Structure-activity relationship studies on 2,5,6-trisubstituted benzimidazoles targeting Mtb-FtsZ as antitubercular agents.
Structure-activity relationship studies on 2,5,6-trisubstituted benzimidazoles targeting Mtb-FtsZ as antitubercular agents.
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DOI：
10.1039/d0md00256a
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发表时间：
2020-10
影响因子：
4.1
通讯作者：
Krupanandan Haranahalli;Simon Tong;Saerom Kim;Monaf Awwa;Lei Chen;Susan E. Knudson;R. Slayden;E. Singleton;Riccardo Russo;N. Connell;I. Ojima
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文献类型：
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作者：
Krupanandan Haranahalli;Simon Tong;Saerom Kim;Monaf Awwa;Lei Chen;Susan E. Knudson;R. Slayden;E. Singleton;Riccardo Russo;N. Connell;I. Ojima
丝状温度敏感蛋白Z（FtsZ）是细菌细胞分裂必需的蛋白质，是开发新的抗菌治疗药物的有希望的靶点。作为我们正在进行的2，5，6-三取代的苯并咪唑作为靶向Mtb-FtsZ的抗结核药物的SAR研究的一部分，设计、合成了在2位具有修饰的化合物的新库，并评价了它们对Mtb-H37 Rv的活性。这个新的三取代苯并咪唑文库显示出0.004-50 μg mL-1范围内的MIC值。化合物6 b、6c、20 f和20 g表现出优异的生长抑制活性，范围为0.004-0.08 μg mL-1。该SAR研究发现了一种非常有效的化合物20 g（MIC 0.0039 μg mL-1;归一化MIC 0.015 μg mL-1）。我们的3DQSAR模型预测20 g是库中最有效的化合物。
Filamenting temperature sensitive protein Z (FtsZ) is an essential bacterial cell division protein and a promising target for the development of new antibacterial therapeutics. As a part of our ongoing SAR studies on 2,5,6-trisubstituted benzimidazoles as antitubercular agents targeting Mtb-FtsZ, a new library of compounds with modifications at the 2 position was designed, synthesized and evaluated for their activity against Mtb-H37Rv. This new library of trisubstituted benzimidazoles exhibited MIC values in the range of 0.004-50 μg mL-1. Compounds 6b, 6c, 20f and 20g showed excellent growth inhibitory activities ranging from 0.004-0.08 μg mL-1. This SAR study has led to the discovery of a remarkably potent compound 20g (MIC 0.0039 μg mL-1; normalized MIC 0.015 μg mL-1). Our 3DQSAR model predicted 20g as the most potent compound in the library.