药品
药物发现
效力
肺结核
计算生物学
药理学
化学
生物
组合化学
医学
体外
生物信息学
生物化学
病理
作者
Veena Yadav,Helena I. Boshoff,Lena Trifonov,José Santinni Roma,Thomas R. Ioerger,Clifton E. Barry,Seung-Ha Oh
标识
DOI:10.1021/acsmedchemlett.3c00295
摘要
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.
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