Synthesis and Structure-Activity Relationships of a New Class of Oxadiazoles Targeting DprE1 as Antitubercular Agents.

The continuing prevalence of drug-resistant tuberculosis threatens global TB control programs, highlighting the need to discover new drug candidates to feed the drug development pipeline. In this study, we describe a high-throughput screening hit (4-benzylpiperidin-1-yl)(1-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone () as a potent antitubercular agent. Structure-activity guided synthesis led to the discovery of several analogs with high potency. was found to have promising potency against many drug-resistant strains, as well as drug-susceptible clinical isolates. It also showed cidality against growing in host macrophages. Whole genome sequencing of genomic DNA from resistant mutants raised to revealed mutations in decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1). This novel oxadiazole scaffold expands the set of chemical tools for targeting a well-validated pathway to treat tuberculosis.