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

Year: 2023

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 ( P1 ) as a potent antitubercular agent. Structure–activity guided synthesis led to the discovery of several analogs with high in vitro potency. P1 was found to have promising potency against many drug-resistant strains, as well as drug-susceptible clinical isolates. It also showed cidality against Mtb growing in host macrophages. Whole genome sequencing of genomic DNA from resistant mutants raised to P1 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.3c00295