In this study, three novel series of benzoxazinone, benzothiopyranone and benzopyranone derivatives were designed and synthesized through scaffold morphing from benzothiazinones targeting DprE1. All compounds were evaluated for their in vitro activities against Mycobacterium tuberculosis (M. tuberculosis) and cytotoxicity against Vero cell line. Among the three series, the benzothiopyranone series displayed excellent antimycobacterial activity and low cytotoxicity. Compound 6b exhibited potent in vitro activity against both drug-susceptible and drug-resistant M. tuberculosis clinical strains with MICs < 0.016 μg/mL. In addition, compound 6b demonstrated excellent ADME/T and PK properties and potent in vivo efficacy with bactericidal activity comparable to human equivalent dose of isoniazid (INH) in an acute mouse model of TB. Compound 6b which exhibits good inhibitory activity against DprE1 is under evaluation as a potential drug candidate for the treatment of tuberculosis. The current study provided new insight into the structural and pharmacological requirements for DprE1 inhibitors as potent antitubercular agents.

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A convenient and efficient synthesis of gem-difluorinated compounds is reported. The synthetic route toward various 2-substituted and 3-substituted 1,1-difluoro-6-nitro-2,3-dihydro-1H-indene derivatives is described starting from commercially available indanone. The key gem-difluorination step is accomplished in good yield by treatment of in situ generated bromine fluoride (BrF) with a dithioketal. A plausible mechanism discussing the competition between substitution and elimination is provided to rationalize the outcome of the reactions of the 3-brominated compounds with different amines.

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