactions of Miltefosine, Current Drug Metabolism, vol.10, issue.3, pp.247-255, 2009.

J. R. Luque-ortega, L. Rivas, and . Miltefosine, Hexadecylphosphocholine) Inhibits Cytochrome c Oxidase in Leishmania Donovani Promastigotes, Antimicrobial Agents and Chemotherapy, vol.51, issue.4, pp.1327-1332, 2007.

C. Paris, P. M. Loiseau, C. Bories, and J. Breard, Miltefosine Induces Apoptosis-Like Death in Leishmania Donovani Promastigotes, Antimicrobial Agents and Chemotherapy, vol.48, issue.3, pp.852-859, 2004.

K. Seifert, F. J. Pérez-victoria, M. Stettler, M. P. Sánchez-cañete, S. Castanys et al., Inactivation of the Miltefosine Transporter, LdMT, Causes Miltefosine Resistance That Is Conferred to the Amastigote Stage of Leishmania Donovani and Persists in Vivo, International Journal of Antimicrobial Agents, vol.30, issue.3, pp.229-235, 2007.

E. Castanys-munoz, J. M. Perez-victoria, F. Gamarro, and S. Castanys, Characterization of an ABCG-Like Transporter from the Protozoan Parasite Leishmania with a Role in Drug Resistance and Transbilayer Lipid Movement, Antimicrobial Agents and Chemotherapy, vol.52, issue.10, pp.3573-3579, 2008.

P. Büscher, G. Cecchi, V. Jamonneau, and G. Priotto, Human African Trypanosomiasis. The Lancet, vol.390, pp.2397-2409, 2017.

D. Steverding, The History of African Trypanosomiasis, Parasites & Vectors, vol.1, issue.1, p.3, 2008.

J. Willinsky, The Access Principle: The Case for Open Access to Research and Scholarship; Digital libraries and electronic publishing, 2006.

M. Barrett, The Fall and Rise of Sleeping Sickness, Lancet, vol.353, pp.1113-1114, 1999.

D. Mumba, E. Bohorquez, J. Messina, V. Kande, S. M. Taylor et al., Prevalence of Human African Trypanosomiasis in the Democratic Republic of the Congo, PLoS Neglected Tropical Diseases, vol.5, issue.8, p.1246, 2011.

F. N. Wamwiri and R. E. Changasi, Tsetse Flies ( Glossina ) as Vectors of Human African Trypanosomiasis: A Review, BioMed Research International, pp.1-8, 2016.

P. Simarro, J. Franco, A. Diarra, and J. Jannin, Epidemiology of Human African Trypanosomiasis, Clinical Epidemiology, p.257, 2014.

D. H. Molyneux, Host-Trypanosome Interactions in Glossina, International Journal of Tropical Insect Science, vol.1980, issue.01, pp.39-46

P. Capewell, N. J. Veitch, C. M. Turner, J. Raper, M. Berriman et al., Differences between Trypanosoma Brucei Gambiense Groups 1 and 2 in Their Resistance to Killing by Trypanolytic Factor 1, PLoS Neglected Tropical Diseases, vol.5, issue.9, p.1287, 2011.

F. Giordani, L. J. Morrison, T. G. Rowan, H. P. De-koning, and M. P. Barrett, The Animal Trypanosomiases and Their Chemotherapy: A Review, Parasitology, vol.143, issue.14, pp.1862-1889, 2016.

N. A. Dyer, C. Rose, N. O. Ejeh, and A. Acosta-serrano, Flying Tryps: Survival and Maturation of Trypanosomes in Tsetse Flies, Trends in Parasitology, vol.29, issue.4, pp.188-196, 2013.

K. Vickerman, L. Tetley, K. A. Hendry, and C. M. Turner, Biology of African Trypanosomes in the Tsetse Fly, vol.64, pp.109-119, 1988.

K. Kristensson, W. Masocha, and M. Bentivoglio, Mechanisms of CNS Invasion and Damage by Parasites, Handbook of Clinical Neurology

P. G. Kennedy, Clinical Features, Diagnosis, and Treatment of Human African Trypanosomiasis (Sleeping Sickness). The Lancet Neurology, vol.12, pp.186-194, 2013.

V. Lejon, M. Bentivoglio, and J. R. Franco, Human African Trypanosomiasis. In Handbook of, Clinical Neurology

J. Blum, C. Schmid, and C. Burri, Clinical Aspects of 2541 Patients with Second Stage Human African Trypanosomiasis, Acta Tropica, vol.97, issue.1, pp.55-64, 2006.

D. Steverding, The History of Chagas Disease, Parasites & Vectors, vol.7, issue.1, p.317, 2014.

J. A. Pérez-molina, I. Molina, and . Chagas-disease, The Lancet, vol.391, pp.82-94, 2018.

C. Bern and . Chagas'-disease, New England Journal of Medicine, vol.373, issue.5, pp.456-466, 2015.

B. Zingales, M. A. Miles, D. A. Campbell, M. Tibayrenc, A. M. Macedo et al., The Revised Trypanosoma Cruzi Subspecific Nomenclature: Rationale, Epidemiological Relevance and Research Applications, Genetics and Evolution, vol.12, issue.2, pp.240-253, 2012.

B. Zingales, S. Andrade, M. Briones, D. Campbell, E. Chiari et al., A New Consensus for Trypanosoma Cruzi Intraspecific Nomenclature: Second Revision Meeting Recommends TcI to TcVI. Memórias do Instituto Oswaldo Cruz, vol.104, pp.1051-1054, 2009.

C. Bern, D. L. Martin, and R. H. Gilman, Acute and Congenital Chagas Disease, Advances in Parasitology

A. Rassi and A. Rassi, Infectious Disease Clinics of North America, J, vol.26, issue.2, pp.275-291, 2012.

F. Salvador, B. Trevióo, E. Sulleiro, D. Pou, A. Sánchez-montalvá et al., Trypanosoma Cruzi Infection in a Non-Endemic Country: Epidemiological and Clinical Profile, Clinical Microbiology and Infection, vol.20, issue.7, pp.706-712, 2014.

R. B. De-oliveira and U. G. Meneghelli, Gastrointestinal Manifestations of Chagas' Disease, vol.93, p.6, 1998.

D. Horn, Antigenic Variation in African Trypanosomes, Molecular and Biochemical Parasitology, vol.195, issue.2, pp.123-129, 2014.

N. Baker, H. P. De-koning, P. Mäser, and D. Horn, Drug Resistance in African Trypanosomiasis: The Melarsoprol and Pentamidine Story, Trends in Parasitology, vol.29, issue.3, pp.110-118, 2013.

M. P. Barrett, I. M. Vincent, R. J. Burchmore, A. J. Kazibwe, and E. Matovu, Drug Resistance in Human African Trypanosomiasis, Future Microbiology, vol.6, issue.9, pp.1037-1047, 2011.

P. Babokhov, A. O. Sanyaolu, W. A. Oyibo, A. F. Fagbenro-beyioku, and N. C. Iriemenam, A Current Analysis of Chemotherapy Strategies for the Treatment of Human African Trypanosomiasis. Pathogens and Global Health, vol.107, pp.242-252, 2013.

T. A. Shapiro and P. T. Englund, Selective Cleavage of Kinetoplast DNA Minicircles Promoted by Antitrypanosomal Drugs, Proceedings of the National Academy of Sciences, vol.87, issue.3, pp.950-954, 1990.

D. Damper and C. L. Patton, Pentamidine Transport and Sensitivity in Brucei -Group Trypanosomes*, The Journal of Protozoology, vol.23, issue.2, pp.349-356, 1976.

B. J. Berger, Uptake of Diamidine Drugs by the P2 Nucleoside Transporter in Melarsen-Sensitive andResistant Trypanosoma Brucei Brucei, Journal of Biological Chemistry, vol.270, issue.47, pp.28153-28157, 1995.

H. P. De-koning, Transporters in African Trypanosomes: Role in Drug Action and Resistance, International Journal for Parasitology, vol.31, issue.5-6, pp.512-522, 2001.

T. Voogd, E. Vansterkenburg, J. Wilting, and L. Janssen, Recent Research on the Biological Activity of Suramin. Pharmacol. Rev, vol.45, pp.177-203, 1993.

F. Hawking, Concentration of Bayer 205 (Germanin) in Human Blood and Cerebrospinal Fluid after Treatment, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol.34, issue.1, pp.37-52, 1940.

A. J. Nok, Arsenicals (Melarsoprol), Pentamidine and Suramin in the Treatment of Human African Trypanosomiasis, Parasitol. Rev, vol.90, pp.71-79, 2003.

J. Pépin and F. Milord, The Treatment of Human African Trypanosomiasis, Advances in Parasitology

M. Balasegaram, H. Young, F. Chappuis, G. Priotto, M. Raguenaud et al., Effectiveness of Melarsoprol and Eflornithine as First-Line Regimens for Gambiense Sleeping Sickness in Nine Médecins Sans Frontières Programmes, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol.103, issue.3, pp.280-290, 2009.

C. Schmid, M. Richer, C. M. Bilenge, T. Josenando, F. Chappuis et al., Effectiveness of a 10-Day Melarsoprol Schedule for the Treatment of Late-Stage Human African Trypanosomiasis: Confirmation from a Multinational Study (I MPAMEL II), The Journal of Infectious Diseases, vol.191, issue.11, pp.1922-1931, 2005.

J. Keiser, Investigations of the Metabolites of the Trypanocidal Drug Melarsoprol, Clinical Pharmacology & Therapeutics, vol.67, issue.5, pp.478-488, 2000.

M. L. Cunningham, M. J. Zvelebil, and A. H. Fairlamb, Mechanism of Inhibition of Trypanothione Reductase and Glutathione Reductase by Trivalent Organic Arsenicals, European Journal of Biochemistry, vol.221, issue.1, pp.285-295, 1994.

A. H. Fairlamb and D. Horn, Melarsoprol Resistance in African Trypanosomiasis, Trends in Parasitology, vol.34, issue.6, pp.481-492, 2018.

N. S. Carter and A. H. Fairlamb, Arsenical-Resistant Trypanosomes Lack an Unusual Adenosine Transporter, Nature, vol.361, pp.173-176, 1993.

M. R. Perry, S. Wyllie, A. Raab, J. Feldmann, and A. H. Fairlamb, Chronic Exposure to Arsenic in Drinking Water Can Lead to Resistance to Antimonial Drugs in a Mouse Model of Visceral Leishmaniasis, Proceedings of the National Academy of Sciences, issue.49, pp.19932-19937, 2013.

D. Steverding, The Development of Drugs for Treatment of Sleeping Sickness: A Historical Review, Parasites & Vectors, vol.2010, issue.1, p.15

G. Priotto, L. Pinoges, I. B. Fursa, B. Burke, N. Nicolay et al., Safety and Effectiveness of First Line Eflornithine for Trypanosoma Brucei Gambiense Sleeping Sickness in Sudan: Cohort Study, BMJ, vol.336, issue.7646, pp.705-708, 2008.

P. P. Simarro, J. Franco, A. Diarra, J. A. Postigo, and J. Jannin, Update on Field Use of the Available Drugs for the Chemotherapy of Human African Trypanosomiasis, Parasitology, vol.2012, issue.07, pp.842-846

C. J. Bacchi, J. Garofalo, D. Mockenhaupt, P. P. Mckann, K. A. Diekema et al., IN VIVO EFFECTS OF A-DL-DIFLUOROMETHYLORNITHINE ON THE METABOLISM AND MORPHOLOGY OF TRYPANOSOMA BRUCEI BRUCEI. Mol. Biochem. Parasitol, vol.7, pp.209-225, 1983.

N. Yarlett and C. J. Bacchi, Effect of DL-O~-Difluoromethylornithine on Polyamine Synthesis and Interconversion in Trichomonas Vaginalis Grown in a Semi-Defined Medium, Mol. Biochem. Parasitol, vol.31, issue.1, pp.1-9, 1988.

I. M. Vincent, D. Creek, D. G. Watson, M. A. Kamleh, D. J. Woods et al., A Molecular Mechanism for Eflornithine Resistance in African Trypanosomes, PLoS Pathogens, vol.6, issue.11, p.1001204, 2010.

P. G. Janssens and A. De-muynck, Clinical Trials with "nifurtimox" in African Trypanosomiasis, Ann. Soc. Belg. Med. Trop, vol.57, issue.4-5, pp.475-480, 1977.

M. Kaiser, M. A. Bray, M. Cal, B. Bourdin-trunz, E. Torreele et al., Antitrypanosomal Activity of Fexinidazole, a New Oral Nitroimidazole Drug Candidate for Treatment of Sleeping Sickness, Antimicrobial Agents and Chemotherapy, vol.55, issue.12, pp.5602-5608, 2011.

J. Pépin, F. Milord, F. Meurice, L. Ethier, L. Loko et al., High-Dose Nifurtimox for ArsenoResistant Trypanosoma Brucei Gambiense Sleeping Sickness: An Open Trial in Central Zaire, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol.86, issue.3, pp.254-256, 1992.

G. Eperon, M. Balasegaram, J. Potet, C. Mowbray, O. Valverde et al., Treatment Options for Second-Stage Gambiense Human African Trypanosomiasis, Expert Review of Anti-infective Therapy, vol.12, issue.11, pp.1407-1417, 2014.

A. Buschini, L. Ferrarini, S. Franzoni, S. Galati, M. Lazzaretti et al., Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole, Journal of Parasitology Research, pp.1-11, 2009.

B. S. Hall, C. Bot, and S. R. Wilkinson, Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites, Journal of Biological Chemistry, vol.286, issue.15, pp.13088-13095, 2011.

S. Patterson and S. Wyllie, Nitro Drugs for the Treatment of Trypanosomatid Diseases: Past, Present, and Future Prospects, Trends in Parasitology, vol.30, issue.6, pp.289-298, 2014.

G. Priotto, C. Fogg, M. Balasegaram, O. Erphas, A. Louga et al., Three Drug Combinations for Late-Stage Trypanosoma Brucei Gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda, PLoS Clinical Trials, vol.1, issue.8, p.39, 2006.

C. Schmid, A. Kuemmerle, J. Blum, S. Ghabri, V. Kande et al., Hospital Safety in Field Conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. b. Gambiense Sleeping Sickness, vol.2012, p.1920

J. R. Coura, S. L. Castro, and . De, A Critical Review on Chagas Disease Chemotherapy. Memórias do Instituto Oswaldo Cruz, vol.97, pp.3-24, 2002.

S. R. Wilkinson, M. C. Taylor, D. Horn, J. M. Kelly, and I. Cheeseman, A Mechanism for Cross-Resistance to Nifurtimox and Benznidazole in Trypanosomes, Proceedings of the National Academy of Sciences, issue.13, pp.5022-5027, 2008.

S. M. Murta, R. T. Gazzinelli, Z. Brener, and A. J. Romanha, Molecular Characterization of Susceptible and Naturally Resistant Strains of Trypanosoma Cruzi to Benznidazole and Nifurtimox, Molecular and Biochemical Parasitology, vol.93, issue.2, pp.203-214, 1998.

E. Grunberg, G. Beskid, R. Cleeland, W. F. De-lorenzo, E. Titsworth et al., Antiprotozoan and Antibacterial Activity of 2-Nitroimidazole Derivatives, Antimicrob. Agents Chemother, vol.7, pp.513-519, 1967.

J. D. Alpern, R. Lopez-velez, and W. M. Stauffer, Access to Benznidazole for Chagas Disease in the United States-Cautious Optimism? PLOS Neglected Tropical Diseases, vol.11, p.5794, 2017.

J. R. Cançado, Criteria of Chagas Disease Cure. Memórias do Instituto Oswaldo Cruz, vol.94, pp.331-335, 1999.

P. J. Thornalley, . Protein, . Nucleotide, . By, and . Methylglyoxal, PHYSIOLOGICAL SYSTEMS -ROLE IN AGEING AND DISEASE. Drug Metabolism and Drug Interactions, vol.23, pp.1-2, 2008.

M. C. Campos, L. L. Leon, M. C. Taylor, and J. M. Kelly, Benznidazole-Resistance in Trypanosoma Cruzi: Evidence That Distinct Mechanisms Can Act in Concert, Molecular and Biochemical Parasitology, vol.193, issue.1, pp.17-19, 2014.

M. Philipp and M. L. Bender, Inhibition of Serine Proteases by Arylboronic Acids, Proceedings of the National Academy of Sciences, vol.68, pp.478-480, 1971.

R. T. Jacobs, J. J. Plattner, B. Nare, S. A. Wring, D. Chen et al., A New Class of Potential Drugs for Human African Trypanosomiasis, vol.3, pp.1259-1278, 2011.

A. Mahalingam, A. R. Geonnotti, J. Balzarini, and P. F. Kiser, Activity and Safety of Synthetic Lectins Based on Benzoboroxole-Functionalized Polymers for Inhibition of HIV Entry, Molecular Pharmaceutics, vol.8, issue.6, pp.2465-2475, 2011.

A. Markham and . Tavaborole, First Global Approval. Drugs, vol.74, issue.13, pp.1555-1558, 2014.

E. J. Goldstein, D. M. Citron, K. L. Tyrrell, and C. V. Merriam, Comparative In Vitro Activities of SMT19969, a New Antimicrobial Agent, against Clostridium Difficile and 350 Gram-Positive and GramNegative Aerobic and Anaerobic Intestinal Flora Isolates, Antimicrobial Agents and Chemotherapy, vol.57, issue.10, pp.4872-4876, 2013.

Y. Zhang, J. J. Plattner, E. E. Easom, Y. Zhou, T. Akama et al., Discovery of an Orally Bioavailable Isoxazoline Benzoxaborole ( AN8030 ) as a Long Acting Animal Ectoparasiticide, Bioorganic & Medicinal Chemistry Letters, vol.25, issue.23, pp.5589-5593, 2015.

R. T. Jacobs, B. Nare, S. A. Wring, M. D. Orr, D. Chen et al., SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis, PLoS Neglected Tropical Diseases, vol.5, issue.6, 2011.

D. C. Jones, B. J. Foth, M. D. Urbaniak, S. Patterson, H. B. Ong et al., Genomic and Proteomic Studies on the Mode of Action of Oxaboroles against the African Trypanosome, PLOS Neglected Tropical Diseases, vol.2015, issue.12, p.4299

R. M. Jacob, G. L. Régnier, and C. Crisan, Nitroimidazolealkanols and Acyl Derivatives. US Patent, p.2944061

E. Winkelmann, W. Raether, and A. Sinharay, Chemotherapeutically Active Nitro Compounds. 4.5-Nitroimidazoles (Part II), Arzneimittelforschung, vol.28, issue.3, pp.739-749, 1978.

F. W. Jenning and G. M. Urquhart, The Use of the 2 Substituted 5-Nitroimidazole, Fexinidazole (Hoe 239) in the Treatment of Chronic T. Brucei Infections in Mice, Z Parasitenkd, vol.69, issue.5, pp.577-581, 1983.

E. Torreele, B. Bourdin-trunz, D. Tweats, M. Kaiser, R. Brun et al., Fexinidazole -A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness, PLoS Neglected Tropical Diseases, vol.2010, issue.12, p.923

M. Kaiser, M. A. Bray, M. Cal, B. Bourdin-trunz, E. Torreele et al., Antitrypanosomal Activity of Fexinidazole, a New Oral Nitroimidazole Drug Candidate for Treatment of Sleeping Sickness, Antimicrobial Agents and Chemotherapy, vol.55, issue.12, pp.5602-5608, 2011.

A. Tarral, S. Blesson, O. V. Mordt, E. Torreele, D. Sassella et al., Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies, Clinical Pharmacokinetics, vol.53, issue.6, pp.565-580, 2014.

V. K. Mesu, W. M. Kalonji, C. Bardonneau, O. V. Mordt, S. Blesson et al., Oral Fexinidazole for Late-Stage African Trypanosoma Brucei Gambiense Trypanosomiasis: A Pivotal Multicentre, Randomised, Non-Inferiority Trial, The Lancet, vol.391, pp.144-154, 2018.

A. Y. Sokolova, S. Wyllie, S. Patterson, S. L. Oza, K. D. Read et al., Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis, Antimicrobial Agents and Chemotherapy, vol.54, issue.7, pp.2893-2900, 2010.

C. Yeates, Sitamaquine (GlaxoSmithKline/Walter Reed Army Institute), Curr Opin Investig Drugs, vol.3, issue.10, pp.1446-1452, 2002.

E. Beveridge, L. G. Goodwin, and L. P. Walls, A New Series of Leishmanicides, Nature, vol.1958, issue.4631, pp.316-317

K. E. Kinnamon, E. A. Steck, P. S. Loizeaux, W. L. Hanson, W. L. Chapman et al., The Antileishmanial Activity of Lepidines, Am. J. Trop. Med. Hyg, vol.27, issue.4, pp.751-757, 1978.

J. A. Sherwood, G. S. Gachihi, R. K. Muigai, D. R. Skillman, M. Mugo et al., Phase 2 Efficacy Trial of an Oral 8-Aminoquinoline (WR6026) for Treatment of Visceral Leishmaniasis, Clinical Infectious Diseases, vol.19, issue.6, pp.1034-1039, 1994.

L. C. Valli, M. Grogl, B. Schuster, T. Brewer, J. Sanchez et al., Phase 2 Trial of WR6026, an Orally Administered 8-Aminoquinoline, in the Treatment of Visceral Leishmaniasis Caused by Leishmania Chagasi, The American Journal of Tropical Medicine and Hygiene, vol.65, issue.6, pp.685-689, 2001.

M. K. Wasunna, J. R. Rashid, J. Mbui, G. Kirigi, D. Kinoti et al., Am. J. Trop. Med. Hyg, p.6, 2005.

P. K. Sinha, K. Mohamed, M. Al-banna, S. Sundar, A. K. Miller et al., Pharmacokinetics of Oral Sitamaquine Taken with or without Food and Safety and Efficacy for Treatment of Visceral Leishmaniais: A Randomized Study in Bihar, The American Journal of Tropical Medicine and Hygiene, vol.84, issue.6, pp.892-900, 2011.

P. M. Loiseau, S. Cojean, and J. Schrével, Sitamaquine as a Putative Antileishmanial Drug Candidate: From the Mechanism of Action to the Risk of Drug Resistance, Parasite, vol.18, issue.2, pp.115-119, 2011.

A. M. Dueñas-romero, P. M. Loiseau, and M. Saint-pierre-chazalet, Interaction of Sitamaquine with Membrane Lipids of Leishmania Donovani Promastigotes, Biochimica et Biophysica Acta (BBA) -Biomembranes, vol.1768, issue.2, pp.246-252, 2007.

C. Lopez-martin, J. M. Perez-victoria, L. Carvalho, S. Castanys, and F. Gamarro, Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes, Antimicrobial Agents and Chemotherapy, vol.52, issue.11, pp.4030-4036, 2008.

S. Wyllie, S. Patterson, L. Stojanovski, F. R. Simeons, S. Norval et al., The Anti-Trypanosome Drug Fexinidazole Shows Potential for Treating Visceral Leishmaniasis, Science Translational Medicine, vol.2012, issue.119, pp.119-120

M. T. Bahia, A. F. Nascimento, A. L. Mazzeti, L. F. Marques, K. R. Gonçalves et al., Antitrypanosomal Activity of Fexinidazole Metabolites, Potential New Drug Candidates for Chagas Disease, vol.58, pp.4362-4370, 2014.

A. H. Fairlamb and S. Patterson, Current and Future Prospects of Nitro-Compounds as Drugs for Trypanosomiasis and Leishmaniasis, Current Medicinal Chemistry, p.25, 2018.

J. A. Urbina, Recent Clinical Trials for the Etiological Treatment of Chronic Chagas Disease: Advances, Challenges and Perspectives, Journal of Eukaryotic Microbiology, vol.62, issue.1, pp.149-156, 2015.

L. Diniz, F. De, A. L. Mazzeti, I. S. Caldas, I. Ribeiro et al., Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma Cruzi Strain in Mice, Antimicrobial Agents and Chemotherapy, vol.62, issue.6, pp.401-419, 2018.

C. Mowbray, Anti-Leishmanial Drug Discovery: Past, Present and Future Perspectives. In Drug Discovery for Leishmaniasis, pp.24-36, 2017.

M. Van-den-kerkhof, D. Mabille, E. Chatelain, C. E. Mowbray, S. Braillard et al., In Vitro and in Vivo Pharmacodynamics of Three Novel Antileishmanial Lead Series, International Journal for Parasitology: Drugs and Drug Resistance, vol.8, issue.1, pp.81-86, 2018.

A. M. Thompson, P. D. O'connor, A. Blaser, V. Yardley, L. Maes et al., Oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis, vol.59, pp.2530-2550, 2016.

A. M. Thompson, P. D. O'connor, A. J. Marshall, A. Blaser, V. Yardley et al., Development of (6 R )-2-Nitro-6, A New Lead for Visceral Leishmaniasis, pp.2329-2352, 2018.

C. Mowbray, Anti-Leishmanial Drug Discovery: Past, Present and Future Perspectives. In Drug Discovery for Leishmaniasis, pp.24-36, 2017.

C. E. Mowbray, S. Braillard, W. Speed, P. A. Glossop, G. A. Whitlock et al., Novel Amino-Pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity. Journal of Medicinal Chemistry, vol.58, issue.24, pp.9615-9624, 2015.

M. Berninger, I. Schmidt, A. Ponte-sucre, and U. Holzgrabe, Novel Lead Compounds in Pre-Clinical Development against African Sleeping Sickness, vol.8, pp.1872-1890, 2017.

T. Wenzler, D. W. Boykin, M. A. Ismail, J. E. Hall, R. R. Tidwell et al., New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289, Antimicrobial Agents and Chemotherapy, vol.53, issue.10, pp.4185-4192, 2009.

J. H. Ansede, R. D. Voyksner, M. A. Ismail, D. W. Boykin, R. R. Tidwell et al., In Vitro Metabolism of an Orally Active O -Methyl Amidoxime Prodrug for the Treatment of CNS Trypanosomiasis, Xenobiotica, vol.35, issue.3, pp.211-226, 2005.

J. K. Thuita, K. K. Wolf, G. A. Murilla, A. S. Bridges, D. W. Boykin et al., Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys, PLOS Neglected Tropical Diseases, vol.2015, issue.2, p.3409

H. B. Tatipaka, J. R. Gillespie, A. K. Chatterjee, N. R. Norcross, M. A. Hulverson et al., Substituted 2-Phenylimidazopyridines: A New Class of Drug Leads for Human African Trypanosomiasis, Journal of Medicinal Chemistry, vol.57, issue.3, pp.828-835, 2014.

S. Khare, A. S. Nagle, A. Biggart, Y. H. Lai, F. Liang et al., Proteasome Inhibition for Treatment of Leishmaniasis, Chagas Disease and Sleeping Sickness, Nature, vol.537, issue.7619, pp.229-233, 2016.

D. A. Patrick, J. R. Gillespie, J. Mcqueen, M. A. Hulverson, R. M. Ranade et al., Urea Derivatives of 2-Aryl-Benzothiazol-5-Amines: A New Class of Potential Drugs for Human African Trypanosomiasis, Journal of Medicinal Chemistry, vol.60, issue.3, pp.957-971, 2017.

S. Russell, R. Rahmani, A. J. Jones, H. L. Newson, K. Neilde et al., Hit-to-Lead Optimization of a Novel Class of Potent, BroadSpectrum Trypanosomacides, Journal of Medicinal Chemistry, vol.59, issue.21, pp.9686-9720, 2016.

M. T. Bahia, L. Diniz, F. De, and V. C. Mosqueira, Therapeutical Approaches under Investigation for Treatment of Chagas Disease, Expert Opinion on Investigational Drugs, vol.23, issue.9, pp.1225-1237, 2014.

J. A. Maertens, History of the Development of Azole Derivatives, Clinical Microbiology and Infection, vol.10, pp.1-10, 2004.

C. A. Morillo, H. Waskin, S. Sosa-estani, . Del-carmen, M. Bangher et al., Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers, Journal of the American College of Cardiology, vol.69, issue.8, pp.939-947, 2017.

S. Cronin and P. H. Chandrasekar, Safety of Triazole Antifungal Drugs in Patients with Cancer, Journal of Antimicrobial Chemotherapy, vol.65, issue.3, pp.410-416, 2010.

F. Villalta, M. C. Dobish, P. N. Nde, Y. Y. Kleshchenko, T. Y. Hargrove et al., VNI Cures Acute and Chronic Experimental Chagas Disease, The Journal of Infectious Diseases, vol.208, issue.3, pp.504-511, 2013.

M. Keenan, J. H. Chaplin, P. W. Alexander, M. J. Abbott, W. M. Best et al., Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease, Journal of Medicinal Chemistry, vol.56, issue.24, pp.10158-10170, 2013.

D. Truong and . Tolcapone, Review of Its Pharmacology and Use as Adjunctive Therapy in Patients with Parkinson's Disease, Clinical Interventions in Aging, p.109, 2009.

E. M. Sorkin, S. P. Clissold, R. N. Brogden, and . Nifedipine, A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy, in Ischaemic Heart Disease, Hypertension and Related Cardiovascular Disorders, Drugs, vol.30, issue.3, pp.182-274, 1985.

S. Nakamura, Structure of Azomycin, a New Antibiotic, Pharm. Bull, vol.1955, issue.5, pp.379-383

R. Anderson, P. W. Groundwater, A. Todd, and A. Worsley, Antibacterial Agents: Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications, 2012.

C. W. Ang, A. M. Jarrad, M. A. Cooper, and M. A. Blaskovich, Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases, Journal of Medicinal Chemistry, vol.60, issue.18, pp.7636-7657, 2017.

S. Löfmark, C. Edlund, and C. E. Nord, Metronidazole Is Still the Drug of Choice for Treatment of Anaerobic Infections, Clinical Infectious Diseases, vol.50, issue.s1, pp.16-23, 2010.

J. Samuelson, Why Metronidazole Is Active against Both Bacteria and Parasites, ANTIMICROB. AGENTS CHEMOTHER, vol.43, p.9, 1999.

M. Skold, H. Gnarpe, and L. Hillstrom, Ornidazole: A New Antiprotozoal Compound for Treatment of Trichomonas Vaginalis Infection, Sexually Transmitted Infections, vol.53, issue.1, pp.44-48, 1977.

D. Videau, G. Niel, A. Siboulet, F. Catalan, and . Secnidazole, A 5-Nitroimidazole Derivative with a Long Half-Life, Sexually Transmitted Infections, vol.54, issue.2, pp.77-80, 1978.

F. Nesslany, S. Brugier, M. Mouriès, F. Curieux, and D. Marzin, In Vitro and in Vivo Chromosomal Aberrations Induced by Megazol. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, vol.560, issue.2, pp.147-158, 2004.

G. C. Lancini and L. Lazzari, The Synthesis of Azomycin (2-Nitroimidazole), Experientia, vol.21, issue.2, p.83, 1965.

B. Cavalleri, R. Ballotta, V. Arioli, and G. Lancini, New 5-Substituted 1-Alkyl-2-Nitroimidazoles, Journal of Medicinal Chemistry, vol.16, issue.5, pp.557-560, 1973.

R. Sharma, Nitroimidazole Radiopharmaceuticals in Hypoxia: Part II Cytotoxicity and Radiosensitization Applications. Current Radiopharmaceuticalse, vol.4, pp.379-393, 2011.

J. Williamson, Chemotherapy and Chemoprophylaxis of African Trypanosomiasis, Exp. Parasitol, vol.12, issue.4, pp.323-367, 1962.

S. Patterson and S. Wyllie, Nitro Drugs for the Treatment of Trypanosomatid Diseases: Past, Present, and Future Prospects, Trends in Parasitology, vol.30, issue.6, pp.289-298, 2014.

A. Huttner, E. M. Verhaegh, S. Harbarth, A. E. Muller, U. Theuretzbacher et al., Nitrofurantoin Revisited: A Systematic Review and Meta-Analysis of Controlled Trials, Journal of Antimicrobial Chemotherapy, vol.70, issue.9, pp.2456-2464, 2015.

M. C. Carron, Antibacterial Nitrofurfurylidene Derivatives and Methods of Using Same, 3290213.

B. Begovic, S. Ahmetagic, L. Calkic, M. Vehabovic, S. Kovacevic et al., Open Clinical Trial on Using Nifuroxazide Compared to Probiotics in Treating Acute Diarrhoeas in Adults, Materia Socio Medica, vol.28, issue.6, p.454, 2016.

J. Rossignol and X. Cavier, New Derivative of 2-Benzamido-5-Nitrothiols, Chem. Abstr, vol.83, p.28216, 1975.

J. Rossignol, H. Maisonneuve, and Y. W. Cho, Nitroimidazoles in the Treatment of Trichomoniasis, Giardiasis, and Amebiasis, Int J Clin Pharmacol Ther Toxicol, vol.22, issue.2, pp.63-72, 1984.

C. S. Mcvay and R. Rolfe, Vitro and In Vivo Activities of Nitazoxanide against Clostridium Difficile, vol.44, pp.2254-2258, 2000.

A. K. Saz, L. M. Martinez, . Enzymatic, . Of, and . To-aureomycin, J. Biol. Chem, vol.223, issue.1, pp.282-295, 1956.

N. J. Cartwright and R. B. Cain, Bacterial Degradation of the Nitrobenzoic Acids, Biochemical Journal, vol.71, issue.2, pp.248-261, 1959.

M. D. Roldán, E. Pérez-reinado, F. Castillo, and C. Moreno-vivián, Reduction of Polynitroaromatic Compounds: The Bacterial Nitroreductases, FEMS Microbiology Reviews, vol.32, issue.3, pp.474-500, 2008.

Z. U. Ahmed and L. C. Vining, Evidence for a Chromosomal Location of the Genes Coding for Chloramphenicol Production in Streptomyces Venezuelae, J. BACTERIOL, vol.154, p.6, 1983.

T. Ohmori, S. Hagiwara, A. Ueda, Y. Minosha, and K. Yamada, Production of Pyoluteorin and Its Derivatives from N-Paraffin by Pseudomonas Aeruginosa S10B2, Agricol Biol Chem, vol.42, issue.11, pp.2031-2036, 1978.

M. Hashimoto and K. Hattori, Isopyrrolnitrin: A Metabolite from Pseudomonas, Bull Chem Soc Jpn, vol.39, issue.2, p.410, 1966.

M. Tischler, S. W. Ayer, and R. J. Andersen, Nitrophenols from Northeast Pacific Bryozoans, Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, vol.84, issue.1, pp.43-45, 1986.

K. N. Timmis and D. H. Pieper, Bacteria Designed for Bioremediation, Trends in Biotechnology, vol.17, issue.5, pp.201-204, 1999.

C. C. Somerville, S. F. Nishino, and J. C. Spain, Purification and Characterization of Nitrobenzene Nitroreductase from Pseudomonas Pseudoalcaligenes JS45, Journal of Bacteriology, vol.177, issue.13, pp.3837-3842, 1995.

Y. Xiao, J. Wu, H. Liu, S. Wang, S. Liu et al., Characterization of Genes Involved in the Initial Reactions of 4-Chloronitrobenzene Degradation in Pseudomonas Putida ZWL73, Applied Microbiology and Biotechnology, vol.73, issue.1, pp.166-171, 2006.

J. Rau and A. Stolz, Oxygen-Insensitive Nitroreductases NfsA and NfsB of Escherichia Coli Function under Anaerobic Conditions as Lawsone-Dependent Azo Reductases, Applied and Environmental Microbiology, vol.69, issue.6, pp.3448-3455, 2003.

S. I. Liochev and A. Hausladen, Fridovich, I. Nitroreductase A Is Regulated as a Member of the SoxRS Regulon of Escherichia Coli, Proceedings of the National Academy of Sciences, issue.7, pp.3537-3539, 1999.

M. Kurumata, M. Takahashi, A. Sakamoto, J. L. Ramos, A. Nepovim et al., Tolerance to, and Uptake and Degradation of 2,4,6-Trinitrotoluene (TNT) Are Enhanced by the Expression of a Bacterial Nitroreductase Gene in Arabidopsis Thaliana, Zeitschrift für Naturforschung C, vol.60, issue.3-4, pp.272-278, 2005.

R. J. Knox, F. Friedlos, and M. P. Boland, The Bioactivation of CB 1954 and Its Use as a Prodrug in Antibody-Directed Enzyme Prodrug Therapy (ADEPT). Cancer and Metastasis Reviews, vol.12, pp.195-212, 1993.

S. K. Sharma and K. D. Bagshawe, Translating Antibody Directed Enzyme Prodrug Therapy (ADEPT) and Prospects for Combination, Expert Opinion on Biological Therapy, vol.17, issue.1, pp.1-13, 2017.

A. N. Lukashev, C. Fuerer, M. Chen, P. Searle, and D. R. Iggo, Late Expression of Nitroreductase in an Oncolytic Adenovirus Sensitizes Colon Cancer Cells to the Prodrug CB1954, Human Gene Ther, vol.16, pp.1473-1483, 2005.

A. L. Lovering, E. I. Hyde, P. F. Searle, and S. A. White, The Structure of Escherichia Coli Nitroreductase Complexed with Nicotinic Acid: Three Crystal Forms at 1.7 Å, 1.8 Å and 2.4 Å Resolution, Journal of Molecular Biology, vol.309, issue.1, pp.203-213, 2001.

J. J. Tanner, B. Lei, S. Tu, K. L. Krause, and P. Flavin-reductase, Structure of a Dimeric Enzyme That Reduces Flavin ? , ? . Biochemistry, vol.35, pp.13531-13539, 1996.

P. R. Race, A. L. Lovering, S. A. White, J. I. Grove, P. F. Searle et al., Kinetic and Structural Characterisation of Escherichia Coli Nitroreductase Mutants Showing Improved Efficacy for the Prodrug Substrate CB1954, Journal of Molecular Biology, vol.368, issue.2, pp.481-492, 2007.

F. J. Peterson, R. P. Mason, J. Hovsepian, and J. L. Holzman, Oxygen-Sensitive and -Insensitive Nitroreduction by Escherichia Coli and Rat Hepatic Microsomes, J. Biol. Chem, issue.10, pp.4009-4014, 1979.

L. Hubbard and W. Mcelroy, Cloning, Nucleotide Sequence, and Expressioonf the Nitroreductase Gene from Enterobucter CZoucue, J. Biol. Chem, vol.266, issue.7, pp.4126-4130, 1991.

P. R. Race, A. L. Lovering, R. M. Green, A. Ossor, S. A. White et al., Structural and Mechanistic Studies of Escherichia Coli Nitroreductase with the Antibiotic Nitrofurazone: REVERSED BINDING ORIENTATIONS IN DIFFERENT REDOX STATES OF THE ENZYME, Journal of Biological Chemistry, vol.280, issue.14, pp.13256-13264, 2005.

P. Mason, L. Holtzman, . The, . Of, and . Superoxide-formation, , vol.67

R. L. Koder, C. A. Haynes, M. E. Rodgers, D. W. Rodgers, and A. Miller, Flavin Thermodynamics Explain the Oxygen Insensitivity of Enteric Nitroreductases ?, Biochemistry, issue.48, pp.14197-14205, 2002.

C. A. Haynes, R. L. Koder, A. Miller, and D. W. Rodgers, Structures of Nitroreductase in Three States: EFFECTS OF INHIBITOR BINDING AND REDUCTION, Journal of Biological Chemistry, vol.277, issue.13, pp.11513-11520, 2002.

W. W. Smith, R. M. Burnett, G. D. Darling, and M. L. Ludwig, Structure of the Semiquinone Form of Flavodoxin from Clostridium MP, Journal of Molecular Biology, vol.117, issue.1, pp.195-225, 1977.

S. Wyllie, S. Patterson, and A. H. Fairlamb, Assessing the Essentiality of Leishmania Donovani Nitroreductase and Its Role in Nitro Drug Activation, Antimicrobial Agents and Chemotherapy, vol.57, issue.2, pp.901-906, 2013.

A. A. Voak, V. Gobalakrishnapillai, K. Seifert, E. Balczo, L. Hu et al., An Essential Type I Nitroreductase from Leishmania Major Can Be Used to Activate Leishmanicidal Prodrugs, Journal of Biological Chemistry, vol.288, issue.40, pp.28466-28476, 2013.

S. Patterson, S. Wyllie, S. Norval, L. Stojanovski, F. R. Simeons et al., The Anti-Tubercular Drug Delamanid as a Potential Oral Treatment for Visceral Leishmaniasis, p.5, 2016.

S. Patterson, S. Wyllie, L. Stojanovski, M. R. Perry, F. R. Simeons et al., The R Enantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis, Antimicrobial Agents and Chemotherapy, vol.57, issue.10, pp.4699-4706, 2013.

S. Wyllie, A. J. Roberts, S. Norval, S. Patterson, B. J. Foth et al., Activation of Bicyclic Nitro-Drugs by a Novel Nitroreductase (NTR2) in Leishmania, PLOS Pathogens, vol.12, issue.11, p.1005971, 2016.

S. R. Wilkinson, M. C. Taylor, D. Horn, J. M. Kelly, and I. Cheeseman, A Mechanism for Cross-Resistance to Nifurtimox and Benznidazole in Trypanosomes, Proceedings of the National Academy of Sciences, issue.13, pp.5022-5027, 2008.

D. Leitsch, D. Kolarich, I. B. Wilson, F. Altmann, and M. Duchêne, Nitroimidazole Action in Entamoeba Histolytica: A Central Role for Thioredoxin Reductase, PLoS Biology, vol.5, issue.8, p.211, 2007.

G. F. Whitmore and A. J. Varghese, The Biological Properties of Reduced Nitroheterocyclics and Possible Underlying Biochemical Mechanisms, Biochem. Pharmacol, vol.35, issue.1, pp.97-103, 1986.

J. A. Raleigh and C. J. Koch, Importance of Thiols in the Reductive Binding of 2-Nitroimidazoles to Macromolecules, Biochemical Pharmacology, vol.40, issue.11, pp.2457-2464, 1990.

G. L. Kedderis, L. S. Argenbright, and G. T. Miwa, Covalent Interaction of 5-Nitroimidazoles with DNA and Protein in Vitro: Mechanism of Reductive Activation, Chemical Research in Toxicology, vol.2, issue.3, pp.146-149, 1989.

F. J. Peterson, R. P. Mason, J. Hovsepian, and J. L. Holzman, Oxygen-Sensitive and -Insensitive Nitroreduction by Escherichia Coli and Rat Hepatic Microsomes, J. Biol. Chem, issue.10, pp.4009-4014, 1979.

D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, Drug-Induced Oxidative Stress and Toxicity, Journal of Toxicology, vol.2012, pp.1-13, 2012.

W. L. Neeley and J. M. Essigmann, Mechanisms of Formation, Genotoxicity, and Mutation of Guanine Oxidation Products, Chemical Research in Toxicology, vol.19, issue.4, pp.491-505, 2006.

S. V. Avery, Molecular Targets of Oxidative Stress, Biochemical Journal, vol.434, issue.2, pp.201-210, 2011.

S. Bandyopadhyay and R. Gronostajskiln, Identification of a Conserved Oxidation-Sensitive Cysteine Residue in the NFI Family of DNA-Binding Proteins, J. Biol. Chem, issue.47, pp.29949-29955, 1994.

R. S. Padda, C. Wang, J. B. Hughes, R. Kutty, G. N. Bennett et al., Environmental Toxicology and Chemistry, vol.22, issue.10, p.2293, 2003.

D. Traversi, R. Degan, R. De-marco, G. Gilli, C. Pignata et al., Mutagenic Properties of PM2.5 Urban Pollution in the Northern Italy: The Nitro-Compounds Contribution, Environment International, vol.35, issue.6, pp.905-910, 2009.

P. Kovacic and R. Somanathan, Nitroaromatic Compounds: Environmental Toxicity, Carcinogenicity, Mutagenicity, Therapy and Mechanism: Nitro Aromatic Pollutants, Journal of Applied Toxicology, vol.34, issue.8, pp.810-824, 2014.

A. Buschini, L. Ferrarini, S. Franzoni, S. Galati, M. Lazzaretti et al., Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole, Journal of Parasitology Research, pp.1-11, 2009.

B. N. Ames, W. E. Durston, E. Yamasaki, and F. D. Lee, Carcinogens Are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection, Proceedings of the National Academy of Sciences, pp.2281-2285, 1973.

K. Mortelmans and E. Zeiger, The Ames Salmonella/Microsome Mutagenicity Assay. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol.455, pp.29-60, 2000.

B. N. Ames, F. D. Lee, and W. E. Durston, An Improved Bacterial Test System for the Detection and Classification of Mutagens and Carcinogens, Proceedings of the National Academy of Sciences, vol.70, pp.782-786, 1973.

B. N. Ames, J. Mccann, . Methods, . Detecting, . With et al., Mutat. Res, vol.31, pp.347-364, 1975.

D. E. Levin, E. Yamasaki, and B. N. Ames, A New Salmonella Tester Strain, TA97, for the Detection of Frameshift Mutagens A Run of Cytosines as a Mutational Hot-Spot, Mutat. Res, vol.94, pp.315-330, 1982.

I. M. De-oliveira, A. Zanotto-filho, J. C. Moreira, D. Bonatto, and J. A. Henriques, The Role of Two Putative Nitroreductases, Frm2p and Hbn1p, in the Oxidative Stress Response in Saccharomyces Cerevisiae, 2009.

S. Tejs, The Ames Test: A, Methodological Short Review. Environ. Biotechnol, vol.4, issue.1, pp.7-14, 2008.

D. E. Levin, M. Hollstein, M. F. Christman, E. A. Schwiers, and B. N. Ames, A New Salmonella Tester Strain (TA102) with AT Base Pairs at the Site of Mutation Detects Oxidative Mutagens, Proc. Natl. Soc. Acad. Sci, vol.79, pp.7445-7449, 1982.

K. Tatsumi, T. Doi, H. Yoshimura, H. Koga, and T. Horiushi, Oxygen--Insensitive Nitrofuran Reductases in Salmonella Typhimurium TA100, J. Pharmacobiodyn, vol.5, pp.423-429, 1982.

Y. Yanto, M. Hall, and A. S. Bommarius, Nitroreductase from Salmonella Typhimurium: Characterization and Catalytic Activity, Organic & Biomolecular Chemistry, vol.8, issue.8, p.1826, 2010.

W. T. Speck, J. L. Blumer, E. J. Rosenkranz, and H. S. Rosenkranz, Of Niridazole in Nitroreductase-. Cancer Res, vol.41, pp.2305-2307, 1981.

E. J. Rosenkranz, E. C. Mccoy, R. Mermelstein, and H. S. Rosenkranz, Evidence for the Existence of Distinct Nitroreductases in Salmonella Typhimurium : Roles in Mutagenesis, Carcinogenesis, vol.1982, issue.1, pp.121-123

O. Ostling and K. J. Johanson, Microelectrophoretic Study of Radiation-Induced DNA Damages in Individual Mammalian Cells, Biochem. Biophys. Res. Commun, vol.123, issue.1, pp.291-298, 1984.

N. P. Singh, M. T. Mccoy, R. R. Tice, and E. L. Schneider, A Simple Technique for Quantitation of Low Levels of DNA Damage in Individual Cells, Experimental Cell Research, vol.175, issue.1, pp.184-191, 1988.

R. P. Araldi, T. C. Melo, N. Diniz, J. Mazzuchelli-de-souza, R. F. Carvalho et al., Bovine Papillomavirus Clastogenic Effect Analyzed in Comet Assay. BioMed Research International, pp.1-7, 2013.

A. Azqueta and A. R. Collins, The Essential Comet Assay: A Comprehensive Guide to Measuring DNA Damage and Repair, Archives of Toxicology, vol.87, issue.6, pp.949-968, 2013.

A. R. Collins, Measuring Oxidative Damage to DNA and Its Repair with the Comet Assay, Biochimica et Biophysica Acta (BBA) -General Subjects, vol.1840, issue.2, pp.794-800, 2014.

K. Mortelmans and E. Zeiger, The Ames Salmonella/Microsome Mutagenicity Assay. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol.455, pp.29-60, 2000.

K. B. Gutzkow, T. M. Langleite, S. Meier, A. Graupner, A. R. Collins et al., High-Throughput Comet Assay Using 96 Minigels, Mutagenesis, vol.28, issue.3, pp.333-340, 2013.

H. Perdry, K. B. Gutzkow, M. Chevalier, L. Huc, G. Brunborg et al., Validation of Gelbond® High-Throughput Alkaline and Fpg-Modified Comet Assay Using a Linear Mixed Model: Validation of High-Throughput Comet Assay, Environmental and Molecular Mutagenesis, vol.59, issue.7, pp.595-602, 2018.

G. Krishna and M. Hayashi, In Vivo Rodent Micronucleus Assay: Protocol, Conduct and Data Interpretation. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol.455, pp.155-166, 2000.

S. Bonassi, A. Znaor, M. Ceppi, C. Lando, W. P. Chang et al., An Increased Micronucleus Frequency in Peripheral Blood Lymphocytes Predicts the Risk of Cancer in Humans, Carcinogenesis, vol.28, issue.3, pp.625-631, 2006.

T. Morita, J. T. Macgregor, and M. Hayashi, Micronucleus Assays in Rodent Tissues Other than Bone Marrow, Mutagenesis, vol.26, issue.1, pp.223-230, 2011.

M. Kirsch-volders, T. Sofuni, M. Aardema, S. Albertini, D. Eastmond et al., Report from the in Vitro Micronucleus Assay Working Group, Mutation Research/Genetic Toxicology and Environmental Mutagenesis, vol.540, issue.2, pp.153-163, 2003.

B. Miller, Evaluation of the in Vitro Micronucleus Test as an Alternative to the in Vitro Chromosomal Aberration Assay: Position of the GUM Working Group on the in Vitro Micronucleus Test, Mutation Research/Reviews in Mutation Research, vol.410, issue.1, pp.81-116, 1998.

L. Paloque, P. Verhaeghe, M. Casanova, C. Castera-ducros, A. Dumètre et al., Discovery of a New Antileishmanial Hit in 8-Nitroquinoline Series, European Journal of Medicinal Chemistry, vol.54, pp.75-86, 2012.
URL : https://hal.archives-ouvertes.fr/hal-02049707

C. Kieffer, A. Cohen, P. Verhaeghe, S. Hutter, C. Castera-ducros et al., Looking for New Antileishmanial Derivatives in 8-Nitroquinolin-2(1H)-One Series, European Journal of Medicinal Chemistry, vol.92, pp.282-294, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01460569

C. Kieffer, A. Cohen, P. Verhaeghe, L. Paloque, S. Hutter et al., Antileishmanial Pharmacomodulation in 8-Nitroquinolin-2(1H)-One Series, Bioorganic & Medicinal Chemistry, vol.23, issue.10, pp.2377-2386, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01460646

S. Nwaka, B. Ramirez, R. Brun, L. Maes, F. Douglas et al., Advancing Drug Innovation for Neglected Diseases-Criteria for Lead Progression, PLoS Neglected Tropical Diseases, vol.3, issue.8, p.440, 2009.

K. Katsuno, J. N. Burrows, K. Duncan, R. H. Van-huijsduijnen, T. Kaneko et al., Hit and Lead Criteria in Drug Discovery for Infectious Diseases of the Developing World, Nature Reviews Drug Discovery, vol.14, issue.11, pp.751-758, 2015.

F. Misani and M. T. Bogert, The Search for Superior Drugs for Tropical Diseases; Further Experiments in the Quinoline Group, J. Org. Chem, vol.10, pp.458-463, 1945.

M. I. Shahin, D. A. Abou-el-ella, N. S. Ismail, K. A. Abouzid, and . Design, Synthesis and Biological Evaluation of Type-II VEGFR-2 Inhibitors Based on Quinoxaline Scaffold, Bioorganic Chemistry, vol.56, pp.16-26, 2014.

V. V. Patil and G. S. Shankarling, Steric-Hindrance-Induced Regio-and Chemoselective Oxidation of Aromatic Amines, The Journal of Organic Chemistry, vol.80, issue.16, pp.7876-7883, 2015.

O. H. Johnson and C. S. Hamilton, Syntheses in the Quinoline Series. II. Some Derivatives of 4-Methylquinoline and a Study of Their Structures, Journal of the American Chemical Society, vol.63, issue.11, pp.2864-2867, 1941.

V. P. Andreev and Y. P. Nizhnik, Reaction of 2,4-Dibromoquinoline with Hydrogen Chloride, Russian J. Org. Chem, vol.38, issue.1, pp.137-138, 2002.

K. C. Majumdar and N. Kundu, Carbon-Carbon Bond Formation by Radical Cyclization: Regioselective Synthesis of Spiro Heterocyclic Compounds by n Bu 3 SnH-Mediated Reaction, Synthetic Communications, vol.36, issue.13, pp.1879-1886, 2006.

M. A. Cinelli, B. Cordero, T. S. Dexheimer, Y. Pommier, and M. Cushman, Aminoalkyl-Aminomethyl)Aromathecins as Topoisomerase I Inhibitors: Investigating the Hypothesis of Shared Structure-Activity Relationships, vol.14, pp.7145-7155, 2009.

A. Van-oeveren, M. Motamedi, E. Martinborough, S. Zhao, Y. Shen et al., Novel Selective Androgen Receptor Modulators: SAR Studies on 6-Bisalkylamino-2-Quinolinones, vol.17, pp.1527-1531, 2007.

E. Rosenhauer, Über Reaktionen von N -Alkyl-?-methylen-chinolanen, I.: Diazo-Kupplung der Methylenbase in neutraler Lösung, Mitbearbeitet von O. Dannhofer.). Berichte der deutschen chemischen Gesellschaft (A and B Series, vol.57, pp.1291-1294, 1924.

M. Naik, V. Humnabadkar, S. J. Tantry, M. Panda, A. Narayan et al., 4-Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity, Journal of Medicinal Chemistry, vol.57, issue.12, pp.5419-5434, 2014.

N. J. O'brien, M. Brzozowski, D. J. Wilson, L. W. Deady, and B. M. Abbott, Synthesis and Biological Evaluation of Substituted 3-Anilino-Quinolin-2(1H)-Ones as PDK1 Inhibitors, Bioorganic & Medicinal Chemistry, vol.22, issue.14, pp.3781-3790, 2014.

Y. Nanashima, A. Yokoyama, and T. Yokozawa, Synthesis of Well-Defined Poly(2-Alkoxypyridine-3,5-Diyl) via Ni-Catalyst-Transfer Condensation Polymerization, Macromolecules, vol.2012, issue.5, pp.2609-2613

H. P. Kokatla, D. Sil, S. S. Malladi, R. Balakrishna, A. R. Hermanson et al., Exquisite Selectivity for Human Toll-Like Receptor 8 in Substituted Furo, Quinolines. Journal of Medicinal Chemistry, vol.2, issue.17, pp.6871-6885, 2013.

Y. Koseki, T. Sugimura, K. Ogawa, R. Suzuki, H. Yamada et al., Total Synthesis of Isodesmosine by Stepwise, Regioselective Negishi and Sonogashira CrossCoupling Reactions: Total Synthesis of Isodesmosine, European Journal of Organic Chemistry, issue.18, pp.4024-4032, 2015.

F. Marsais, A. Godard, and G. Queguiner, Directed Ortho-lithiation of Chloroquinolines. Application to Synthesis of 2,3-disubstituted Quinolines, J. Heterocycl. Chem, vol.26, issue.6, pp.1589-1594, 1989.

F. Zaragoza, H. Stephensen, and B. Peschke, Rimvall, K. 2-(4-Alkylpiperazin-1-Yl)Quinolines as a New Class of Imidazole-Free Histamine H 3 Receptor Antagonists, Journal of Medicinal Chemistry, vol.48, issue.1, pp.306-311, 2005.

C. Janiak, Synthesis of 6,6?-Diamino-2,2?-Biquinoline and 2,2?-Bi-1,6-Naphthyridine. Synthesis, pp.959-964, 1999.

N. Elgrishi, K. J. Rountree, B. D. Mccarthy, E. S. Rountree, T. T. Eisenhart et al., A Practical Beginner's Guide to Cyclic Voltammetry, Journal of Chemical Education, vol.95, issue.2, pp.197-206, 2018.

R. I. Zubatyuk, L. Gorb, O. V. Shishkin, M. Qasim, and J. Leszczynski, Exploration of Density Functional Methods for One-Electron Reduction Potential of Nitrobenzenes, Journal of Computational Chemistry, issue.1, pp.144-150, 2010.

M. Uchimiya, L. Gorb, O. Isayev, M. M. Qasim, and J. Leszczynski, One-Electron Standard Reduction Potentials of Nitroaromatic and Cyclic Nitramine Explosives, Environmental Pollution, vol.158, issue.10, pp.3048-3053, 2010.

A. L. Roe, J. E. Snawder, R. W. Benson, D. W. Roberts, and D. A. Casciano, HepG2 Cells: An in Vitro Model for P450-Dependent Metabolism of Acetaminophen, Biochem. Biophys. Res. Commun, vol.190, issue.1, pp.15-19, 1993.

T. Mosmann, Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays, Journal of Immunological Methods, vol.65, issue.1-2, pp.55-63, 1983.

K. Leifso, G. Cohen-freue, N. Dogra, A. Murray, and W. R. Mcmaster, Genomic and Proteomic Expression Analysis of Leishmania Promastigote and Amastigote Life Stages: The Leishmania Genome Is Constitutively Expressed, Molecular and Biochemical Parasitology, vol.152, issue.1, pp.35-46, 2007.

M. A. Esteves, I. Fragiadaki, R. Lopes, E. Scoulica, and M. E. Cruz, Synthesis and Biological Evaluation of Trifluralin Analogues as Antileishmanial Agents, Bioorganic & Medicinal Chemistry, vol.18, issue.1, pp.274-281, 2010.

I. Navizet, Y. Liu, N. Ferré, D. Roca-sanjuán, and R. Lindh, The Chemistry of Bioluminescence: An Analysis of Chemical Functionalities, ChemPhysChem, vol.12, issue.17, pp.3064-3076, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00749782

H. Perdry, K. B. Gutzkow, M. Chevalier, L. Huc, G. Brunborg et al., Validation of Gelbond® High-Throughput Alkaline and Fpg-Modified Comet Assay Using a Linear Mixed Model: Validation of High-Throughput Comet Assay, Environmental and Molecular Mutagenesis, vol.59, issue.7, pp.595-602, 2018.

D. A. Smith, L. Di, and E. H. Kerns, The Effect of Plasma Protein Binding on in Vivo Efficacy: Misconceptions in Drug Discovery, Nature Reviews Drug Discovery, vol.2010, issue.12, pp.929-939

J. Pedron, C. Boudot, S. Hutter, S. Bourgeade-delmas, J. Stigliani et al., Novel 8-Nitroquinolin-2(1 H )-Ones as NTRBioactivated Antikinetoplastid Molecules: Synthesis, Electrochemical and SAR Study, European Journal of Medicinal Chemistry, vol.155, pp.135-152, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01888465

I. G. Moores, K. Smalley, H. Suschitzky, and . Hydrolysis-of-z-, QUINOLINES. J. Fluorine Chem, vol.20, issue.5, pp.573-580, 1982.

M. Ishikawa and K. Kikkawa, Studies on Quinoline Derivatives. IV. Yakugaku Zasshi, vol.75, issue.1, pp.36-39, 1955.

K. Hiramitsu, Y. Morimoto, T. Baba, and I. Hayakawa, Preparation of Novel 2-Quinolinones (Analogs) as Antibacterial Agents, Pharmaceuticals Containing Them (and Conventional Quinolones) for Prevention and/or Treatment of Infectious Diseases, 2014171527.

A. R. Todorov, T. Wirtanen, and J. Helaja, Photoreductive Removal of O -Benzyl Groups from Oxyarene N -Heterocycles Assisted by O -Pyridine-Pyridone Tautomerism. The Journal of Organic Chemistry, vol.82, pp.13756-13767, 2017.

L. S. Ciereszko and L. V. Hankes, Intermediates in the Synthesis of Carboxyl-C14-Labeled 3-Hydroxyanthranilic Acid1, J. Am. Chem. Soc, vol.76, issue.9, pp.2500-2501, 1954.

T. Hashimoto, Synthesis of Alkyl Derivatives of 3-Aminohydrocarbostyril and Diaminohydrocarbostyril, Yakugaku Zasshi, vol.75, issue.3, pp.340-342, 1955.

K. Mislow and J. B. Koepfli, The Synthesis of Potential Antimalarials. Some 2-Substituted 8-(3-Diethylaminopropylamino)-Quinolines 1, Journal of the American Chemical Society, vol.68, issue.8, pp.1553-1556, 1946.

C. Zhang, S. Bourgeade-delmas, Á. Fernández-Álvarez, A. Valentin, C. Hemmert et al., Synthesis, Characterization, and Antileishmanial Activity of Neutral N -Heterocyclic Carbenes Gold(I) Complexes, European Journal of Medicinal Chemistry, vol.143, pp.1635-1643, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01963517

M. De-méo, M. Laget, C. Di-giorgio, H. Guiraud, A. Botta et al., Optimization of the Salmonella/Mammalian Microsome Assay for Urine Mutagenesis by Experimental Designs, Mutation Research/Reviews in Genetic Toxicology, vol.340, issue.2-3, pp.51-65, 1996.

J. Reinhard, Acetaldehyde from Ethylene-A Retrospective on the Discovery of the Wacker Process, Angew. Chem. Int. Ed, vol.48, issue.48, pp.9034-9037, 2009.

N. Miyaura, K. Yamada, and A. Suzuki, A New Stereospecific Cross-Coupling by the Palladium-Catalyzed Reaction of 1-Alkenylboranes with 1-Alkenyl or 1-Alkynyl Halides, Tetrahedron Letters, vol.20, issue.36, pp.3437-3440, 1979.

A. Suzuki, Carbon-Carbon Bonding Made Easy, Chemical Communications, issue.38, p.4759, 2005.

I. Maluenda and O. Navarro, Recent Developments in the Suzuki-Miyaura Reaction, Molecules, vol.2015, issue.5, pp.7528-7557

K. Sonogashira, Y. Tohda, N. Hagihara, . Convenientsynthesisof-acetylenes:-catalyticsu!%titutionosf-acetyleyic, D. Hydrogenwithbro~~al~e~~eiso et al., Tetrahedron Lett, vol.16, pp.4467-4470, 1975.

C. A. Fleckenstein and H. Plenio, Aqueous/Organic Cross Coupling: Sustainable Protocol for Sonogashira Reactions of Heterocycles, Green Chemistry, vol.10, issue.5, p.563, 2008.

B. Liang, M. Dai, J. Chen, and Z. Yang, Copper-Free Sonogashira Coupling Reaction with PdCl 2 in Water under Aerobic Conditions. The Journal of Organic Chemistry, vol.70, pp.391-393, 2005.

M. Schilz and H. Plenio, A Guide to Sonogashira Cross-Coupling Reactions: The Influence of Substituents in Aryl Bromides, Acetylenes, and Phosphines. The Journal of Organic Chemistry, vol.77, pp.2798-2807, 2012.

R. Paterna, V. André, M. T. Duarte, L. F. Veiros, N. R. Candeias et al., Ring-Expansion Reaction of Isatins with Ethyl Diazoacetate Catalyzed by Dirhodium(II)/DBU Metal-Organic System: En Route to Viridicatin Alkaloids: Ring-Expansion Reaction of Isatins En Route to Viridicatin Alkaloids, European Journal of Organic Chemistry, issue.28, pp.6280-6290, 2013.

T. N. Glasnov, W. Stadlbauer, and C. O. Kappe, Microwave-Assisted Multistep Synthesis of Functionalized 4-Arylquinolin-2(1 H )-Ones Using Palladium-Catalyzed Cross-Coupling Chemistry, The Journal of Organic Chemistry, vol.70, issue.10, pp.3864-3870, 2005.

L. Zhang, Y. Luo, S. Yu, and W. Lu, Facile Synthesis of 4-Substituted-2-Quinolinone-3-Carboxylic Acid Ethyl Esters: Facile Synthesis of 4-Substituted-2-Quinolinone-3-Carboxylic Acid Ethyl Esters, Journal of Heterocyclic Chemistry, vol.2012, issue.5, pp.1254-1256

M. S. Tremblay, M. Halim, and D. Sames, Cocktails of Tb 3+ and Eu 3+ Complexes: A General Platform for the Design of Ratiometric Optical Probes, Journal of the American Chemical Society, vol.129, issue.24, pp.7570-7577, 2007.

Z. Zhao, W. H. Leister, R. G. Robinson, S. F. Barnett, D. Defeo-jones et al., Discovery of 2,3,5-Trisubstituted Pyridine Derivatives as Potent Akt1 and Akt2 Dual Inhibitors, Bioorganic & Medicinal Chemistry Letters, vol.15, issue.4, pp.905-909, 2005.

P. Likhar, S. Racharlawar, M. Karkhelikar, M. Subhas, and B. Sridhar, Iodocyclization of N-Aryl-3-Phenylpropiolamides by I2/CAN: A Convenient Route for the Selective Synthesis of Quinolin-2-Ones, Synthesis, issue.15, pp.2407-2414, 2011.

J. Reisch, A. Bathe, and . Naturstoffchemie, Dictamnin und Derivate durch Pd/Cu-katalysierte AlkinKupplung. Liebigs Annalen der Chemie, vol.114, pp.69-73, 1988.

J. Reisch, P. Nordhaus, and . Acetylenchemie, Mitt.: Molekülvariationen Am Rutaceenalkaloid Dictamnin via Pd/Cu Katalysierte Alkin-kupplung, J. Heterocycl. Chem, vol.18, pp.167-171, 1991.

G. B. Smith, G. C. Dezeny, D. L. Hughes, A. O. King, and T. R. Verhoeven, Mechanistic Studies of the Suzuki Cross-Coupling Reaction, The Journal of Organic Chemistry, vol.59, issue.26, pp.8151-8156, 1994.

N. Miyaura and A. Suzuki, Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds, Chemical Reviews, vol.95, issue.7, pp.2457-2483, 1995.

E. Chong and L. L. Schafer, 2-Pyridonate Titanium Complexes for Chemoselectivity. Accessing Intramolecular Hydroaminoalkylation over Hydroamination, Organic Letters, vol.15, issue.23, pp.6002-6005, 2013.

S. D. Kuduk, J. W. Skudlarek, C. N. Di-marco, J. G. Bruno, M. A. Pausch et al., Synthesis and Evaluation of Carbon-Linked Analogs of Dual Orexin Receptor Antagonist Filorexant, Bioorganic & Medicinal Chemistry Letters, vol.24, issue.7, pp.1784-1789, 2014.

T. Sakamoto, M. An-naka, Y. Kondo, and H. Yamanaka, Condensed Heteroaromatic Ring Systems. VIII. : Synthesis of 3-Substituted Isocoumarins from o-Halobenzoic Acid Derivatives, Chem. Pharm. Bull, vol.34, p.2719, 1986.

M. Viaud-massuard, H. Van-de-poël, and G. Guillaumet, Synthesis of Melatonin Analogues Derived from Furo[2,3-b]-and [2,3-c]Pyridines by Use of a Palladium-Copper Catalyst System, HETEROCYCLES, vol.57, issue.1, pp.55-71, 2002.

R. Zhou, W. Wang, Z. Jiang, K. Wang, X. Zheng et al., One-Pot Synthesis of 2-Substituted Benzo[b]Furans via Pd-Tetraphosphine Catalyzed Coupling of 2-Halophenols with Alkynes, Chem. Commun, vol.50, issue.45, pp.6023-6026, 2014.

O. A. Volkov, C. C. Cosner, A. J. Brockway, M. Kramer, M. Booker et al., Identification of Trypanosoma Brucei AdoMetDC Inhibitors Using a High-Throughput Mass Spectrometry-Based Assay, vol.2017, pp.512-526

M. Kansy, F. Senner, and K. Gubernator, Physicochemical High Throughput Screening: Parallel Artificial Membrane Permeation Assay in the Description of Passive Absorption Processes, Journal of Medicinal Chemistry, vol.41, issue.7, pp.1007-1010, 1998.

H. Van-de-waterbeemd, G. Camenisch, G. Folkers, J. R. Chretien, and O. A. Raevsky, Estimation of BloodBrain Barrier Crossing of Drugs Using Molecular Size and Shape, and H-Bonding Descriptors, Journal of Drug Targeting, vol.6, issue.2, pp.151-165, 1998.

J. Pedron, C. Boudot, S. Bourgeade-delmas, A. Sournia-saquet, L. Paloque et al., Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1 H )-One Scaffold Using PalladiumCatalysed Cross-Coupling Reactions, ChemMedChem, vol.13, pp.2217-2228, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01888530

T. N. Glasnov, W. Stadlbauer, and C. O. Kappe, Microwave-Assisted Multistep Synthesis of Functionalized 4-Arylquinolin-2(1H)-Ones Using Palladium-Catalyzed Cross-Coupling Chemistry, The Journal of Organic Chemistry, vol.70, issue.10, pp.3864-3870, 2005.

M. Fernandez, E. De-la-cuesta, and C. Avendano, Metallation of 2(1H)-Quinolinone: Synthesis of 3-Substituted Compounds, Synthesis, issue.11, pp.1362-1364, 1995.

V. Cañibano, J. F. Rodríguez, M. Santos, M. A. Sanz-tejedor, M. C. Carreño et al., Mild Regioselective Halogenation of Activated Pyridines with N-Bromosuccinimide, Synthesis, issue.14, pp.2175-2179, 2001.

O. S. Tee and M. Paventi, Kinetics and Mechanism of Bromination of 2-Pyridinone and Related Derivatives in Aqueous Solution, Journal of the American Chemical Society, vol.104, issue.15, pp.4142-4146, 1982.

P. Naik and L. Cucullo, In Vitro Blood-Brain Barrier Models: Current and Perspective Technologies, Journal of Pharmaceutical Sciences, vol.2012, issue.4, pp.1337-1354