Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents

Decaprenylphosphoryl-β-d-ribose 2′-oxidoreductase (DprE1) is a promising drug target for the development of novel anti-tubercular agents, and inhibitors of DprE1 are being investigated extensively. Among them, the 1,3-benzothiazinone compounds such as BTZ043, and its closer congener, PBTZ169, are undergoing clinical studies. It has been shown that both BTZ compounds are prodrugs, the nitro group is reduced to nitroso first, to which an adjacent Cys387 in the DprE1 binding pocket is covalently bound and results in suicide enzyme inhibition. We figured that replacement of the nitro with an electrophilic warhead would still achieve covalent interaction with nucleophilic Cys387, while the required reductive activation could be circumvented. To test this hypothesis, a number of covalent inhibitors of DprE1 were designed and prepared. The compounds inhibitory potency against DprE1 and anti-tubercular activity were investigated, their chemical reactivity, formation of covalent adduct between the warhead and the enzyme was demonstrated by mass spectrometry. [Display omitted] •Three types of covalent inhibitors of DprE1 were designed.•Most prepared compounds exhibit micromolar range IC50s against DprE1.•Several compounds display less than 1.0 μM MIC against H37Rv.•Covalent modification of DprE1 was confirmed by mass spectrum analysis.•Disruption of mycomembrane synthesis was confirmed.