新型结核分枝杆菌L-丙氨酸脱氢酶抑制剂的设计与开发
Design and development of new class of Mycobacterium tuberculosisl-alanine dehydrogenase inhibitors.
作者信息
Reshma Rudraraju Srilakshmi, Saxena Shalini, Bobesh Karyakulam Andrews, Jeankumar Variam Ullas, Gunda Saritha, Yogeeswari Perumal, Sriram Dharmarajan
机构信息
Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
出版信息
Bioorg Med Chem. 2016 Sep 15;24(18):4499-4508. doi: 10.1016/j.bmc.2016.07.051. Epub 2016 Jul 25.
Mycobacterium tuberculosisl-alanine dehydrogenase (MTB l-AlaDH) is one of the important drug targets for treating latent/persistent tuberculosis. In this study we used crystal structure of the MTB l-AlaDH bound with cofactor NAD(+) as a structural framework for virtual screening of our in-house database to identified new classes of l-AlaDH inhibitor. We identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitor with IC50 of 9.22±0.72μM. Further lead optimization by synthesis leads to compound 1-(isonicotinamido)-N(2),N(4)-bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide (18) with l-AlaDH IC50 of 3.83±0.12μM, 2.0log reduction in nutrient starved dormant MTB model and MIC of 11.81μM in actively replicative MTB.
结核分枝杆菌L-丙氨酸脱氢酶（MTB l-AlaDH）是治疗潜伏性/持续性结核病的重要药物靶点之一。在本研究中，我们使用与辅因子NAD(+)结合的MTB l-AlaDH晶体结构作为结构框架，对我们的内部数据库进行虚拟筛选，以鉴定新型l-AlaDH抑制剂。我们鉴定出氮杂环丁烷-2,4-二甲酰胺衍生物是一种强效抑制剂，IC50为9.22±0.72μM。通过合成进行进一步的先导化合物优化，得到化合物1-(异烟酰胺基)-N(2),N(4)-双(苯并[d]噻唑-2-基)氮杂环丁烷-2,4-二甲酰胺（18），其对l-AlaDH的IC50为3.83±0.12μM，在营养饥饿的休眠MTB模型中降低了2.0个对数，在活跃复制的MTB中的MIC为11.81μM。
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