Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis.

Abstract

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M.tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent invitro inhibitory activity against M.tuberculosis H37Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent invitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.