Synthesis of Novel 2-amino-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile derivatives and their evaluation for anti-mycobacterial activity

Quinolone derivatives are one of the most active classes of chemotherapeutic agents and considered as important weapon against bacterial infections. Quinolones are versatile in their pharmacological activity. Now a day’s quinolones are used as novel target for tuberculosis. A series of novel 2-amino-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile derivatives and evaluate their anti-mycobacterial activity. The ethyl cyanoacetate was used as a starting material to synthesise ethyl-2,2-di(methylthio)methylene cyanoacetate (S,S-acetal), which was further treated with 3-chloro- 4-fluoro aniline under reflux condition to get ethyl 3-((3-chloro-4-fluorophenyl)amino)-2-cyano-3-(methylthio) acrylate (S,N-acetal). Ethyl-3-amino-3-((3-chloro-4-fluorophenyl)amino)-2-cyano-3-acrylate derivatives (N,N-acetal) were synthesized from S,N-acetal by treatment with substituted amines. N,N-acetals were treated with diphenylamine to get 2-amino derivatives of 7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile. All the synthesized compounds were screened for anti-mycobacterial activity by Alamar blue assay method using H37Rv strain. All the compounds were found to be active against the H37Rv strain. Compound 94a emerged out as most potent compound with MIC of 1.6 μg/ml against Mycobacteria as compared to standard drug ciprofloxacin (3.12 μg/ml). It was concluded that the cyano group at third position of quinolone instead of carboxyl group and alkyl chain at second position shows better anti-mycobacterial activity. Hence, synthesis of new series of quinolone derivatives has been of great interest in the elaboration of biologically active compounds for the control of mycobacterial infection.