Novel quinoline and naphthalene derivatives as potent antimycobacterial agents.
We have designed and synthesized both the quinoline and naphthalene based molecules influenced by the unique structural make-up of mefloquine and TMC207, respectively. These compounds were evaluated for their anti-mycobacterial activity against drug sensitive Mycobacterium tuberculosis H37Rv in vitro at single-dose concentration (6.25 microg/mL). The compounds 22, 23, 26 and 27 inhibited the growth of M. tuberculosis H37Rv 99%, 90%, 98% and 91% respectively. Minimum inhibitory concentration of compounds 22, 23, 26 and 27 was found to be 6.25 microg/mL. Our molecular modeling and docking studies of designed compounds showed hydrogen bonding with Glu-61, Tyr-64 and Asn-190 amino acid residues at the putative binding site of ATP synthase, these interactions were coherent as shown by Mefloquine and TMC207, where hydrogen bonding was found with Tyr-64 and Glu-61 respectively. SAR analysis indicates importance of hydroxyl group and nature of substituents on piperazinyl-phenyl ring was critical in dictating the biological activity of newly synthesized compounds.
Institute of Molecular Medicine, Pune 411 057, Maharashtra, India.
Ram Shankar
RS
Upadhayaya
Jaya Kishore
JK
Vandavasi
Ramakant A
RA
Kardile
Santosh V
SV
Lahore
Shailesh S
SS
Dixit
Hemantkumar S
HS
Deokar
Popat D
PD
Shinde
Manash P
MP
Sarmah
Jyoti
J
Chattopadhyaya
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009281:Naphthalenes; D011804:Quinolines; C031721:naphthalene; C037219:quinoline