Bioevaluation of quinoline‐4‐carbonyl derivatives of piperazinyl‐benzothiazinones as promising antimycobacterial agents. Issue 11 (25th July 2022)

• Record Type: Journal Article
• Authors: Sahoo, Santosh K.; Gajula, Siva N. R.; Ahmad, Mohammad N.; Kaul, Grace; Nanduri, Srinivas; Sonti, Rajesh; Dasgupta, Arunava; Chopra, Sidharth; Yaddanapudi, Venkata M.
• Is Part Of: Archiv der Pharmazie. Volume 355:Issue 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-25
• Subjects: covalent docking -- DprE1 inhibitor -- Pfitzinger reaction -- quinoline‐benzothiazinone hybrids -- tuberculosis; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202200168
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: 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 µg/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 µg/ml. A time‐kill study identified a lead compound exhibiting concentration‐dependent bactericidal activity, with 10× 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. Abstract : Scaffold hybridization of the benzothiazinone and quinoline pharmacophoric moieties led to the identification of 6‐(trifluoromethyl)‐2‐[4‐(6‐chloro‐2‐methylquinoline‐4‐carbonyl)piperazin‐1‐yl]‐8‐nitro‐4 H ‐benzo[ e ][1, 3]thiazin‐4‐one as a potent and selective bactericidal antitubercular agent. Several other active compounds of the series manifested all desirable traits of a promising antimycobacterial candidate.