Bioevaluation of quinoline-4-carbonyl derivatives of piperazinyl-benzothiazinones as promising antimycobacterial agents

The quinoline moiety remains a privileged antitubercular (anti-TB) pharmacophore, whereas 8-nitrobenzothiazinones are emerging potent antimycobacterial agents with two investigational candidates in the clinical pipeline. Herein, we report the synthesis and bioevaluation of 30 piperazinyl-benzothiazinone-based quinoline hybrids as prospective anti-TB agents. Preliminary evaluation revealed 24/30 compounds exhibiting substantial activity (minimum inhibitory concentration [MIC] = 0.06-1 mu g/ml) against Mycobacterium tuberculosis (Mtb) H37Rv. Cytotoxicity analysis against Vero cells found these to be devoid of any significant toxicity, with the majority displaying a selectivity index of >80. Furthermore, potent nontoxic compounds, when screened against clinical isolates of drug-resistant Mtb strains, demonstrated equipotent inhibition with MIC values of 0.03-0.25 mu g/ml. A time-kill study identified a lead compound exhibiting concentration-dependent bactericidal activity, with 10x MIC completely eliminating Mtb bacilli within 7 days. Along with acceptable aqueous solubility and microsomal stability, the optimum active compounds of the series manifested all desirable traits of a promising antimycobacterial candidate.