Synthesis and structure-activity relationship of new chalcone linked 5-phenyl-3-isoxazolecarboxylic acid methyl esters potentially active against drug resistant Mycobacterium tuberculosis

• Published in: European journal of medicinal chemistry 2021-10, Vol.222, p.113580-113580, Article 113580
• Main Authors: Sahoo, Santosh Kumar, Rani, Bandela, Gaikwad, Nikhil Baliram, Ahmad, Mohammad Naiyaz, Kaul, Grace, Shukla, Manjulika, Nanduri, Srinivas, Dasgupta, Arunava, Chopra, Sidharth, Yaddanapudi, Venkata Madhavi
• Format: Article
• Language: English
• Subjects: Anti-tubercular; Chalcone; Drug-resistant; Hybrid; Isoxazole; Time kill kinetics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113580

In search of novel therapeutic agents active against emerging drug-resistant Mycobacterium tuberculosis and to counter the long treatment protocol of existing drugs, herein we present synthesis and biological evaluation of a new series of 5-phenyl-3-isoxazolecarboxylic acid methyl ester-chalcone hybrids. Among 35 synthesized compounds, 32 analogues displayed potent in-vitro activity against Mycobacterium tuberculosis H37Rv with MIC 0.12–16 μg/mL. Cell viability test against Vero cells indicated 29 compounds to be non-cytotoxic (CC50 > 20 μg/mL & SI > 10). Most potent compounds with MIC 0.12 μg/mL (7 b, 7j, 7 ab) exhibited selectivity index (SI) in excess of 320. Further studies on activity against drug-resistant Mycobacterium tuberculosis revealed 7j as the most potent compound with MIC 0.03–0.5 μg/mL. Time-kill kinetic study suggested compound 7j displaying concentration-dependent bactericidal killing activity with relatively comparable potency to that of current first-line anti-TB drugs. Taken together, 7j presents a novel hit with potential to be translated into a potent antimycobacterial. [Display omitted] •35 isoxazole methyl ester based chalcone hybrids were designed and synthesized.•In-vitro anti-tubercular activity against Mtb H37Rv was evaluated.•Antibacterial screening and cytotoxic activity against Vero cells were performed.•MIC against drug resistance Mycobacterium tuberculosis was determined.•Time kill assay was conducted revealing compound 7j as potential anti-TB lead for further exploration.