Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis

Journal of Medicinal Chemistry

Volumn 58, Issue 2, 2015, Pages 613-624

  Šink, Roman ^a   Sosič, Izidor ^a   Živec, Matej ^a   Fernandez Menendez, Raquel ^b   Turk, Samo ^a   Pajk, Stane ^a   Alvarez Gomez, Daniel ^b   Lopez Roman, Eva Maria ^b   Gonzales Cortez, Carolina ^b   Rullas Triconado, Joaquin ^b   Angulo Barturen, Inigo ^b   Barros, David ^b   Ballell Pages, Lluís ^b   Young, Robert J ^c   Encinas, Lourdes ^b   Gobec, Stanislav ^a  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

^b GLAXOSMITHKLINE   (Spain)

^c GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 METHYLTHIAZOL 2 YL) 1 (5 [[6 (PIPERIDIN 1 YL)PYRIDIN 2 YL]AMINO]1,3,4 THIADIAZOL 2 YL]ETHAN 1 OL; 1 (4 METHYLTHIAZOL 2 YL) 1 [5 (PYRIDIN 2 YLAMINO) 1,3,4 THIADIAZOL 2 YL]ETHAN 1 OL; 1 (4 METHYLTHIAZOL 2 YL) 1 [5 (PYRIMIDIN 2 YLAMINO) 1,3,4 THIADIAZOL 2 YL]ETHAN 1 OL; 1 (4 METHYLTHIAZOL 2 YL) 1 [5 [(6 MORPHOLINOPYRIDIN 2 YL)AMINO]1,2,4 THIADIAZOL 2 YL]ETHAN 1 OL; 1 (4 METHYLTHIAZOL 2 YL) 1 [5 [[6 (TRI UOROMETHYL)PYRIDIN 2 YL]AMINO]1,3,4 THIADIAZOL 2 YL]ETHAN 1 OL; 1 [5 [(1 METHYL 1H 1,2,3 TRIAZOL 4 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(1 METHYL 1H PYRAZOL 3 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(1 METHYL 1H PYRAZOL 4 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(2 METHOXYPYRIDIN 4 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(2 METHYLPYRIDIN 3 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(3 BROMO 4 FLUOROPHENYL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(5 BROMO 6 METHYLPYRIDIN 2 YL)AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(5 FLUOROPYRIDIN 2 YL)AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(5 METHYLPYRIDIN 3 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(6 BROMOPYRIDIN 2 YL)AMINO] 1,3,4 THIADIAZOL 2 YL) 1 (4 METHYLTHIAZOL 2 YL)ETHANOL; 1 [5 [(6 BROMOPYRIDIN 2 YL)AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(6 CYCLOPROPYLPYRIDIN 2 YL)AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(6 FLUOROPYRIDIN 2 YL)AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(6 METHYLPYRIDIN 2 YL)AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [(6 METHYLPYRIDIN 4 YL)AMINO] 1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 1 [5 [[5 BROMO 6 (TRIFLUOROMETHYL)PYRIDIN 2 YL]AMINO]1,3,4 THIADIAZOL 2 YL] 1 (4 METHYLTHIAZOL 2 YL)ETHAN 1 OL; 6 [[5 (1 HYDROXY 1 (4 METHYLTHIAZOL 2 YL)ETHYL] 1,3,4 THIADIAZOL 2 YL]AMINO]PYRIDIN 2 OL; OXIDOREDUCTASE INHIBITOR; THIADIAZOLE DERIVATIVE; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG; BACTERIAL PROTEIN; INHA PROTEIN, MYCOBACTERIUM; OXIDOREDUCTASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIAL GROWTH; CARBON NUCLEAR MAGNETIC RESONANCE; CONTROLLED STUDY; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; LUNG TUBERCULOSIS; MEMBRANE PERMEABILITY; MINIMUM INHIBITORY CONCENTRATION; MOUSE; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PHYSICAL CHEMISTRY; ANIMAL; ANTAGONISTS AND INHIBITORS; C57BL MOUSE; CHEMISTRY; HEPG2 CELL LINE; HUMAN; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANIMALS; ANTITUBERCULAR AGENTS; BACTERIAL PROTEINS; DRUG DESIGN; FEMALE; HEP G2 CELLS; HUMANS; MICE; MICE, INBRED C57BL; OXIDOREDUCTASES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THIADIAZOLES;

EID: 84921454584     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm501029r     Document Type: Article

References (48)

1. WHO Global Tuberculosis Report 2014; World Health Organization: Geneva, 2014; http://www.who.int/tb/publications/global-report/en/ (accessed February 11, 2014).
2. Zumla, A.; Hafner, R.; Lienhardt, C.; Hoelscher, M.; Nunn, A. Advancing the development of tuberculosis therapy Nature Rev. Drug Discovery 2012, 11, 170-171
3. Jain, A.; Mondal, R. Extensively drug-resistant tuberculosis: current challenges and threats FEMS Immunol. Med. Microbiol. 2008, 53, 145-150
4. Global Tuberculosis Report 2013; World Health Organization: Geneva, 2013; http://www.who.int/tb/publications/factsheet-global.pdf (accessed on February 11, 2014).
5. Udwadia, Z. F.; Amale, R. A.; Ajbani, K. K.; Rodrigues, C. Totally drug-resistant tuberculosis in India Clin. Infect. Dis. 2012, 54, 579-581
6. Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. The challenge of new drug discovery for tuberculosis Nature 2011, 469, 483-490
7. Palomino, J. C.; Martin, A. TMC207 becomes bedaquiline, a new anti-TB drug Future Microbiol. 2013, 8, 1071-1080
8. Fox, G. J.; Menzies, D. A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis Infect. Dis. Ther. 2013, 2, 123-144
9. Ballell, L.; Field, R. A.; Duncan, K.; Young, R. J. New small-molecule synthetic antimycobacterials Antimicrob. Agents Chemother. 2005, 49, 2153-2163
10. Cole, S. T.; Riccardi, G. New tuberculosis drugs on the horizon Curr. Opin. Microbiol. 2011, 14, 570-576
11. Gerusz, V.; Denis, A.; Faivre, F.; Bonvin, Y.; Oxoby, M.; Briet, S.; LeFralliec, G.; Oliveira, C.; Desroy, N.; Raymond, C.; Peltier, L.; Moreau, F.; Escaich, S.; Vongsouthi, V.; Floquet, S.; Drocourt, E.; Walton, A.; Prouvensier, L.; Saccomani, M.; Durant, L.; Genevard, J. M.; Sam-Sambo, V.; Soulama-Mouze, C. From Triclosan toward the clinic: discovery of nonbiocidal, potent FabI inhibitors for the treatment of resistant bacteria J. Med. Chem. 2012, 55, 9914-9928
12. Wright, H. T.; Reynolds, K. A. Antibacterial targets in fatty acid biosynthesis Curr. Opin. Microbiol. 2007, 10, 447-453
13. Zhang, Y. M.; White, S. W.; Rock, C. O. Inhibiting bacterial fatty acid synthesis J. Biol. Chem. 2006, 281, 17541-17544
14. Parikh, S.; Moynihan, D. P.; Xiao, G. P.; Tonge, P. J. Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis Biochemistry 1999, 38, 13623-13634
15. Dessen, A.; Quemard, A.; Blanchard, J. S.; Jacobs, W. R.; Sacchettini, J. C. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis Science 1995, 267, 1638-1641
16. Rozwarski, D. A.; Vilcheze, C.; Sugantino, M.; Bittman, R.; Sacchettini, J. C. Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD(+) and a C16 fatty acyl substrate J. Biol. Chem. 1999, 274, 15582-15589
17. Rawat, R.; Whitty, A.; Tonge, P. J. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 13881-13886
18. Hazbon, M. H.; Brimacombe, M.; del Valle, M. B.; Cavatore, M.; Guerrero, M. I.; Varma-Basil, M.; Billman-Jacobe, H.; Lavender, C.; Fyfe, J.; Garcia-Garcia, L.; Leon, C. I.; Bose, M.; Chaves, F.; Murray, M.; Eisenach, K. D.; Sifuentes-Osornio, J.; Cave, M. D.; de Leon, A. P.; Alland, D. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobactetium tuberculosis Antimicrob. Agents Chemother. 2006, 50, 2640-2649
19. Morlock, G. P.; Metchock, B.; Sikes, D.; Crawford, J. T.; Cooksey, R. C. EthA, InhA, and KatG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates Antimicrob. Agents Chemother. 2003, 47, 3799-3805
20. Freundlich, J. S.; Wang, F.; Vilcheze, C.; Gulten, G.; Langley, R.; Schiehser, G. A.; Jacobus, D. R.; Jacobs, W. R.; Sacchettini, J. C. Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis ChemMedChem 2009, 4, 241-248
21. Parikh, S. L.; Xiao, G. P.; Tonge, P. J. Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid Biochemistry 2000, 39, 7645-7650
22. Kuo, M. R.; Morbidoni, H. R.; Alland, D.; Sneddon, S. F.; Gourlie, B. B.; Staveski, M. M.; Leonard, M.; Gregory, J. S.; Janjigian, A. D.; Yee, C.; Musser, J. M.; Kreiswirth, B.; Iwamoto, H.; Perozzo, R.; Jacobs, W. R.; Sacchettini, J. C.; Fidock, D. A. Targeting tuberculosis and malaria through inhibition of enoyl reductase J. Biol. Chem. 2003, 278, 20851-20859
23. Sivaraman, S.; Sullivan, T. J.; Johnson, F.; Novichenok, P.; Cui, G. L.; Simmerling, C.; Tonge, P. J. Inhibition of the bacterial enoyl reductase FabI by triclosan: A structure-reactivity analysis of FabI inhibition by triclosan analogues J. Med. Chem. 2004, 47, 509-518
24. Ballell Pages, L.; Castro Pichel, J.; Fernandez Menendez, R.; Fernandez Velando, E. P.; Gonzalez del Valle, S.; Leon Diaz, M. L.; Mendoza Losana, A.; Wolfendale, M. J. (Pyrazol-3-yl)-1,3,4-thiadiazole- 2-amine and (Pyrazol-3-yl)-1,3,4-thiazol-2-amine Compounds. WO/2010/118852, 2010.
25. Shirude, P. S.; Madhavapeddi, P.; Naik, M.; Murugan, K.; Shinde, V.; Nandishaiah, R.; Bhat, J.; Kumar, A.; Hameed, S.; Holdgate, G.; Davies, G.; McMiken, H.; Hegde, N.; Ambady, A.; Venkatraman, J.; Panda, M.; Bandodkar, B.; Sambandamurthy, V. K.; Read, J. A. Methyl-thiazoles: a novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in Mycobacterium tuberculosis J. Med. Chem. 2013, 56, 8533-8542
26. Crosby, J.; Stone, R.; Lienhard, G. E. Mechanisms of thiamine-catalyzed reactions-decarboxylation of 2-(1-carboxy-1-hydroxyethyl)-3,4-dimethylthiazolium chloride J. Am. Chem. Soc. 1970, 92, 2891-2900
27. Siwek, A.; Paneth, P. Computational studies of the cyclization of thiosemicarbazides J. Phys. Org. Chem. 2007, 20, 463-468
28. Young, R. J.; Green, D. V. S.; Luscombe, C. N.; Hill, A. P. Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity Drug Discovery Today 2011, 16, 822-830
29. Hill Hill, A. P.; Young, R. J. Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity Drug Discovery Today 2010, 15, 648-655
30. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9, 430-431
31. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nature Rev. Drug Discovery 2007, 6, 881-890
32. Murray, C. W.; Erlanson, D. A.; Hopkins, A. L.; Keseru, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H.; Richmond, N. J. Validity of ligand efficiency metrics ACS Med. Chem. Lett. 2014, 5, 616-618
33. Rinaki, E.; Valsami, G.; Macheras, P. Quantitative biopharmaceutics classification system: the central role of dose/solubility ratio Pharm. Res. 2003, 20, 1917-1925
34. Kasim, N. A.; Whitehouse, M.; Ramachandran, C.; Bermejo, M.; Lennernas, H.; Hussain, A. S.; Junginger, H. E.; Stavchansky, S. A.; Midha, K. K.; Shah, V. P.; Amidon, G. L. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification Mol. Pharmaceutics 2004, 1, 85-96
35. Drug Interaction Studies-Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations; Center for Drug Evaluation and Research, Food and Drug Administration: Silver Spring, MD, 2012; http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf (accessed on February 11, 2014).
36. Lewis, D. F. V. Modelling human cytochromes P450 involved in drug metabolism from the CYP2C5 crystallographic template J. Inorg. Biochem. 2002, 91, 502-514
37. Lewis, D. F. V. Molecular modeling of human cytochrome P450-substrate interactions Drug Metab. Rev. 2002, 34, 55-67
38. Lewis, D. F. V. 57 varieties: the human cytochromes P450 Pharmacogenomics 2004, 5, 305-318
39. Lewis, D. F. V. Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450CYP2 family enzymes Toxicol. in Vitro 2004, 18, 89-97
40. Lewis, D. F. V.; Dickins, M. Factors influencing rates and clearance in P450-mediated reactions: QSARs for substrates of the xenobiotic-metabolizing hepatic microsomal P450s Toxicology 2002, 170, 45-53
41. Lewis, D. F. V.; Jacobs, M. N.; Dickins, M. Compound lipophilicity for substrate binding to human P450s in drug metabolism Drug Discovery Today 2004, 9, 530-537
42. Lewis, D. F. V.; Jacobs, M. N.; Dickins, M.; Lake, B. G. Quantitative structure-activity relationships for inducers of cytochromes P450 and nuclear receptor ligands involved in P450 regulation within the CYP1, CYP2, CYP3 and CYP4 families Toxicology 2002, 176, 51-57
43. Lewis, D. F. V.; Modi, S.; Dickins, M. Structure-activity relationship for human cytochrome P450 substrates and inhibitors Drug Metab. Rev. 2002, 34, 69-82
44. Encinas, L.; OKeefe, H.; Neu, M.; Remuinan, M. J.; Patel, A. M.; Guardia, A.; Davie, C. P.; Perez-Macias, N.; Yang, H. F.; Convery, M. A.; Messer, J. A.; Perez-Herran, E.; Centrella, P. A.; Alvarez-Gomez, D.; Clark, M. A.; Huss, S.; ODonovan, G. K.; Ortega-Muro, F.; McDowell, W.; Castaneda, P.; Arico-Muendel, C. C.; Pajk, S.; Rullas, J.; Angulo-Barturen, I.; Alvarez-Ruiz, E.; Mendoza-Losana, A.; Pages, L. B.; Castro-Pichel, J.; Evindar, G. Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA J. Med. Chem. 2014, 57, 1276-1288
45. Hartkoorn, R. C.; Sala, C.; Neres, J.; Pojer, F.; Magnet, S.; Mukherjee, R.; Uplekar, S.; Boy-Rottger, S.; Altmann, K. H.; Cole, S. T. Towards a new tuberculosis drug: pyridomycin-natures isoniazid EMBO Mol. Med. 2012, 4, 1032-1042
46. Pan, P.; Knudson, S. E.; Bommineni, G. R.; Li, H. J.; Lai, C. T.; Liu, N. N.; Garcia-Diaz, M.; Simmerling, C.; Patil, S. S.; Slayden, R. A.; Tonge, P. J. Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy ChemMedChem 2014, 9, 776-791
47. Martin, A.; Camacho, M.; Portaels, F.; Palomino, J. C. Resazurin microtiter assay plate testing of Mycobacterium tuberculosis susceptibilities to second-line drugs: rapid, simple, and inexpensive method Antimicrob. Agents Chemother. 2003, 47, 3616-3619
48. Rullas, J.; Garcia, J. I.; Beltran, M.; Cardona, P. J.; Cáceres, N.; García-Bustos, J. F.; Angulo-Barturen, I. Fast standardized therapeutic efficacy assay for drug discovery against tuberculosis Antimicrob. Agents Chemother. 2010, 54, 2262-2264