P. Casino, V. Rubio, and A. Marina, The Mechanism of Signal Transduction by Two-Component Systems, Current Opinion in Structural Biology, issue.6, pp.763-771, 2010.

S. M. Wurgler-murphy, Two-component signal transducers and MAPK cascades, Trends in Biochemical Sciences, vol.22, issue.5, pp.172-176, 2002.

N. Ni, M. Li, J. Wang, and B. Wang, Inhibitors and Antagonists of Bacterial Quorum Sensing, Medicinal Research Reviews, vol.29, issue.1, pp.65-124, 2009.

L. E. Ulrich, E. Koonin, and I. B. V;-zhulin, One-Component Systems Dominate Signal Transduction in Prokaryotes, Trends in Microbiology, vol.13, issue.2, pp.52-56, 2005.

E. Calva and R. Oropeza, Two-Component Signal Transduction Systems, Environmental Signals, and Virulence. Microbial Ecology, vol.51, pp.166-176, 2006.

P. Cashin, L. Goldsack, D. Hall, and R. O'toole, Contrasting Signal Transduction Mechanisms in Bacterial and Eukaryotic Gene Transcription, FEMS Microbiol. Lett, vol.261, issue.2, pp.155-164, 2006.

M. Kato, T. Mizuno, T. Shimizu, and T. Hakoshima, Insights into Multistep Phosphorelay from the Crystal Structure of the C-Terminal HPt Domain of ArcB, vol.88, pp.717-723, 1997.

P. Thomason and R. Kay, Eukaryotic Signal Transduction via Histidine-Aspartate Phosphorelay, J. Cell Sci, vol.113, pp.3141-3150, 2000.

R. Gross and D. Beier, Two-Component Systems in Bacteria, 2012.

C. P. Zschiedrich, V. Keidel, and H. Szurmant, Molecular Mechanisms of Two-Component Signal Transduction, Journal of Molecular Biology, vol.428, issue.19, pp.3752-3775, 2016.

S. Wang, Bacterial Two-Component Systems: Structures and Signaling Mechanisms. In Protein Phosphorylation in Human Health, 2012.

A. M. Stock, V. L. Robinson, and P. N. Goudreau, Two-Component Signal Transduction, Annu. Rev. Biochem, vol.69, pp.183-215, 2000.

A. H. West and A. M. Stock, Histidine Kinases and Response Regulator Proteins in Two-Component Signaling Systems, Trends in Biochemical Sciences, vol.26, issue.6, pp.1852-1859, 2001.

M. T. Laub and M. Goulian, Specificity in Two-Component Signal Transduction Pathways, Annu. Rev. Genet, vol.41, issue.1, pp.121-145, 2007.

K. Stephenson and J. A. Hoch, Virulence-and Antibiotic Resistance-Associated Two-Component Signal Transduction Systems of Gram-Positive Pathogenic Bacteria as Targets for Antimicrobial Therapy, vol.93, pp.293-305, 2002.

, , pp.198-203

H. Szurmant, Essential Two-Component Systems of Gram-Positive Bacteria. In Twocomponent systems in Bacteria, pp.127-147, 2012.

Y. Gotoh, Y. Eguchi, T. Watanabe, S. Okamoto, A. Doi et al., Two-Component Signal Transduction as Potential Drug Targets in Pathogenic Bacteria, Current Opinion in Microbiology, vol.13, issue.2, pp.232-239, 2010.

H. Szurmant, K. Nelson, E. J. Kim, M. Perego, and J. A. Hoch, YycH Regulates the Activity of the Essential YycFG Two-Component System in Bacillus Subtilis, J. Bacteriol, vol.187, issue.15, pp.5419-5426, 2005.

S. Dubrac, I. G. Boneca, O. Poupel, and T. Msadek, New Insights into the WalK/WalR (YycG/YycF) Essential Signal Transduction Pathway Reveal a Major Role in Controlling Cell Wall Metabolism and Biofilm Formation in Staphylococcus Aureus, J. Bacteriol, vol.189, issue.22, pp.8257-8269, 2007.
URL : https://hal.archives-ouvertes.fr/hal-00189231

P. Bisicchia, D. Noone, E. Lioliou, A. Howell, S. Quigley et al., The Essential YycFG Two-Component System Controls Cell Wall Metabolism in Bacillus Subtilis, Mol. Microbiol, vol.65, issue.1, pp.180-200, 2007.

S. Dubrac, P. Bisicchia, K. M. Devine, and T. Msadek, A Matter of Life and Death: Cell Wall Homeostasis and the WalKR (YycGF) Essential Signal Transduction Pathway, Mol Microbiol, vol.70, issue.6, pp.1307-1322, 2008.
URL : https://hal.archives-ouvertes.fr/hal-00332455

A. D. Grossman, Genetic Networks Controlling the Initiation of Sporulation and the Development of Genetic Competence in Bacillus Subtilis, Annu. Rev. Genet, vol.29, issue.1, pp.477-508, 1995.

M. Jiang, W. Shao, M. Perego, and J. A. Hoch, Multiple Histidine Kinases Regulate Entry into Stationary Phase and Sporulation in Bacillus Subtilis, Mol. Microbiol, vol.38, issue.3, pp.535-542, 2000.

P. Eswaramoorthy, D. Duan, J. Dinh, A. Dravis, S. N. Devi et al., The Threshold Level of the Sensor Histidine Kinase KinA Governs Entry into Sporulation in Bacillus Subtilis, J. Bacteriol, issue.15, pp.3870-3882, 2010.

B. Winnen, E. Anderson, J. L. Cole, G. F. King, and S. L. Rowland, Role of the PAS Sensor Domains in the Bacillus Subtilis Sporulation Kinase KinA, J. Bacteriol, vol.195, issue.10, pp.2349-2358, 2013.

B. Mielich-süss and D. Lopez, Molecular Mechanisms Involved in Bacillus Subtilis Biofilm Formation, Environmental Microbiology, vol.17, issue.3, pp.555-565, 2015.

M. R. Parsek and P. K. Singh, Bacterial Biofilms: An Emerging Link to Disease Pathogenesis, Annu. Rev. Microbiol, vol.57, issue.1, pp.677-701, 2003.

X. Cai, J. Zhang, M. Chen, Y. Wu, X. Wang et al., The Effect of the Potential Phoq Histidine Kinase Inhibitors on Shigella Flexneri Virulence, PLoS One, issue.8, p.6, 2011.

S. Crépin, S. M. Chekabab, G. Le-bihan, N. Bertrand, C. M. Dozois et al., The Pho Regulon and the Pathogenesis of Escherichia Coli, Vet. Microbiol, vol.153, issue.1-2, pp.82-88, 2011.

E. Härtig and D. Jahn, Regulation of the Anaerobic Metabolism in Bacillus Subtilis, Adv. Microb. Physiol, vol.61, pp.195-216, 2012.

Y. H. Foo, C. Spahn, H. Zhang, M. Heilemann, and L. J. Kenney, Single Cell Super-Resolution Imaging of E. Coli OmpR during Environmental Stress, Integr. Biol, vol.7, issue.10, pp.1297-1308, 2015.

C. B. Whitchurch, T. E. Erova, J. A. Emery, J. L. Sargent, J. M. Harris et al., Phosphorylation of the Pseudomonas Aeruginosa Response Regulator AlgR Is Essential for Type IV Fimbria-Mediated Twitching Motility, J. Bacteriol, vol.184, issue.16, pp.4544-4554, 2002.

K. Koteva, H. J. Hong, X. D. Wang, I. Nazi, D. Hughes et al., A Vancomycin Photoprobe Identifies the Histidine Kinase VanSsc as a Vancomycin Receptor, Nat. Chem. Biol, vol.6, issue.5, pp.327-329, 2010.

V. Sperandio, J. L. Mellies, W. Nguyen, S. Shin, and J. B. Kaper, Quorum Sensing Controls Expression of the Type III Secretion Gene Transcription and Protein Secretion in Enterohemorrhagic and Enteropathogenic Escherichia Coli, Proc. Natl. Acad. Sci. U. S. A, vol.96, issue.26, pp.15196-15201, 1999.

M. B. Clarke, D. T. Hughes, C. Zhu, E. C. Boedeker, and V. Sperandio, The QseC Sensor Kinase: A Bacterial Adrenergic Receptor, Proc. Natl. Acad. Sci, vol.103, pp.10420-10425, 2006.

X. Wang, A. Vu, K. Lee, and F. W. Dahlquist, CheA-Receptor Interaction Sites in Bacterial Chemotaxis, J. Mol. Biol, vol.2012, issue.2, pp.282-290

V. Weiss, G. Kramer, T. Dunnebier, and A. Flotho, Mechanism of Regulation of the Bifunctional Further Reading, J. Mol. Microbrol. Biotechnol, vol.4, issue.3, pp.229-233, 2002.

T. Watanabe, A. Okada, Y. Gotoh, and R. Utsumi, Inhibitors Targeting Two-Component Signal Transduction. In Bacterial signal transduction: Network and drug targets, pp.229-236, 2008.

S. Roychoudhury, N. A. Zielinski, A. J. Ninfa, N. E. Allen, L. N. Jungheim et al., Inhibitors of Two-Component Signal Transduction Systems: Inhibition of Alginate Gene Activation in Pseudomonas Aeruginosa, Proc. Natl. Acad. Sci. U. S. A, vol.90, issue.3, pp.965-969, 1993.

M. Matsushita, Histidine Kinases as Targets for New Antimicrobial Agents, Bioorganic {&} Med. Chem, vol.10, issue.4, pp.855-867, 2002.

, , pp.355-363

K. Yamamoto, T. Kitayama, N. Ishida, T. Watanabe, H. Tanabe et al., Identification and Characterization of a Potent Antibacterial Agent, NH125 against Drug-Resistant Bacteria, Biosci. Biotechnol. Biochem, vol.64, issue.4, pp.919-923, 2000.

K. Yamamoto, T. Kitayama, S. Minagawa, T. Watanabe, S. Sawada et al., Antibacterial Agents That Inhibit Histidine Protein Kinase YycG of Bacillus Subtilis, Biosci. Biotechnol. Biochem, vol.65, issue.10, pp.2306-2310, 2001.

J. P. Demers, S. Johnson, M. A. Weidner-wells, R. M. Kanojia, S. A. Fraga-spano et al., Triphenylalkyl Antimicrobial Agents. US5643950A1, 1995.

J. P. Demers, Triphenylalkyl Antimicrobial Agents. WO9748676A1, 1997.

J. F. Barrett, R. M. Goldschmidt, L. E. Lawrence, B. Foleno, R. Chen et al., Antibacterial Agents That Inhibit Two-Component Signal Transduction Systems, Proc. Natl. Acad. Sci. U. S. A, vol.95, issue.9, pp.5317-5322, 1998.

R. Frechette and M. A. Weidner-wells, Benzoxazine Antimicrobial Agents. WO97/17333, 1997.

M. J. Macielag and R. Goldschmidt, Inhibitors of Bacterial Two-Component Signalling Systems Inhibitors of Bacterial Two-Component Signalling Systems, Exp. Opin. Invest. Drugs, vol.9, issue.10, pp.2351-2369, 2000.

R. F. Frechette and &. M. Beach, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry The Preparation of 2-Hydroxyethyl-2,3-Dihydro-2h-1,4-Benzoxazin-3(4h)-One Derivatives, Synth. Commun. An Int. J. Rapid Commun. Synth. Org. Chem, pp.3471-3478, 1998.

D. J. Hlasta, J. P. Demers, B. D. Foleno, S. A. Fraga-spano, J. Guan et al., Novel Inhibitors of Bacterial Two-Component Systems with Gram-positive Antibacterial Activity: Pharmacophore Identification Based on the Screening Hit Closantel, Bioorganic Med. Chem. Lett, vol.8, issue.14, pp.1923-1928, 1998.

, , pp.326-332

M. A. Janssen, V. K. Sipido, and . Janssen, , vol.4005218, 1977.

M. J. Macielag, J. P. Demers, S. A. Fraga-spano, D. J. Hlasta, S. G. Johnson et al., Substituted Salicylanilides as Inhibitors of Two-Component Regulatory Systems in Bacteria, pp.2939-2945, 1998.

Z. Sui, J. Guan, D. J. Hlasta, M. J. Macielag, B. D. Foleno et al., SAR Studies of diaryltriazoles against bacterial twocomponent regulatory systems and their antibacterial activities, Bioorg. Med. Chem. Lett, vol.8, issue.14, pp.1929-1934, 1998.

R. Alvarez, S. Velázquez, A. San-félix, S. Aquaro, E. De-clercq et al., J, vol.1, p.3

. Analogs, Synthesis and Anti-HIV-1 Activity, J. Med. Chem, issue.24, pp.4185-4194, 1994.

R. Kharb, P. C. Sharma, and M. S. Yar, Pharmacological Significance of Triazole Scaffold, J. Enzyme Inhib. Med. Chem, vol.26, issue.1, pp.1-21, 2011.

R. M. Kanojia, W. Murray, J. Bernstein, J. Fernandez, B. D. Foleno et al., 6-Oxa Isosteres of Anacardic Acids as Potent Inhibitors of Bacterial Histidine Protein Kinase (HPK)-Mediated Two-Component Regulatory Systems, Bioorganic Med. Chem. Lett, vol.9, issue.20, pp.2947-2952, 1999.

, , pp.508-517

T. Kitayama, T. Okamoto, R. K. Hill, Y. Kawai, S. Takahashi et al., Chemistry of Zerumbone. 1. Simplified Isolation, Conjugate Addition Reactions, and a Unique Ring Contracting Transannular Reaction of Its Dibromide, J. Org. Chem, vol.64, issue.8, pp.2667-2672, 1999.

T. Kitayama, K. Yamamoto, R. Utsumi, M. Takatani, Y. Kawai et al., Chemistry of Zerumbone. 2. Regulation of Ring Bond Cleavage and Unique Antibacterial Activities of Zerumbone Derivatives Takashi, Biosci. Biotechnol. Biochem, vol.65, issue.10, pp.2193-2199, 2001.

T. Kitayama, R. Iwabuchi, S. Minagawa, F. Shiomi, J. Cappiello et al., Unprecedented Olefin-Dependent Histidine-Kinase Inhibitory of Zerumbone Ring-Opening Material, Bioorganic Med. Chem. Lett, issue.23, pp.5943-5946, 2004.

T. Kitayama, R. Iwabuchi, S. Minagawa, S. Sawada, R. Okumura et al., Synthesis of a Novel Inhibitor against MRSA and VRE: Preparation from Zerumbone Ring Opening Material Showing Histidine-Kinase Inhibition, Bioorganic Med. Chem. Lett, vol.17, issue.4, pp.1098-1101, 2007.

M. A. Weidner-wells, K. A. Ohemeng, V. N. Nguyen, S. Fraga-spano, M. J. Macielag et al., Amidino Benzimidazole Inhibitors of Bacterial Two-Component Systems, Bioorg. Med. Chem. Lett, issue.12, pp.1545-1548, 2001.

, , pp.24-29

K. A. Ohemeng and V. Nguyen, 2-Substituted Phenyl-Benzimidazole Antibacterial Agents. US5942532, 1999.

D. A. Rasko, C. G. Moreira, R. L. De, N. C. Reading, J. M. Ritchie et al., Targeting QseC Signaling and Virulence for Antibiotic Development, Science, vol.321, issue.5892, pp.1078-1080, 2008.

R. J. Worthington, M. S. Blackledge, and C. Melander, Small-Molecule Inhibition of Bacterial Two-Component Systems to Combat Antibiotic Resistance and Virulence, Futur. Med Chem, vol.5, issue.11, pp.1265-1284, 2013.

V. Sperandio, J. R. Falck, and D. Stewart, Methods of inhibiting bacterial virulence and compounds relating thereto. WO2009088549A2, 2007.

Z. Qin, J. Zhang, B. Xu, L. Chen, Y. Wu et al., Structure-Based Discovery of Inhibitors of the YycG Histidine Kinase: New Chemical Leads to Combat Staphylococcus Epidermidis Infections, BMC Microbiol, vol.6, issue.96, pp.1-18, 2006.

B. Pan, R. Z. Huang, S. Q. Han, D. Qu, M. L. Zhu et al., Synthesis, and Antibiofilm Activity of 2-Arylimino-3-Aryl-Thiazolidine-4-Ones

, Bioorganic Med. Chem. Lett, issue.8, pp.2461-2464, 2010.

B. Pan, R. Huang, L. Zheng, C. Chen, S. Han et al., Thiazolidione Derivatives as Novel Antibiofilm Agents: Design, Synthesis, Biological Evaluation, and Structure-Activity Relationships, Eur. J. Med. Chem, vol.46, issue.3, pp.819-824, 2011.

R. Z. Huang, L. K. Zheng, H. Y. Liu, B. Pan, J. Hu et al.,

Y. Wu and Y. C. Wu, Thiazolidione Derivatives Targeting the Histidine Kinase YycG Are Effective against Both Planktonic and Biofilm-Associated Staphylococcus Epidermidis, Acta Pharmacol. Sin, vol.2012, issue.3, pp.418-425

D. Zhao, C. Chen, H. Liu, L. Zheng, Y. Tong et al., Biological Evaluation of Halogenated Thiazolo[3,2-a]Pyrimidin-3-One Carboxylic Acid Derivatives Targeting the YycG Histidine Kinase, Eur. J. Med. Chem, vol.87, pp.500-507, 2014.

K. E. Wilke, S. Francis, and E. E. Carlson, Inactivation of Multiple Bacterial Histidine Kinases by Targeting the ATP-Binding Domain, ACS Chem. Biol, vol.10, issue.1, pp.328-335, 2015.

M. Goswami, K. E. Wilke, and E. E. Carlson, Rational Design of Selective Adenine-Based Sca Ff Olds for Inactivation of Bacterial Histidine Kinases, vol.60, pp.8170-8182, 2017.

S. A. Laufer, D. M. Domeyer, T. R. Scior, W. Albrecht, and D. R. Hauser, Synthesis and Biological Testing of Purine Derivatives as Potential ATP-Competitive Kinase Inhibitors, J. Med. Chem, vol.48, issue.3, pp.710-722, 2005.

E. E. Carlson, Antibacterial Agents Including Histidine Kinase Inhibitors. WO2018217884A1, 2018.

C. D. Vo, H. L. Shebert, S. Zikovich, R. A. Dryer, T. P. Huang et al., Repurposing Hsp90 Inhibitors as Antibiotics Targeting Histidine Kinases, Bioorg. Med. Chem. Lett, vol.2017, issue.23, pp.5235-5244

E. I. Negishi and S. Baba, Novel Stereoselective Alkenyl-Aryl Coupling via Nickel-Catalysed Reaction of Alkenylanes with Aryl Halides, J. Chem. Soc. Chem. Commun, issue.15, 1976.

S. Baba and E. I. Negishi, A Novel Stereospecific Alkenyl-Alkenyl Cross-Coupling by a Palladium-or Nickel-Catalyzed Reaction of Alkenylalanes with Alkenyl Halides, J. Am. Chem. Soc, vol.98, issue.21, pp.6729-6731, 1976.

A. O. King, N. Okukado, and E. I. Negishi, Highly General Stereo-, Regio-, and Chemo-Selective Synthesis of Terminal and Internal Conjugated Enynes by the Pd-Catalysed Reaction of Alkynylzinc Reagents with Alkenyl Halides, J. Chem. Soc. Chem. Commun, pp.683-684, 1977.

E. Negishi, A. O. King, and N. Okukado, Selective Carbon-Carbon Bond Formation via Transition Metal Catalysis. 3. A Highly Selective Synthesis of Unsymmetrical Biaryls and Diarylmethanes by the Nickel-or Palladium-Catalyzed Reaction of Aryl-and Benzylzinc Derivatives with Aryl Halides, J. Org. Chem, issue.10, pp.1821-1823, 1977.

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

, , pp.95429-95431

N. Miyaura and A. Suzuki, Stereoselective Synthesis of Arylated (E) -Alkenes by the Reaction of Alk-1-Enylboranes with Aryl Halides in the Presence of Palladium Catalyst, J. Chem. Soc. Chem. Commun, issue.19, pp.866-867, 1979.

S. Kotha, K. Lahiri, and D. Kashinath, Recent Applications of the Suzuki-Miyaura Cross-Coupling Reaction in Organic Synthesis, Tetrahedron, vol.58, issue.48, pp.9633-9695, 2002.

, , pp.1188-1190

A. F. Biajoli, C. S. Schwalm, J. Limberger, T. S. Claudino, and A. L. Monteiro, Recent Progress in the Use of Pd-Catalyzed C-C Cross-Coupling Reactions in the Synthesis of Pharmaceutical Compounds, J. Braz. Chem. Soc, vol.25, issue.12, pp.2186-2214, 2014.

R. Martin and S. L. Buchwald, Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands, Acc. Chem. Res, issue.11, pp.1461-1473, 2008.

H. Zhang, F. Y. Kwong, Y. Tian, and K. S. Chan, Base and Cation Effects on the Suzuki Cross-Coupling of Bulky Arylboronic Acid with Halopyridines: Synthesis of Pyridylphenols, J. Org. Chem, vol.63, issue.20, pp.6886-6890, 1998.

C. Liu and M. Szostak, Decarbonylative Phosphorylation of Amides by Palladium and Nickel Catalysis: The Hirao Cross-Coupling of Amide Derivatives. Angew. Chemie -Int, vol.56, pp.12718-12722, 2017.

T. Hirao, T. Masunaga, Y. Ohshiro, and T. Agawa, Stereoselective Synthesis of Vinylphosphonate, Tetrahedron Lett, vol.21, issue.37, pp.3595-3598, 1980.

A. S. Guram, R. A. Rennels, and S. L. Buchwald, A Simple Catalytic Method for the Conversion of Aryl Bromides to Arylamines, Angew. Chemie Int. Ed. English, vol.34, issue.12, pp.1348-1350, 1995.

F. Paul, J. Patt, and J. F. Hartwig, Palladium-Catalyzed Formation of Carbon-Nitrogen Bonds. Reaction Intermediates and Catalyst Improvements in the Hetero Cross-Coupling of Aryl Halides and Tin Amides, J. Am. Chem. Soc, vol.116, issue.13, pp.5969-5970, 1994.

T. Boibessot, C. P. Zschiedrich, A. Lebeau, D. Bénimèlis, C. Dunyach-rémy et al., The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases, J. Med. Chem, issue.19, pp.8830-8847, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01543599

Z. Huang, Substituted 7-Aza-Benzothiophene Compounds as Lipid Kinase Inhibitors. SG184586A1, 2012.

T. Qi, T. Deschrijver, and I. Huc, Large-Scale and Chromatography-Free Synthesis of an Octameric Quinoline-Based Aromatic Amide Helical Foldamer, Nat. Protoc, vol.8, issue.4, pp.693-708, 2013.

J. M. Barker, P. R. Huddleston, M. L. Wood, and S. A. Burkitt, Nitration of Methyl-3-Hydroxy-and 5-Methyl-3-Hydroxy-Thiophene-2-Carboxylate, and Some Chemistry of the Products, J. Chem. Res. -Part S, vol.445, issue.10, pp.401-402, 2001.

A. Millet, M. Plaisant, C. Ronco, M. Cerezo, P. Abbe et al., Discovery and Optimization of N-(4-(3-Aminophenyl)Thiazol-2-Yl)Acetamide as a Novel Scaffold Active against Sensitive and Resistant Cancer Cells, J. Med. Chem, issue.18, pp.8276-8292, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01590452

F. Yousef, O. Mansour, J. Herbali, and . Sulfonamides, In-vitro in-vivo in-silico J, Historical Discovery Development (Structure-Activity Relationship Notes), vol.1, pp.1-15, 2018.

A. Tacic, V. Nikolic, L. Nikolic, and I. Savic, Antimicrobial Sulfonamide Drugs. Adv. Technol, vol.2017, issue.1, pp.58-71

S. Apayd?n and M. Török, Sulfonamide Derivatives as Multi-Target Agents for Complex Diseases, Bioorg. Med. Chem. Lett, issue.16, pp.2042-2050, 2019.

N. Shukla, Sulfonamides : A Novel Approach for Antimicrobial Chemotherapy, Biosci. Biotechnol. Res. Asia, vol.01, issue.1, pp.27-62, 2003.

C. Schenkels, B. Erni, and J. L. Reymond, Phosphofurylalanine, a Stable Analog of Phosphohistidine, Bioorganic Med. Chem. Lett, vol.9, issue.10, pp.1443-1446, 1999.

, , pp.209-216

S. Mukai, G. R. Flematti, L. T. Byrne, P. G. Besant, P. V. Attwood et al., Stable Triazolylphosphonate Analogues of Phosphohistidine, Amino Acids, vol.2012, issue.2, pp.857-874

J. Kee, B. Villani, L. R. Carpenter, and T. W. Muir, Development of Stable Phosphohistidine Analogues, J. Am. Chem. Soc, issue.41, pp.14327-14329, 2010.

T. W. Muir and J. Kee, , 2012.

M. C. Pirrung, K. D. James, V. S. Rana, . Thiophosphorylation, and . Histidine, J. Org. Chem, issue.25, pp.8448-8453, 2000.

T. E. Mcallister and M. E. Webb, Triazole Phosphohistidine Analogues Compatible with the Fmoc-Strategy, Org. Biomol. Chem, vol.2012, issue.20, pp.4043-4049

T. E. Mcallister, J. J. Hollins, and M. E. Webb, Prospects for Stable Analogues of Phosphohistidine, Biochem. Soc. Trans, vol.41, issue.4, pp.1072-1077, 2013.

T. E. Mcallister, K. A. Horner, and M. E. Webb, Evaluation of the Interaction between Phosphohistidine Analogues and Phosphotyrosine Binding Domains, ChemBioChem, vol.15, issue.8, pp.1088-1091, 2014.

J. M. Kee, R. C. Oslund, A. D. Couvillon, and T. W. Muir, A Second-Generation Phosphohistidine Analog for Production of Phosphohistidine Antibodies, Org. Lett, vol.17, issue.2, pp.187-189, 2015.

M. Lilley, B. Mambwe, M. J. Thompson, R. F. Jackson, and R. Muimo, 4-Phosphopyrazol-2-Yl Alanine: A Non-Hydrolysable Analogue of Phosphohistidine, Chem. Commun, vol.51, issue.34, pp.7305-7308, 2015.

R. Jackson, R. Muimo, and M. Lilley, Phosphohistidine and Phosphotyrosine Analogs. GB2517930A, 2013.

R. Jackson, R. Muimo, and M. Lilley, Phosphohistidine and Phosphotyrosine Analogues

M. Lilley, B. Mambwe, R. F. Jackson, and R. Muimo, 4-Phosphothiophen-2-Yl Alanine: A New 5-Membered Analogue of Phosphotyrosine, Chem. Commun, vol.50, issue.66, pp.9343-9345, 2014.

, Nous pouvons imaginer deux hypothèses : lors de l'ajout du dérivé halogéné (R)-66 la formation de l'alcynure n'a pas été totale et l'excès de LDA favoriserait la formation du produit d'élimination 45. Il est aussi possible qu'il soit responsable de l'élimination par son caractère basique (compétition entre la substitution et l'élimination), alors que le dérivé chloré (R)-66 a été consommé. L'apparition du produit d'élimination 45 est de même observé, vol.11

, En d'autres termes, l'alcynure une fois formé sera ajouté lentement au (R)-66. Cela permettrait à (R)-66 de se retrouver dans un milieu moins basique et donc favoriser la substitution. (Schéma 12) Cependant, la formation majoritaire de 45 est retrouvée

, Première tentative d'alkylation en milieu basique, vol.12

, 66 a été remplacé par (S)-67. Ce dernier est synthétisé par réaction d'Appel en mettant en jeu l'alcool (R)-51a en présence de tétrachlorure de carbone et de la triphénylphosphine pour obtenir (S)-67 en 46% de rendement, Par conséquent, vol.17, issue.13

, Cette première étape d'iodation a été décrite auparavant par Ayed et ses collaborateurs, en utilisant du diiode en présence de morpholine dans du benzène sur l'alcyne (R)-56a. 49 (Schéma 18) Schéma 18 : Synthèse de (R)-73 décrite par Ayed et ses collaborateurs (i) I2, morpholine

, Etant donné que l'utilisation du benzène est très contrôlée actuellement, celui-ci a été remplacé par du toluène qui possède des propriétés physico-chimiques similaires. Or, dans ce solvant, vol.19

, Afin de réaliser cette iodation, les conditions décrites par Crossley et Hein ont été appliquées sur (R)-56a. 50,51 Dans un premier temps, la formation de l'iodure d

, Ensuite, l'ajout de l'alcyne (R)-56a avec de CuI conduit au produit iodé (R)-73 avec un rendement de 45%

, Bestmann-Ohira reagent (0.029 mol; 5.55 g). The crude product was purified by flash chromatography (eluent: 0-80% PE/EtOAc) and 1.65 g (38% yield) of pure product were obtained as yellow oil

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.40, 1.42, 1.50 (3s, 15H, C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, 3 (C(CH3)2, C-5), vol.93

. Pe/etoac, 8/2; Ninhydrin)

, S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanoate

X. Method, Starting from azide (S)-44a (3.0 mmol, vol.730

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.33 (s, 9H, C(CH3)3); 1.38 (s, 9H, C(CH3)3); 3.64 (s, 3H, CO2CH3)

1. , N. H. , and J. =. , Hz, vol.7, p.39

C. Nmr-(dmso--d6,-75 and M. , CH3)3); 28.3 (3-CH3, (CH3)3); 35.6 (CH2, C-5), vol.49, pp.28-29

/. Etoac and . Pe,

, UPLC: tR: 3.52 min; purity, p.96

M. , calcd for C17H30N5O6, 400.2196, found 400.2195. (R) methyl-2-((tert-butoxycarbonyl)amino)-3-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1, HRMS, vol.2

X. Method, Starting from azide (R)-44b (2.4 mmol; 600 mg), N-Boc-propargylamine 47 (2.4 mmol; 380 mg), sodium L-ascorbate (0.48 mmol; 95 mg) and CuSO4?5H2O (0.24 mmol

, The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 758 mg

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.33 (s, 9H, C(CH3)3); 1.38 (s, 9H, C(CH3)3); 3.64 (s, 3H, CO2CH3)

1. , N. H. , and J. =. , Hz, vol.7, p.39

C. Nmr-(dmso--d6,-75 and M. , CH3)3); 28.3 (3-CH3, (CH3)3); 35.6 (CH2, C-5), vol.49, pp.28-29

, >99.5%. UPLC: tR: 3.43 min; purity: 98%. HRMS

, S) methyl -2-((tert-butoxycarbonyl)amino)-3-(4-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-1-yl)propanoate

X. Method, Starting from azide (S)-44a (1.84 mmol; 450 mg), N-Boc butynylamine 49 (1.84 mmol; 310 mg), sodium L-ascorbate (0.36 mmol; 70 mg) and CuSO4?5H2O (0.18 mmol

, The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 634 mg

H. Nmr and . Dmso--d6,

H. Hz,

C. Nmr and . Dmso--d6,

, IR (cm -1, p.1684

, EtOAc/PE: 8/2; Ninhydrin)

, UPLC: tR: 3.46 min; purity, p.97

M. , (R) methyl -2-((tert-butoxycarbonyl)amino)-3-(4-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-1-yl)propanoate, HRMS

X. Method, Starting from azide (R)-44b (2.0 mmol, vol.500

, 340 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 634 mg

H. Nmr and . Dmso--d6,

H. Hz,

C. Nmr and . Dmso--d6,

, EtOAc/PE: 8/2; Ninhydrin)

, UPLC: tR: 3.48 min; purity, >99.5%, p.100

, S) methyl-2-((tert-butoxycarbonyl)amino)-3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoate

X. Method, 0 mmol; 500 mg), but-3-yn-1-ol 57b (2.0 mmol; 155 µl), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography, Starting from azide (S)-44a, p.76

H. Nmr and . Dmso--d6, CH3)3); 2.74 (t, 2H, CH2, J = 6, 300 MHz) ?: 1.33 (s, 9H, vol.9

N. H. Hz, 79 (s, 1H, CH, vol.7

C. Nmr and . Dmso--d6, CH3)3); 29.1 (CH2, C-5), vol.49

M. , , pp.80-82

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.54 min; purity, p.100

M. , HRMS

H. Nmr and . Dmso--d6, CH3)3); 2.74 (t, 2H, CH2, J = 6, 300 MHz) ?: 1.33 (s, 9H, vol.9

N. H. Hz, 79 (s, 1H, CH, vol.7

C. Nmr and . Dmso--d6, CH3)3); 29.1 (CH2, C-5), vol.49

M. , , pp.80-82

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.52 min; purity, p.98

M. , Chapitre 2 : Partie expérimentale (S) methyl-1-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate, HRMS, issue.S

X. Method, Starting from azide (S)-44a (1.84 mmol; 450 mg), methyl propiolate 59a (1, vol.84

, 165 µl), sodium L-ascorbate (0.36 mmol; 70 mg) and CuSO4?5H2O (0.18 mmol; 45 mg). The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 510 mg

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.30 (s, 9H, (CH3)3); 3.66 (s, 3H, CO2CH3)

C. Nmr and . Dmso--d6, 75 MHz) ?: 27, vol.9, pp.3-3

/. Etoac and . Pe,

, UPLC: tR: 3.01 min; purity, p.96

, HRMS

, R) methyl-1-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate

X. Method, Starting from azide (R)-44b (2.0 mmol; 500 mg), methyl propiolate 59a (2.0 mmol

, 182 µl), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 566 mg

H. Nmr, DMSO -d6, 300 MHz) ?: 1.30 (s, 9H

C. Nmr and . Dmso--d6, 75 MHz) ?: 27, vol.9, pp.3-3

/. Etoac and . Pe,

, UPLC: tR: 3.02 min; purity, p.98

M. , -((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)acetic acid, HRMS, issue.2

X. Method, Starting from azide (S)-44a (4.0 mmol; 1.00 g), but-3-ynoic acid 59b (4.0 mmol; 340 mg), sodium L-ascorbate (0.8 mmol; 160 mg) and CuSO4?5H2O (0.4 mmol; 100 mg). The crude product was purified by C18 flash chromatography, p.64

H. Nmr and . Dmso--d6,

C. Nmr and . Dmso--d6, CH3)3); 35.6 (CH2, C-5), 75 MHz) ?: 28, vol.9, pp.3-3

, 2 (CO2H, C-6), vol.170

, IR (cm -1, p.1704

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.45 min; purity, p.86

, HRMS

, -((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)acetic acid

X. Method, 0 mmol; 1.00 g), but-3-ynoic acid 59b (4.0 mmol; 340 mg), sodium L-ascorbate (0.8 mmol; 160 mg) and CuSO4?5H2O (0.4 mmol; 100 mg). The crude product was purified by C18 flash chromatography, Starting from azide (R)-44b

H. Nmr and . Dmso--d6,

C. Nmr and . Dmso--d6, C-5); 49.0 (CH2, C-2), vol.34

, IR (cm -1, p.1704

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.62 min; purity, p.97

M. , (R)-tert-butyl 6-(1-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl, HRMS, issue.2

X. Method, 0 mmol; 500 mg), alkyne (R)-56a (2.0 mmol; 460 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-50% PE/EtOAc) and 655 mg, Starting from azide (S)-44a

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.55 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.93 min; purity, p.97

, HRMS

, tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.56 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.93 min; purity, p.98

M. , 2615, found 470.2613. (S)tert-butyl-6-(1-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl, HRMS, vol.470, issue.2

X. Method, 0 mmol; 500 mg), alkyne (S)-56b (2.0 mmol; 460 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-50% PE/EtOAc) and 790 mg, Starting from azide (S)-44a

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.56 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.90 min; purity, p.98

, HRMS

, tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)-2,2-dimethyloxazolidine-3-carboxylate

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.55 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6,

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.91 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (S)-58a (0.75 mmol; 300 mg). The crude product was purified

H. Hz,

C. Nmr-(d2o, 75 MHz) ?: 34.1 (CH2, C-5), vol.53

, IR (cm -1 ): 1587 (?C=O), vol.3012

, D 25 = -12 (H2O; c = 1.30)

, UPLC: tR: 0.52 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (R)-58b (0.75 mmol; 300 mg). The crude product was purified

H. Hz,

C. Nmr-(d2o, 75 MHz) ?: 34.1 (CH2, C-5), vol.53

, C-4), vol.176

, UPLC: tR: 0.52 min; purity, p.96

M. , HRMS

Y. Method, Starting from triazole (S)-58c (0.72 mmol; 300 mg). The crude product was purified

, H-5); 3.30 (t, 2H, J =, vol.6, issue.6

C. Nmr-(d2o, 75 MHz) ?: 22.9 (CH2, C-5), vol.38

, IR (cm -1, p.1601

, UPLC: tR: 0.53 min; purity, p.91

M. , HRMS, 1147.

Y. Method, Starting from triazole (R)-58d (0.72 mmol; 300 mg). The crude product was purified

H. Nmr, H-5); 3.30 (t, 2H, D2O, 300 MHz) ?: 3.08 (t, 2H, J = 6.9 Hz, vol.6

C. Nmr-(d2o, 75 MHz) ?: 22.9 (CH2, C-5), vol.38

, C-3), vol.143

, IR (cm -1, p.1599

, UPLC: tR: 0.53 min; purity, p.90

M. , HRMS, 1147.

Y. Method, Starting from triazole (S)-58e (0.99 mmol; 300 mg). The crude product was purified

H. Hz, 97 (s, 1H, vol.7

C. Nmr-(d2o, 75 MHz) ?: 49.7 (CH2, C-5), vol.54

, UPLC: tR: 0.58 min; purity, p.88

M. , HRMS

Y. Method, Starting from triazole (R)-58f (1.6 mmol; 485 mg). The crude product was purified

H. Hz,

C. Nmr-(d2o, 75 MHz) ?: 49.7 (CH2, C-5), vol.54

, C-4), vol.170

, UPLC: tR: 0.58 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (S)-58g (0.63 mmol; 200 mg). The crude product was purified

C. Nmr-(d2o, 75 MHz) ?: 27.6 (CH2, C-5)

, UPLC: tR: 0.66 min; purity, p.96

M. , HRMS

Y. Method, Starting from triazole (R)-58h (0.63 mmol; 200 mg). The crude product was purified

J. 1h,

C. Nmr-(d2o, 75 MHz) ?: 27.6 (CH2, C-5)

, UPLC: tR: 0.68 min; purity, p.86

M. , HRMS

Y. Method, Starting from triazole (S)-60a (0.60 mmol; 200 mg). The crude product was purified

H. Nmr,

, 66 (s, 1H, H-3), vol.8

C. Nmr and . Dmso--d6, C-2); 52.0 (CH, C-1), 75 MHz) ?: 48.9 (CH2, vol.130

, UPLC: tR: 0.57 min; purity, p.90

M. , HRMS

Y. Method, Starting from triazole (R)-60b (0.60 mmol; 200 mg). The crude product was purified

H. Nmr,

, 65 (s, 1H, H-3), vol.8

C. Nmr and . Dmso--d6, C-2), 75 MHz) ?: 48.9 (CH2, vol.51

, UPLC: tR: 0.57 min; purity, p.90

M. , HRMS

Y. Method, Starting from triazole (S)-60c (0.60 mmol; 200 mg). The crude product was purified

C. Nmr-(d2o, 75 MHz) ?: 31.5 (CH2, C-5), vol.49

(. and C. ,

, IR (cm -1, p.1580

, UPLC: tR: 0.63 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (R)-60d (0.60 mmol; 200 mg). The crude product was purified

H. Nmr-(d2o, 300 MHz) ?: 3.79 (s, 2H, H-5)

C. Nmr-(d2o, 75 MHz) ?: 33.1 (CH2, C-5), vol.49

(. and C. ,

, IR (cm -1, p.1575

, UPLC: tR: 0.63 min; purity: 100%

M. , (R)-1-amino-2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS

Y. Method, Starting from triazole (2S, 6R)-61a (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 20 mg

H. Nmr, D2O, 300 MHz) ?: 3.94 (m, 2H, CH2

C. Nmr-(d2o, 75 MHz) ?: 48.6 (CH2, C-5), vol.51

, C-3), vol.143

, UPLC: tR: 0.52 min; purity: 100%

M. , (R)-2-amino-3-(6-((R)-1-amino-2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS

Y. Method, Starting from triazole (2R, 6R)-61b (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 40 mg

C. Nmr-(d2o, 75 MHz) ?: 48.5 (CH2, C-5), vol.49, p.6

, C-3), vol.141

, UPLC: tR: 0.52 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (2S, 6S)-61c (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 33 mg

H. Nmr, D2O, 300 MHz) ?: 3.95 (m, 2H, CH2

C. Nmr-(d2o, 75 MHz) ?: 48.5 (CH2, C-5); 51.5 (CH2, C-2), vol.54

, C-3); 143.0 (C, C-4), vol.173

, UPLC: tR: 0.52 min; purity: 100%

M. , (R)-2-amino-3-(6-((S)-1-amino-2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS

Y. Method, Starting from triazole (2R, 6S)-61d (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 20 mg

H. Nmr, D2O, 300 MHz) ?: 3.91 (m, 2H, CH2

C. Nmr-(d2o, 75 MHz) ?: 48.6 (CH2, C-5), vol.52

, C-3); 144.5 (C, C-4), vol.174

, UPLC: tR: 0.52 min; purity: 100%

M. , + calcd for C7H14N5O3, 216.1097, found 216.1105. (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-chloropropanoate, HRMS, p.66

Z. Method, Starting from N-Boc-serine methyl ester (S)-42a (2 g, 9.12 mmol), p.10

, 37 g, 10 mmol). The crude product was purified by flash chromatography (eluent: 0-10% PE/EtOAc) and 1.08 g (50% yield) of pure product were obtained as white powder

C. Nmr and . Dmso--d6,

, PE/EtOAc: 9/1; Ninhydrin)

, S)-tert-butyl 4-(chloromethyl)-2,2-dimethyloxazolidine-3-carboxylate, p.67

A. A. Method, Starting from alcohol oxazolidine alcohol (S)-51a (2 g, 8.64 mmol), PPh3 (2.95 g, 11 mmol) and CCl4 (1.1 mL, 11 mmol). The crude product was purified by flash chromatography (eluent: 0-10% PE/EtOAc) and 990 mg

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.42, 1.48 (2s, 15H, C(CH3)3, H-5 and H-6)

C. Nmr and . Dmso--d6,

, PE/EtOAc: 9/1; Ninhydrin)

, S)-tert-butyl 4-(iodoethynyl)-2,2-dimethyloxazolidine-3-carboxylate, p.73

A. B. Method, CuI (42 mg, 0.22 mmol), Niodomorpholine (1.66 g, 4.88 mmol). The crude product was purified by flash chromatography (eluent: 0-10% PE/EtOAc) and 1 g, Starting from alkyne (R)-56a (1 g, 4.43 mmol)

H. Nmr and . Dmso--d6, , vol.3

C. Nmr and . Dmso--d6, C(CH3)3, C-6 and C-7); 29.8 (C?CI, C-1), 75 MHz) ?: 24.5, 25.9, vol.66

, PE/EtOAc: 9/1; Ninhydrin)

W. Vollmer, D. Blanot, and M. A. De-pedro, Peptidoglycan Structure and Architecture, FEMS Microbiol. Rev, vol.32, issue.2, pp.149-167, 2008.

C. Mayer, R. M. Kluj, M. Mühleck, A. Walter, S. Unsleber et al., Bacteria's Different Ways to Recycle Their Own Cell Wall, Int. J. Med. Microbiol, vol.2019, 151326-04.

P. Matteï, D. Neves, and A. Dessen, Bridging Cell Wall Biosynthesis and Bacterial Morphogenesis, Curr. Opin. Struct. Biol, issue.6, pp.749-755, 2010.

S. Rausch, A. Hänchen, A. Denisiuk, M. Löhken, T. Schneider et al., Feglymycin Is an Inhibitor of the Enzymes MurA and MurC of the Peptidoglycan Biosynthesis Pathway, ChemBioChem, vol.12, issue.8, pp.1171-1173, 2011.

J. Van-heijenoort, Recent Advances in the Formation of the Bacterial Peptidoglycan Monomer Unit, Nat. Prod. Rep, vol.18, issue.5, pp.503-519, 2001.

H. Barreteau, A. Kova?, A. Boniface, M. Sova, S. Gobec et al., Cytoplasmic Steps of Peptidoglycan Biosynthesis, FEMS Microbiol. Rev, vol.32, issue.2, pp.168-207, 2008.

S. Eschenburg, W. Kabsch, M. L. Healy, and E. Schonbrunn, A New View of the Mechanisms of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) and 5-Enolpyruvylshikimate-3-Phosphate Synthase (AroA) Derived from X-Ray Structures of Their Tetrahedral Reaction Intermediate States, J. Biol. Chem, vol.278, issue.49, pp.49215-49222, 2003.

M. Hrast, I. Sosi?, R. ?ink, and S. Gobec, Inhibitors of the Peptidoglycan Biosynthesis Enzymes MurA-F, Bioorg. Chem, vol.55, pp.2-15, 2014.

A. L. Lovering, S. S. Safadi, and N. C. Strynadka, Structural Perspective of Peptidoglycan Biosynthesis and Assembly, Annu. Rev. Biochem, vol.2012, issue.1, pp.451-478

M. M. Miyachiro, D. Granato, D. M. Trindade, C. Ebel, A. F. Paes-leme et al., Complex Formation between Mur Enzymes from Streptococcus Pneumoniae, Biochemistry, vol.2019, issue.30, pp.3314-3324
URL : https://hal.archives-ouvertes.fr/hal-02268985

T. D. Bugg, D. Braddick, C. G. Dowson, D. I. Roper, C. Mayer et al., Inhibitors of the Peptidoglycan Biosynthesis Enzymes MurA-F, Nat. Prod. Rep, vol.55, issue.3, pp.167-173, 2011.

A. Bouhss, A. E. Trunkfield, T. D. Bugg, and D. Mengin-lecreulx, The Biosynthesis of Peptidoglycan Lipid-Linked Intermediates, FEMS Microbiol. Rev, vol.32, issue.2, pp.208-233, 2008.

H. Hao, G. Cheng, M. Dai, Q. Wu, and . Yuan, Z. Inhibitors Targeting on Cell Wall Biosynthesis Pathway of MRSA. Mol. Biosyst, vol.2012, issue.11, pp.2828-2838

T. Mohammadi, V. Van-dam, R. Sijbrandi, T. Vernet, A. Zapun et al., Identification of FtsW as a Transporter of Lipid-Linked Cell Wall Precursors across the Membrane, EMBO J, vol.30, issue.8, pp.1425-1432, 2011.

C. A. Hutton, M. A. Perugini, and J. A. Gerrard, Inhibition of Lysine Biosynthesis: An Evolving Antibiotic Strategy, Mol. Biosyst, vol.3, issue.7, pp.458-465, 2007.

M. Kale and M. S. Shaikh, Exploration of Lysine Pathway for Developing Newer Anti-Microbial Analogs through Enzyme Inhibition Approach, Int. J. Pharm. Sci. Rev. Res, vol.25, issue.2, pp.221-230, 2014.

R. J. Cox, The DAP Pathway to Lysine as a Target for Antimicrobial Agents, Nat. Prod. Rep, vol.13, issue.1, pp.29-43, 1996.

Y. Liu, S. Xie, and J. Yu, Genome-Wide Analysis of the Lysine Biosynthesis Pathway Network during Maize Seed Development, PLoS One, vol.11, issue.2, pp.1-21, 2016.

T. L. Born and J. S. Blanchard, Structure/Function Studies on Enzymes in the Diaminopimelate Pathway of Bacterial Cell Wall Biosynthesis, Curr. Opin. Chem. Biol, vol.3, issue.5, pp.607-613, 1999.

, , pp.16-18

F. Fazius, C. Zaehle, and M. Brock, Lysine Biosynthesis in Microbes: Relevance as Drug Target and Prospects for ?-Lactam Antibiotics Production, Appl. Microbiol. Biotechnol, vol.97, issue.9, pp.3763-3772, 2013.

M. S. Pavelka and W. R. Jacobs, Biosynthesis of Diaminopimelate, the Precursor of Lysine and a Component of Peptidoglycan, Is an Essential Function of Mycobacterium Smegmatis, J. Bacteriol, vol.178, issue.22, pp.6496-6507, 1996.

C. Momany, R. Ghosh, and M. L. Hackert, Structural Motifs for Pyridoxal-5?-phosphate Binding in Decarboxylases: An Analysis Based on the Crystal Structure of the Lactobacillus 30a Ornithine Decarboxylase, Protein Sci, vol.1995, issue.5, pp.849-854

E. Sandmeier, T. I. Hale, and P. Christen, Multiple Evolutionary Origin of Pyridoxal-5?-phosphate-dependent Amino Acid Decarboxylases, Eur. J. Biochem, vol.221, issue.3, pp.997-1002, 1994.

R. J. Cox, A. Sutherland, and J. C. Vederas, Bacterial Diaminopimelate Metabolism as a Target for Antibiotic Design, Bioorganic Med. Chem, vol.8, issue.5, pp.843-871, 2000.

, , pp.44-48

Y. C. Ahn, C. Fischer, M. J. Van-belkum, and J. C. Vederas, PLP-Independent Racemization: Mechanistic and Mutational Studies of: O -Ureidoserine Racemase (DcsC), Org. Biomol. Chem, issue.7, pp.1126-1133, 2018.

W. Carolyn, K. Blanchard, and J. S. , Chemical Mechanism of Haemophilus Influenzae Diaminopimelate Epimerase, Biochemistry, vol.38, issue.14, pp.4416-4422, 1999.

R. J. Cox, The DAP Pathway to Lysine as a Target for Antimicrobial Agents, Nat. Prod. Rep, vol.13, issue.1, pp.29-43, 1996.

M. Hartmann, A. Tauch, L. Eggeling, B. Bathe, B. Möckel et al., Identification and Characterization of the Last Two Unknown Genes, DapC and DapF, in the Succinylase Branch of the L-Lysine Biosynthesis of Corynebacterium Glutamicum, J. Biotechnol, vol.104, issue.1-3, pp.199-211, 2003.

, , pp.156-157

J. Girodeau, C. Agouridas, M. Masson, R. Pineau, and F. Le-goffic, The Lysine Pathway as a Target for a New Genera of Synthetic Antibacterial Antibiotics?, J. Med. Chem, issue.6, pp.1023-1030, 1986.

J. G. Kelland, L. D. Arnold, M. M. Palcic, M. A. Pickard, and J. C. Vederas, Analogs of Diaminopimelic Acid as Inhibitors of Meso-Diaminopimelate Decarboxylase from Bacillus Sphaericus and Wheat Germ, J. Biol. Chem, issue.28, pp.13216-13223, 1986.

L. K. Lam, L. D. Arnold, T. H. Kalantar, J. G. Kelland, P. M. Lane-bell et al., Analogs of Diaminopimelic Acid as Inhibitors of Meso-Diaminopimelate Dehydrogenase and LL-Diaminopimelate Epimerase, J. Biol. Chem, vol.263, issue.24, pp.11814-11819, 1988.

R. J. Baumann, E. H. Bohme, J. S. Wiseman, M. Vaal, and J. S. Merrell, Inhibition of Escherichia Coli Growth and Diaminopimelic Acid Epimerase by 3-Chlorodiaminopimelic Acid Downloaded From, vol.32, 1988.

M. H. Gelb, Y. Lin, M. A. Pickard, Y. Song, and J. C. Vederas, Synthesis of 3-Fluorodiaminopimelic Acid Isomers as Inhibitors of Diaminopimelate Epimerase: Stereocontrolled Enzymatic Elimination of Hydrogen Fluoride, J. Am. Chem. Soc, vol.112, issue.12, pp.4932-4942, 1990.

A. Sutherland and J. C. Vederas, The First Isolation of an Alkoxy-N,N-Dialkylaminodifluorosulfane from the Reaction of an Alcohol and DAST: An Efficient Synthesis of (2S,3R,6S)-3-Fluoro-2,6-Diaminopimelic Acid, Chem. Comm, pp.1739-1740, 1999.

F. Gerhart, W. Higgins, C. Tardif, and J. B. Ducep, 2-(4-Amino-4-Carboxybutyl)Aziridine-2-Carboxylic Acid. A Potent Irreversible Inhibitor of Diaminopimelic Acid Epimerase. Spontaneous Formation from ?-(Halomethy 1) Diaminopimelic Acids, J. Med. Chem, issue.8, pp.2157-2162, 1990.

W. Higgins, C. Tardif, C. Richaud, M. A. Krivanek, and A. Cardin, Expression of Recombinant Diaminopimelate Epimerase in Escherichia Coli Isolation and Inhibition with an Irreversible Inhibitor, Eur. J. Biochem, vol.186, issue.1-2, pp.137-143, 1989.

S. Abbott, P. Lane-bell, K. P. Sidhu, and J. C. Vederas, Synthesis and Testing of Heterocyclic Analogues of Diaminopimelic Acid (DAP) as Inhibitors of DAP Dehydrogenase and DAP Epimerase, J. Am. Chem. Soc, vol.116, issue.15, pp.6513-6520, 1994.

R. M. Williams, G. J. Fegley, R. Gallegos, F. Schaefer, and D. L. Pruess, Asymmetric Syntheses of (2S,3S,6S)-, (2S,3S,6R)-, and (2R,3R,6S)-2,3-Methano-2,6-Diaminopimelic Acids. Studies Directed to the Design of Novel Substrate-Based Inhibitors of L,L-Diaminopimelate Epimerase, Tetrahedron, vol.52, issue.4, pp.1149-1164, 1996.

J. F. Caplan, R. Zheng, J. S. Blanchard, and J. C. Vederas, Vinylogous Amide Analogues of Diaminopimelic Acid (DAP) as Inhibitors of Enzymes Involved in Bacterial Lysine Biosynthesis, Org. Lett, vol.2, issue.24, pp.3857-3860, 2000.

R. J. Cox, J. Durston, and D. I. Roper, Synthesis and in Vitro Enzyme Activity of an Oxa Analogue of Azi-DAP, J. Chem. Soc. Perkin, vol.1, pp.1029-1035, 2002.

M. S. Shaikh, M. A. Kale, and K. Sharuk, Discovery of Heterocyclic Analogs of Diaminopimelic Acid as Promising Antibacterial Agents Through Enzyme Targeted Inhibition of Lysine Biosynthesis, Curr. Enzym. Inhib, vol.2017, issue.2, pp.120-130

T. Boibessot, D. Bénimèlis, M. Jean, Z. Benfodda, and P. Meffre, Synthesis of a Novel Rhizobitoxine-Like Triazole-Containing Amino Acid, Synlett, vol.2016, issue.19, pp.2685-2688
URL : https://hal.archives-ouvertes.fr/hal-01404310

T. T. Denton, X. Zhang, and J. R. Cashman, 5-Substituted, 6-Substituted, and Unsubstituted 3-Heteroaromatic Pyridine Analogues of Nicotine as Selective Inhibitors of Cytochrome P-450 2A6, J. Med. Chem, vol.48, issue.1, pp.224-239, 2005.

E. Ranyuk, R. Lebel, Y. Bérubé-lauzière, K. Klarskov, R. Lecomte et al., Guérin, B. 68Ga/DOTA-and 64Cu/NOTA-Phthalocyanine Conjugates as Fluorescent/PET Bimodal Imaging Probes, Bioconjug. Chem, vol.24, issue.9, pp.1624-1633, 2013.

Z. Benfodda, D. Benimélis, G. Reginato, and P. Meffre, Ethynylglycine Synthon, a Useful Precursor for the Synthesis of Biologically Active Compounds: An Update. Part II: Synthetic Uses of Ethynylglycine Synthon, Amino Acids, vol.50, issue.10, pp.1307-1328, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01676812

F. Berrabah, T. Balliau, E. H. Aït-salem, J. George, M. Zivy et al., Control of the Ethylene Signaling Pathway Prevents Plant Defenses during Intracellular Accommodation of the Rhizobia, New Phytol, vol.219, issue.1, pp.310-323, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02402863

A. S. Karpov and T. J. Müller, Straightforward Novel One-Pot Enaminone and Pyrimidine Syntheses by Coupling-Addition-Cyclocondensation Sequences, Synthesis (Stuttg), issue.18, pp.2815-2826, 2003.

M. Lilley, B. Mambwe, R. F. Jackson, and R. Muimo, 4-Phosphothiophen-2-Yl Alanine: A New 5-Membered Analogue of Phosphotyrosine, Chem. Commun, vol.50, issue.66, pp.9343-9345, 2014.

C. Ayed, S. Palmier, N. Lubin-germain, J. Uziel, and J. Augé, Indium-Mediated Alkynylation of Sugars: Synthesis of C-Glycosyl Compounds Bearing a Protected Amino Alcohol Moiety, Carbohydr. Res, issue.17, pp.2566-2570, 2010.

J. A. Crossley and D. L. Browne, An Alkynyliodide Cycloaddition Strategy for the Construction of Iodoisoxazoles, J. Org. Chem, issue.15, pp.5414-5416, 2010.

J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless, and V. V. Fokin, Copper(I)-Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes. Angew. Chemie Int, vol.48, pp.8018-8021, 2009.

L. M. Yang, L. F. Huang, and T. Y. Luh, Kumada-Corriu Reactions of Alkyl Halides with Alkynyl Nucleophiles, Org. Lett, vol.6, issue.9, pp.1461-1463, 2004.

M. Ijsselstijn, J. Kaiser, F. L. Van-delft, H. E. Schoemaker, and F. P. Rutjes, Synthesis of Novel Acetylene-Containing Amino Acids, Amino Acids, vol.24, issue.3, pp.263-266, 2003.

R. F. Jackson and M. Perez-gonzalez, Synthesis of N-( Tert -Butoxycarbonyl)-?-Iodoalanine Methyl Ester: A Useful Building Block in the Synthesis of Nonnatural ?-Amino Acids via Palladium Catalyzed Cross Coupling Reactions, Organic Syntheses, vol.81, pp.77-88, 2005.

P. Meffre, L. Gauzy, E. Branquet, P. Durand, and F. Le-goffic, Synthesis of Optically Active ?,?-Alkynylglycine Derivatives, Tetrahedron, vol.52, issue.34, pp.11215-11238, 1996.
URL : https://hal.archives-ouvertes.fr/hal-02002738

C. Selvam, I. A. Lemasson, I. Brabet, N. Oueslati, B. Karaman et al., Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual Sites, J. Med. Chem, issue.5, pp.1969-1989, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02018007

A. Dondoni and D. Perrone, Synthesis of 1,1-Dimethylethyl (S)-4-Formyl-2,2-Dimethyl-3-Oxazolidinecarboxylate by Oxidation of the Alcohol, Organic Syntheses, vol.77, pp.64-64, 2003.

A. Ollivier, M. Goubert, A. Tursun, I. Canet, and M. Sinibaldi, Orthogonally Protected Glycerols and 2-Aminodiols: Useful Building Blocks in Heterocyclic Chemistry
URL : https://hal.archives-ouvertes.fr/hal-00506251

L. Williams, Z. Zhang, F. Shao, P. J. Carroll, and M. M. Joullié, Grignard Reactions to Chiral Oxazolidine Aldehydes, Tetrahedron, vol.52, issue.36, pp.11673-11694, 1996.

, , pp.672-674

M. Gajewski, B. Seaver, C. S. Esslinger, and . Design, Synthesis, and Biological Activity of Novel Triazole Amino Acids Used to Probe Binding Interactions between Ligand and Neutral Amino Acid Transport Protein SN1, Bioorganic Med. Chem. Lett, issue.15, pp.4163-4166, 2007.

M. N. Kenworthy, J. Paul-kilburn, and R. J. Taylor, Highly Functionalized Organolithium Reagents for Enantiomerically Pure R-Amino Acid Synthesis, J. Chem. Soc., Perkin Trans. 1, vol.1989, issue.2

C. Ayed, J. Picard, N. Lubin-germain, J. Uziel, and J. Auge, Synthesis of Alkynes and Alkynyl Iodides Bearing a Protected Amino Alcohol Moiety as Functionalized Amino Acids Precursors, Science China Chemistry, vol.53, pp.1921-1926, 2010.

, Résumé de la thèse

, Cela est d'autant plus accentué par la mauvaise utilisation des antibiotiques combinée au manque d'intérêt de l'industrie pharmaceutique. Il est donc urgent de trouver de nouvelles cibles antibactériennes et de nouveaux agents antibactériens pour lutter contre les bactéries multirésistantes, L'émergence récente et continuelle de souches bactériennes résistantes aux antibiotiques

, La première stratégie vise à concevoir et à synthétiser de nouveaux inhibiteurs d'histidine kinase (HK, protéine impliquée dans le mécanisme de résistance) à caractère d'adjuvant d'antibiotiques

, Parmi les 47 composés synthétisés, deux dérivés thiophènes, deux dérivés sulfonates et trois dérivés sulfonamides présentent des valeurs inhibitrices de HK inférieures à 50 µM. Ces valeurs ont été améliorées par rapport aux précédents inhibiteurs synthétisés au laboratoire. Par ailleurs, trois dérivés furanes ont inhibé la croissance bactérienne de bactéries à Gram-positif comme à

, Gram-négatif. Finalement, un chlorhydrate d'amine présente une activité adjuvante d'antibiotique

, La deuxième stratégie menée, vise à inhiber la voie de biosynthèse de la lysine qui est un des principaux résidus impliqués dans la biosynthèse du peptidoglycane. Ceci est possible par la synthèse d'acides aminés non usuels à base de triazole ou d'alcyne, analogues de l'acide diaminopimélique (précurseur de la lysine, Au total 16 acides aminés de type triazole ont été synthétisés et leurs activités biologiques sont en cours de réalisation