乙酰胺
化学
抗细菌
异烟肼
结核分枝杆菌
利福平
吡唑
乙胺丁醇
组合化学
药理学
肺结核
立体化学
生物化学
抗生素
医学
有机化学
病理
作者
Yang Liu,Xueping Hu,Lijun Yang,Ruifeng Xu,Yujuan Xu,Wei Ma,Md. Shah Alam,Tianyu Zhang,Xin Chai,Yixuan Lei,Qing Ye,Xiaowu Dong,Yu Kang,Jinxin Che,Tingjun Hou,Dan Li
标识
DOI:10.1021/acs.jmedchem.3c01703
摘要
Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is a promising target for treating tuberculosis (TB). Currently, most novel DprE1 inhibitors are discovered through high-throughput screening, while computer-aided drug design (CADD) strategies are expected to promote the discovery process. In this study, with the aid of structure-based virtual screening and computationally guided design, a series of novel scaffold N-(1-(6-oxo-1,6-dihydropyrimidine)-pyrazole) acetamide derivatives with significant antimycobacterial activities were identified. Among them, compounds LK-60 and LK-75 are capable of effectively suppressing the proliferation of Mtb with MICMtb values of 0.78-1.56 μM, comparable with isoniazid and much superior to the phase II candidate TBA-7371 (MICMtb = 12.5 μM). LK-60 is also the most active DprE1 inhibitor derived from CADD so far. Further studies confirmed their high affinity to DprE1, good safety profiles to gut microbiota and human cells, and synergy effects with either rifampicin or ethambutol, indicating their broad potential for clinical applications.
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