Lead optimization of 1,4-azaindoles as antimycobacterial agents

Journal of Medicinal Chemistry

Volumn 57, Issue 13, 2014, Pages 5728-5737

  Shirude, Pravin S ^a,c   Shandil, Radha K ^a   Manjunatha, M R ^a   Sadler, Claire ^a   Panda, Manoranjan ^a   Panduga, Vijender ^a   Reddy, Jitendar ^a   Saralaya, Ramanatha ^a   Nanduri, Robert ^a   Ambady, Anisha ^a   Ravishankar, Sudha ^a   Sambandamurthy, Vasan K ^a   Humnabadkar, Vaishali ^a   Jena, Lalit K ^a   Suresh, Rudrapatna S ^a   Srivastava, Abhishek ^a   Prabhakar, K R ^a   Whiteaker, James ^a   McLaughlin, Robert E ^a   Sharma, Sreevalli ^a   Cooper, Christopher B ^b   Mdluli, Khisi ^b   Butler, Scott ^a   Iyer, Pravin S ^a   Narayanan, Shridhar ^a   Chatterji, Monalisa ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT   (United States)

^c SAI Life Sciences Ltd   (India)

Author keywords

[No Author keywords available]

Indexed keywords

1 [(3,5 DIMETHYLPYRAZIN 2 YL)METHYL] N (2 FLUOROETHYL) 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [(5 FLUORO 2 METHOXYPYRIDIN 3 YL)METHYL] N (2 FLUOROPORPYL) 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [[6 (DIFLUOROMETHOXY) 5 METHYLPYRIMIDIN 4 YL]METHYL] N (2 HYDROXYETHYL) 6 METHOXY 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [[6 (DIFLUOROMETHOXY) 5 METHYLPYRIMIDIN 4 YL]METHYL] N (2 HYDROXYETHYL) 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [[6 (DIMETHYLAMINO) 5 METHYLPYRIMIDIN 4 YL]METHYL] N (2 FLUOROETHYL) 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [[6 (DIMETHYLAMINO) 5 METHYLPYRIMIDIN 4 YL]METHYL] N (2 FLUOROETHYL) 6 METHOXY 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [[6 (DIMETHYLAMINO) 5 METHYLPYRIMIDIN 4 YL]METHYL] N (2 HYDROXYETHYL) 6 METHOXY 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1 [[6 (DIMETHYLAMINO) 5 METHYLPYRIMIDIN 4 YL]METHYL] N (2 HYDROXYETHYL) 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; 1,4 AZAINDOLE DERIVATIVE; INDOLE DERIVATIVE; ISONIAZID; MOXIFLOXACIN; N (2 FLUOROETHYL) 1 [(6 METHOXY 5 METHYLPYRIMIDIN 4 YL)METHYL] 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2 FLUOROETHYL) 1 [(6 METHOXY 5 METHYLPYRIMIDIN 4 YL)METHYL] 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2 FLUOROETHYL) 6 METHOXY 1 [(6 METHOXY 5 METHYLPYRIDIN 4 YL)METHYL] 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2 FLUOROETHYL) 6 METHYL 1 [[3 METHYL 4 (2,2,2 TRIFLUOROETHOXY)PYRIDIN 2 YL]METHYL] 1H PYRROLO[3,2 B] PYRIDINE 3 CARBOXAMIDE; N (2 HYDROXYETHYL) 1 [(6 METHOXY 5 METHYLPYRIMIDIN 4 YL)METHYL] 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2 HYDROXYETHYL) 1 [[2 METHOXY 5 (TRIFLUOROMETHYL) PYRIDI 3 YL]METHYL] 6 METHYL 1H PYRROL[3,2 B]PYRDIINE 3 CARBOXAMIDE; N (2 HYDROXYETHYL) 6 METHOXY 1 [(6 METHOXY 5 METHYLPYRIDIN 4 YL)METHYL] 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2,2 DIFLUOROETHYL) 1 [(6 METHOXY 5 METHYLPYRIMIDIN 4 YL)METHYL] 6 METHYL 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2,2 DIFLUOROETHYL) 1 [[6 (DIFLUOROMETHOXY) 5 METHYLPYRIMIDIN 4 YL]METHYL] 6 METHOXY 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2,2 DIFLUOROETHYL) 1 [[6 (DIMETHYLAMINO) 5 METHYLPYRIMIDIN 4 YL]METHYL] 6 METHOXY 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (2,2 DIFLUOROETHYL) 6 METHOXY 1 [(6 METHOXY 5 METHYLPYRIDIN 4 YL)METHYL] 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; N (CYCLOPROPYLMETHYL) 1 [(6 METHOXY 5 METHYLPYRIMIDIN 4 YL)METHYL] 1H PYRROLO[3,2 B]PYRIDINE 3 CARBOXAMIDE; PHOSPHODIESTERASE VI; PHOSPHODIESTERASE VII INHIBITOR; RIFAMPICIN; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; BACTERICIDAL ACTIVITY; CONTROLLED STUDY; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG PROTEIN BINDING; ENZYME INHIBITION; HUMAN; HUMAN CELL; IN VITRO STUDY; LIVER MICROSOME; MAXIMUM PLASMA CONCENTRATION; MINIMUM INHIBITORY CONCENTRATION; MOUSE; MYCOBACTERIUM SMEGMATIS; NONHUMAN; PHYSICAL CHEMISTRY; RAT; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION; TUBERCULOSIS;

ANIMALS; ANTITUBERCULAR AGENTS; BACTERIAL PROTEINS; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 6; DISEASE MODELS, ANIMAL; HUMANS; INDOLES; MICE; MYCOBACTERIUM TUBERCULOSIS; OXIDOREDUCTASES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84904364464     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500571f     Document Type: Article

References (12)

1. Global Tuberculosis Report 2013; World Health Organization: Geneva, Switzerland, 2013.
2. Raviglione, M.; Marais, B.; Floyd, K.; Lönnroth, K.; Getahun, H.; Migliori, G. B.; Harries, A. D.; Nunn, P.; Lienhardt, C.; Graham, S.; Chakaya, J.; Weyer, K.; Cole, S.; Kaufmann, S. H.; Zumla, A. Scaling up interventions to achieve global tuberculosis control: progress and new developments Lancet 2012, 379, 1902-1913
3. Shirude, P. S.; Shandil, R.; Sadler, C.; Naik, M.; Hosagrahara, V.; Hameed, S.; Shinde, V.; Bathula, C.; Humnabadkar, V.; Kumar, N.; Reddy, J.; Panduga, V.; Sharma, S.; Ambady, A.; Hegde, N.; Whiteaker, J.; McLaughlin, B.; Gardner, H.; Madhavapeddi, P.; Ramachandran, V.; Kaur, P.; Narayan, A.; Guptha, S.; Awasthy, D.; Narayan, C.; Mahadevaswamy, J.; Vishwas, K. G.; Ahuja, V.; Srivastava, A.; Prabhakar, K. R.; Bharath, S.; Kale, R.; Ramaiah, M.; Roy Choudhury, N.; Sambandamurthy, V.; Solapure, S.; Iyer, P.; Narayanan, S.; Chatterji, M. Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo J. Med. Chem. 2013, 56, 9701-9708
4. Mikušová, K.; Huang, H.; Yagi, T.; Holsters, M.; Vereecke, D.; D'Haeze, W.; Scherman, M. S.; Brennan, P. J.; McNeil, M. R.; Crick, D. C. Decaprenylphosphoryl arabinofuranose, the donor of the d -arabinofuranosyl residues of mycobacterial arabinan, is formed via a two step epimerization of decaprenylphosphoryl ribose J. Bacteriol. 2005, 187, 8020-8025 (Pubitemid 41691695)
5. Makarov, V.; Manina, G.; Mikušová, K.; Möllmann, U.; Ryabova, O.; Saint-Joanis, B.; Dhar, N.; Pasca, M. R.; Buroni, S.; Lucarelli, A. P.; Milano, A.; De Rossi, E.; Belanova, M.; Bobovska, A.; Dianiskova, P.; Kordulakova, J.; Sala, C.; Fullam, E.; Schneider, P.; McKinney, J. D.; Brodin, P.; Christophe, T.; Waddell, S.; Butcher, P.; Albrethsen, J.; Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.; Gaonkar, S.; Shandil, R. K.; Balasubramanian, V.; Balganesh, T.; Tyagi, S.; Grosset, J.; Riccardi, G.; Cole, S. T. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis Science 2009, 324, 801-804
6. Glide6.1, small-molecule drug discovery suite 2013-3; Schrödinger, LLC: New York, 2013.
7. Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes J. Med. Chem. 2006, 49, 6177-6196 (Pubitemid 44595196)
8. Makarov, V.; Lechartier, B.; Zhang, M.; Neres, J.; Van der Sar, A. M.; Raadsen, S. A.; Hartkoorn, R. C.; Ryabova, O. B.; Vocat, A.; Decosterd, L. A.; Widmer, N.; Buclin, T.; Bitter, W.; Andries, K.; Pojer, F.; Dyson, P. J.; Cole, S. T. Towards a new combination therapy for tuberculosis with next generation benzothiazinones EMBO Mol. Med. 2014, 6, 372-383
9. Neres, J.; Pojer, F.; Molteni, E.; Chiarelli, L. R.; Dhar, N.; Boy-Röttger, S.; Buroni, S.; Fullam, E.; Degiacomi, G.; Lucarelli, A. P.; Read, R. J.; Zanoni, G.; Edmondson, D. E.; De Rossi, E.; Pasca, M. R.; McKinney, J. D.; Dyson, P. J.; Riccardi, G.; Mattevi, A.; Cole, S. T.; Binda, C. Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis Sci. Transl. Med. 2012, 4, 150ra121
10. Batt, S. M.; Jabeen, T.; Bhowruth, V.; Quill, L.; Lund, P. A.; Eggeling, L.; Alderwick, L. J.; Futterer, K.; Besra, G. S. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 11354-11359
11. Sassetti, C. M.; Boyd, D. H.; Rubin, E. J. Genes required for mycobacterial growth defined by high density mutagenesis Mol. Microbiol. 2003, 48, 77-84 (Pubitemid 36411469)
12. Gaonkar, S.; Bharath, S.; Kumar, N.; Balasubramanian, V.; Shandil, R. K. Aerosol infection model of tuberculosis in Wistar rats Int. J. Microbiol. 2010, 426035