Novel N-linked aminopiperidine-based gyrase inhibitors with improved hERG and in vivo efficacy against mycobacterium tuberculosis

Journal of Medicinal Chemistry

Volumn 57, Issue 11, 2014, Pages 4889-4905

  Hameed P, Shahul ^a   Patil, Vikas ^a   Solapure, Suresh ^a   Sharma, Umender ^a   Madhavapeddi, Prashanti ^a   Raichurkar, Anandkumar ^a   Chinnapattu, Murugan ^a   Manjrekar, Praveena ^a   Shanbhag, Gajanan ^a   Puttur, Jayashree ^a   Shinde, Vikas ^a   Menasinakai, Sreenivasaiah ^a   Rudrapatana, Suresh ^a   Achar, Vijayashree ^a   Awasthy, Disha ^a   Nandishaiah, Radha ^a   Humnabadkar, Vaishali ^a   Ghosh, Anirban ^a   Narayan, Chandan ^a   Ramya, V K ^a   Kaur, Parvinder ^a   Sharma, Sreevalli ^a   Werngren, Jim ^c   Hoffner, Sven ^c   Panduga, Vijender ^a   Kumar, C N Naveen ^a   Reddy, Jitendar ^a   Kumar Kn, Mahesh ^a   Ganguly, Samit ^a   Bharath, Sowmya ^a   Bheemarao, Ugarkar ^a   Mukherjee, Kakoli ^a   Arora, Uma ^a   Gaonkar, Sheshagiri ^a   Coulson, Michelle ^a   Waterson, David ^b   Sambandamurthy, Vasan K ^a   De Sousa, Sunita M ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b Medicines for Malaria Venture MMV   (Switzerland)

^c SWEDISH INSTITUTE FOR INFECTIOUS DISEASE CONTROL   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 [4 [(5 CYANO 6 METHYLPYRIDIN 3 YL)METHYLAMINO]PIPERDIN 1 YL]ETHYL] 2 OXO 1,2 DIHYDROQUINOLINE 7 CARBONITRILE; 5 [[1 [2 (7 METHOXY 2 OXO 1,5 NAPHTHYRIDIN 1(2H) YL)ETHYL]PIPERIDIN 4 YLAMINO]METHYL] 2 METHYLNICOTINONITRILE; 6 [[3 FLUORO 1 [2 (7 FLUORO 2 OXO 1,5 NAPHTHYRIDIN 1(2H) YL)ETHYL]PIPERIDIN 4 YLAMINO]METHYL] 2H PYRIDOL[3,2 B][1,4]OXAZIN 3(4H) ONE; 6 [[3 FLUORO 1 [2 (7 FLUORO 2 OXO 1,5 NAPHTHYRIDIN 1(2H) YL)ETHYL]PIPERIDIN 4 YLAMINO]METHYL] 2H PYRIDO[3,2 B][1,4]OXAZIN 3(4H) ONE; 6 [[3 FLUORO 1 [2 (7 METHOXY 2 OXO 1,5 NAPHTHYRIDIN 1(2H) YL)ETHYL]PIPERIDIN 4 YLAMINO]METHYL] 2H PYRIDO[3,2 B][1,4]OXAZIN 3(4H) ONE; ALKYL GROUP; AMINOPIPERIDINE DERIVATIVE; AMINOPYRAZINAMIDE DERIVATIVE; ANTIINFECTIVE AGENT; BACTERIAL ENZYME; BISTHIAZOLE DERIVATIVE; CIPROFLOXACIN; DNA TOPOISOMERASE (ATP HYDROLYSING); GSK 299423; GSK 966587; GYRASE INHIBITOR; ION CHANNEL; ISONIAZID; MOXIFLOXACIN; NAPHTHYRIDONE DERIVATIVE; POTASSIUM CHANNEL HERG; PYRROLAMIDE DERIVATIVE; QUINOLONE DERIVATIVE; RIFAMPICIN; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ALKYLATION; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBACTERIAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BACTERIAL GROWTH; BACTERICIDAL ACTIVITY; CONTROLLED STUDY; DNA CLEAVAGE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG MECHANISM; DRUG PENETRATION; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; IN VIVO STUDY; MACROPHAGE; MINIMUM INHIBITORY CONCENTRATION; MOLECULAR DOCKING; MOUSE; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PHARMACODYNAMICS; RAT; STRUCTURE ACTIVITY RELATION; TUBERCULOSIS;

ACUTE DISEASE; ADMINISTRATION, ORAL; ANIMALS; ANTITUBERCULAR AGENTS; BACTERIAL PROTEINS; BIOLOGICAL AVAILABILITY; CHRONIC DISEASE; DNA GYRASE; DRUG RESISTANCE, BACTERIAL; ETHER-A-GO-GO POTASSIUM CHANNELS; FLUOROQUINOLONES; HUMANS; MACROPHAGES; MICE, INBRED BALB C; MICROBIAL SENSITIVITY TESTS; MOLECULAR DOCKING SIMULATION; MUTATION; MYCOBACTERIUM TUBERCULOSIS; PIPERIDINES; PROTEIN SUBUNITS; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TOPOISOMERASE II INHIBITORS; TUBERCULOSIS, PULMONARY;

EID: 84902499633     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500432n     Document Type: Article

References (43)

1. World Health Organization. Global tuberculosis control. WHO 2012 report (http://www.who.int/mediacentre/news/releases/2011/tb-20111011/en/index.html); WHO: Geneva, 2012.
2. World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB); WHO 2010 Global report on surveillance and response; WHO: Geneva, 2010.
3. Cole, S. T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher1, C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.; Barry, C. E., III; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M. A.; Rajandream, M.-A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J. E.; Taylor, K.; Whitehead, S.; Barrell, B. G. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence Nature 1998, 393, 537-544 (Pubitemid 28319235)
4. Sharma, U. Current possibilities and unresolved issues of drug target validation in Mycobacterium tuberculosis Expert Opin. Drug Discovery 2011, 6, 1171-1186
5. Burman, W. J.; Goldberg, S.; Johnson, J. L.; Muzanye, G.; Engle, M.; Mosher, A. W.; Choudhari, S.; Daley, C. L.; Munsiff, S. S.; Zhao, Z.; Vernon, A.; Chaisson, R. E. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis Am. J. Respir. Crit. Care Med. 2006, 174, 331-338 (Pubitemid 44156613)
6. Conde, M. B.; Efron, A.; Loredo, C.; De Souza, G. R.; Graca, N. P.; Cezar, M. C.; Ram, M.; Chaudhary, M. A.; Bishai, W. R.; Kritski, A. L.; Chaisson, R. E. Moxifloxacin in the initial therapy of tuberculosis: A randomized, phase 2 trial Lancet 2009, 373, 1183-1189
7. Diacon, A. H.; Dawson, R.; von Groote-Bidlingmaler, F.; Symons, G.; Venter, A.; Donald, P. R.; van Niekerk, C.; Everitt, D.; Winter, H.; Becker, P.; Mendel, C. M.; Spigelman, M. K. 14 day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: A randomized trial Lancet 2012, 380, 986-993
8. Duong, D. A.; Nguyen, T. H.; Nguyen, T. N.; Dai, V. H.; Dang, T. M.; Vo, S. K.; Do, D. A.; Nguyen, V. V.; Nguyen, H. D.; Dinh, N. S.; Farrar, J.; Caws, M. Beijing genotype of Mycobacterium tuberculosis is significantly associated with high-level fluoroquinolone resistance in Vietnam Antimicrob. Agents Chemother. 2009, 53, 4835-4839
9. Drlica, K.; Malik, M.; Kerns, R. J.; Zhao, X. Quinolone-mediated bacterial death Antimicrob. Agents Chemother. 2008, 52, 385-392 (Pubitemid 351170804)
10. Bisacchi, G S.; Dumas, J. Recent advances in the inhibition of bacterial type II topoisomerases. In Annual Reports in Medicinal Chemistry; Macor, J. E., Ed.; Academic Press: Burlington, MA, 2009; Vol. 44, pp 379-396.
11. Shirude, P. S.; Hameed, S. Nonfluoroquinolone-based inhibitorsof mycobacterial type II topoisomerase as potential therapeutic agentsfor TB. In Annual Reports in Medicinal Chemistry; Desai, M. C., Ed.; Academic Press: Burlington, MA, 2012; Vol. 47, pp 319-330.
12. Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry, D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.; Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.; Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Shillings, A.; Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Type IIA topoisomerase inhibition by a new class of antibacterial agents Nature 2010, 466, 935-940
13. Tretter, E. M.; Schoeffler, A. J.; Weisfild, S. R.; Berger, J. M. Crystal structure of the DNA gyrase GyrA N-terminal domain from Mycobacterium tuberculosis Proteins 2010, 78, 492-495
14. Breault, G.; Eyermann, C. J.; Geng, B.; Morningstar, M.; Reck, F. Preparation of quinolinones and analogs for the treatment of multi-drug resistant bacterial infections. WO2006134378, 2006.
15. Janelle, C. P.; Mark, C.; Geng, B.; Aydon, G. A.; Reck, F. Preparation of 2-quinolinone and 2-quinoxalinone derivatives as antibacterial agents. WO2008071961, 2008.
16. Breault, G.; Vincent, G.; Reck, F. Preparation of naphthyridines as bactericides for treating bacterial infections. WO2008071964, 2008.
17. Geng, B.; Morningstar, M.; Reck, F. Preparation of piperidines for the treatment of bacterial infections. WO2008071981, 2008.
18. Reck, F.; Alm, R.; Brassil, P.; Newman, J.; DeJonge, B.; Eyermann, C. J.; Breault, G.; Breen, J.; Comita-Prevoir, J.; Cronin, M.; Davis, H.; Ehmann, D.; Galullo, V.; Geng, B.; Grebe, T.; Morningstar, M.; Walker, P.; Hayter, B.; Fisher, S. Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: Broad-spectrum antibacterial agents with reduced hERG activity J. Med. Chem. 2011, 54, 7834-7847
19. Reck, F.; Alm, R.; Brassil, P.; Newman, J.; Ciaccio, P.; McNulty, J.; Barthlow, H.; Goteti, K.; Breen, J.; Comita-Prevoir, J.; Cronin, M.; Ehmann, D.; Geng, B.; Godfrey, A.; Fisher, S. Novel N-Linked aminopiperidine inhibitors of bacterial topoisomerase type II with reduced pKa: Antibacterial agents with an improved safety profile J. Med. Chem. 2012, 55, 6916-6933
20. Alemparte-Gallardo, C.; Ballell-Pages, L.; Barros-Aguirre, D.; Cacho-Izquierdo, M.; Castro-Pichel, J.; Fiandor Roman, J. M.; Hennessy, A. J.; Pearson, N. D.; Remuinan-Blanco, J. M. Naphthyridin-2(1 H)-one compounds as antibacterial agents and their preparation, pharmaceutical compositions and use in the treatment of tuberculosis. WO 2009090222, 2009.
21. Alemparte-Gallardo, C.; Barfoot, C.; Barros-Aguirre, D.; Cacho-Izquierdo, M.; Fiandor Roman, J. M.; Hennessy, A. J.; Pearson, N. D.; Remuinan-Blanco, M. J. Preparation of tricyclic nitrogen containing compounds as antibacterials. WO2009141398, 2009.
22. Alemparte-Gallardo, C.; Barros-Aguirre, D.; Cacho-Izquierdo, M.; Fiandor-Roman, J. M.; Lavandera Diaz, J. L.; Remuinan-Blanco, M. J. Naphthyridin-2(1 H)-one compounds as antibacterials and their preparation and use for the treatment of bacterial infections. WO2010081874, 2010.
23. Miles, T. J.; Hennessy, A. J.; Bax, B.; Brooks, G.; Brown, B. S.; Brown, P.; Cailleau, N.; Chen, D.; Dabbs, S.; Davies, T. D.; Esken, J. M.; Giordano, L.; Hoover, J. L.; Huang, J.; Jones, G. E.; Sukmar, S. K. K.; Spitzfaden, C.; Markwell, R. E.; Mlingthorn, E. A.; Rittenhouse, S.; Gwynn, M. N.; Pearson, N. D. Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases Bioorg. Med. Chem. Lett. 2013, 23, 5437-5441
24. Barrows, D. Recent advances in TB drug development. 40th IUATLD Meeting, Cancun, Mexico, 2009.
25. Presentations, 2009. http://www.newtbdrugs.org/eventfiles/p4/ Novel%20Mtb%20DNA%20Gyrase%20inhibitors-The%20Union-40th.pdf.
26. Eric, A. V.; Hao, Y.; Susan, V. D.; Stacie, A. C.; Hayao, M.; Ilaria, G.; Alan, J. H.; Richard, M. G.; Jeffery, L. W. Target-directed synthesis of antibacterial drug candidate GSK966587 Org. Lett. 2010, 12, 3422-3425
27. Ballell, L.; Barros, D.; Brooks, G.; Castro, P. J.; Dabbs, S.; Daines, R. A.; Davies, D. T.; Fiandor, R. J. M.; Giardano, I.; Hennessy, A. J.; Hoffman, J. B.; Jones, G. E.; Miles, T. J.; Peason, N. D.; Pendrak, I.; Remuinan, B. M. J.; Rossi, J. A.; Zhang, L. L. Derivatives and analog of N -ethylquinolones and N -ethylazaquinolones as antibacterial agents and their preparation. WO2008009700, 2008.
28. Brooks, G.; Dabbs, S.; Davies, T. D.; Hennessy, A. J.; Jones, G. E.; Markwell, R. E.; Miles, T. J.; Owston, N. A.; Pearson, N. D.; Peng, T. W. The design of efficient and selective routes to pyridyl analogues of 3-oxo-3,4-dihydro-2 H -1,4-(benzothiazine or benzoxazine)-6-carbaldehydes Tetrahedron Lett. 2010, 51, 5035-5037
29. Hameed, P. S.; Shanbhag, G.; Shinde, V.; Chinnapattu, M.; Manjrekar, P.; Puttur, J.; Patil, V.; Ugarkar, B. Short and efficient synthesis of oxazinone and thiazinone containing bicyclic heteroaromatic aldehydes Syn.com. 2013, 43, 3315-3321
30. Shandil, R. K.; Jayaram, R.; Kaur, P.; Gaonkar, S.; Suresh, B. L.; Mahesh, B. N.; Jayashree, R.; Nandi, V.; Bharath, S.; Balasubramanian, V. Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis: Evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy Antimicrob. Agents Chemother. 2007, 51, 576-82 (Pubitemid 46185275)
31. Brvar, M.1.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors J. Med. Chem. 2012, 55, 6413-6426
32. Shirude, P. S.; Madhavapeddi, P.; Tucker, J. A.; Murugan, K.; Patil, V.; Basavarajappa, H.; Raichurkar, A. V.; Humnabadkar, V.; Hussein, S.; Sharma, S.; Ramya, V. K.; Narayan, C. B.; Balganesh, T. S.; Sambandamurthy, V. K. Aminopyrazinamides. Novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis ACS Chem. Biol. 2013, 8, 519-523
33. Kale, M. G.; Raichurkar, A.; Hameed, S. P.; Waterson, D.; McKinney, D.; Manjunatha, M. R.; Kranthi, U.; Koushik, K.; Jena, L.; Shinde, V.; Rudrapatna, S.; Barde, S.; Humnabadkar, V.; Madhavapeddi, P.; Basavarajappa, H.; Ghosh, A.; Ramya, V. K.; Guptha, S.; Sharma, S.; Vachaspati, P.; Mahesh Kumar, K. N.; Giridhar, J.; Reddy, J.; Panduga, V.; Ganguly, S.; Ahuja, V.; Gaonkar, S.; Naveen Kumar, C. N.; Ogg, D.; Tucker, J. A.; Bori-ack-Sjodin, A. P.; de Sousa, S. M.; Sambandamurthy, V. K.; Ghorpade, S. R. Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA gyrase B J. Med. Chem. 2013, 56, 8834-8848
34. Hameed, S. P.; Solapure, S.; Mukherjee, K.; Nandi, V.; Waterson, D.; Shandil, R.; Balganesh, M.; Sambandamurthy, V. K.; Raichurkar, A.; Deshpande, A.; Ghosh, A.; Awasthy, D.; Shanbhag, G.; Sheikh, G.; McMiken, H.; Puttur, P.; Reddy, J.; Werngren, J.; Read, J.; Kumar, M.; Ramaiah, M.; Chinnapattu1, M.; Madhavapeddi, P.; Manjrekar, P.; Basu, R.; Gaonkar, S.; Sharma, S.; Hoffner, S.; Humnabadkar, V.; Subbulakshmi, V.; Panduga, V. Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: Structure-activity relationship and in vivo efficacy in a mouse model of tuberculosis Antimicrob. Agents Chemother. 2013, 58, 6-70
35. Kale, R. R.; Kale, M. G.; Waterson, D.; Raichurkar, A.; Hameed, S. P.; Manjunatha, M. R.; Kishore Reddy, B. K.; Malolanarasimhan, K.; Shinde, V.; Koushik, K.; Jena, L. K.; Menasinakai, S.; Humnabadkar, V.; Madhavapeddi, P.; Basavarajappa, H.; Sharma, S.; Nandishaiah, R.; Mahesh Kumar, K. N.; Ganguly, S.; Ahuja, V.; Gaonkar, S.; Naveen Kumar, C. N.; Ogg, D.; Boriack-Sjodin, P. A.; Sambandamurthy, V. K.; de Sousa, S. M.; Ghorpade, S. R. Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy Bioorg. Med. Chem. Lett. 2014, 24, 870-879
36. ROCS 3.2.0.4; OpenEye Scientific Software, Santa Fe, NM. http://www.eyesopen.com.
37. Hawkins, P. C. D.; Skillman, A. G.; Nicholls, A. Comparison of shape-matching and docking as virtual screening tools J. Med. Chem. 2007, 50, 74-82 (Pubitemid 46105500)
38. Molecular operating environment (MOE), 2013.08; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada H3A 2R7, 2013.
39. FRED 2.0; OpenEye scientific software, Santa Fe, NM. http://www.eyesopen. com.
40. McGann, M. FRED pose prediction and virtual screening accuracy J. Chem. Inf. Model 2011, 51, 578-596
41. McGrath, M.; Gey van Pittius, N. C.; Sirgel, F. A.; Van Helden, P. D.; Warren, R. M. Moxifloxacin retains anti-mycobacterial activity in the presence of gyrA mutations Antimicrob. Agents Chemother. 2014, 58, 2912-2915
42. Jayaram, R.; Gaonkar, S.; Kaur, P.; Suresh, B. L.; Mahesh, B. N.; Jayashree, R.; Nandi, V.; Bharat, S.; Shandil, R. K.; Kantharaj, E.; Balasubramanian, V. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis Antimicrob. Agents Chemother. 2003, 47, 2118-2124 (Pubitemid 36753560)
43. Huitric, E.; Verhasselt, P.; Andries, K.; Hoffner, S. E. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor Antimicrob. Agents Chemother. 2007, 51, 4202-4204 (Pubitemid 350057830)