title: Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis.
abstract: The mycobacterial F0F1-ATP synthase (ATPase) is a validated target for the development of tuberculosis (TB) therapeutics. Therefore, a series of eighteen novel compounds has been designed, synthesized and evaluated against Mycobacterium smegmatis ATPase. The observed ATPase inhibitory activities (IC50) of these compounds range between 0.36 and 5.45μM. The lead compound 9d [N-(7-chloro-2-methylquinolin-4-yl)-N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-2,3-dichlorobenzenesulfonamide] with null cytotoxicity (CC50>300μg/mL) and excellent anti-mycobacterial activity and selectivity (mycobacterium ATPase IC50=0.51μM, mammalian ATPase IC50>100μM, and selectivity >200) exhibited a complete growth inhibition of replicating Mycobacterium tuberculosis H37Rv at 3.12μg/mL. In addition, it also exhibited bactericidal effect (approximately 2.4log10 reductions in CFU) in the hypoxic culture of non-replicating M. tuberculosis at 100μg/mL (32-fold of its MIC) as compared to positive control isoniazid [approximately 0.2log10 reduction in CFU at 5μg/mL (50-fold of its MIC)]. The pharmacokinetics of 9d after p.o. and IV administration in male Sprague-Dawley rats indicated its quick absorption, distribution and slow elimination. It exhibited a high volume of distribution (Vss, 0.41L/kg), moderate clearance (0.06L/h/kg), long half-life (4.2h) and low absolute bioavailability (1.72%). In the murine model system of chronic TB, 9d showed 2.12log10 reductions in CFU in both lung and spleen at 173μmol/kg dose as compared to the growth of untreated control group of Balb/C male mice infected with replicating M. tuberculosis H37Rv. The in vivo efficacy of 9d is at least double of the control drug ethambutol. These results suggest 9d as a promising candidate molecule for further preclinical evaluation against resistant TB strains.
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Supriya
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Shaheb R
authors.initials: SR
authors.lastname: Khan
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Vivek Kr
authors.initials: VK
authors.lastname: Kashyap
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Abhisheak
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Jaiswal
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Manju Yasoda
authors.initials: MY
authors.lastname: Krishnan
authors.affiliation: Division of Drug Target Discovery and Development, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Chaturvedi
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
authors.affiliation: Division of Drug Target Discovery and Development, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Sinha
authors.forename: Arunava
authors.initials: A
authors.lastname: Dasgupta
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Arnab D
authors.initials: AD
authors.lastname: Gupta
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: anilsak@gmail.com.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000255:Adenosine Triphosphate; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D009165:Mycobacterium Infections, Nontuberculous / Q000188:drug therapy / Q000382:microbiology; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011804:Quinolines; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases
keywords: ATP synthase; Dormancy; Quinoline; Sulfonamide; Tuberculosis