AISSMS College of Pharmacy, Kennedy Road, Pune, Maharashtra, India.
Sir Parshurambhau College, affiliated to SP Pune University, Pune, Maharashtra, India.
Curr Comput Aided Drug Des. 2021;17(1):134-143. doi: 10.2174/1573409916666200129095952.
Diarylquinolines like Bedaquiline have shown promising antitubercular activity by their action of Mycobacterial ATPase.
The structural features necessary for a good antitubercular activity for a series of quinoline derivatives were explored through computational chemistry tools like QSAR and combinatorial library generation. In the current study, 3-Chloro-4-(2-mercaptoquinoline-3-yl)-1- substitutedphenylazitidin-2-one derivatives have been designed and synthesized based on molecular modeling studies as anti-tubercular agents.
2D and 3D QSAR analyses were used to designed compounds having a quinoline scaffold. The synthesized compounds were evaluated against active and dormant strains of Mycobacterium tuberculosis (MTB) H37 Ra and Mycobacterium bovis BCG. The compounds were also tested for cytotoxicity against MCF-7, A549 and Panc-1 cell lines using MTT assay. The binding affinity of designed compounds was gauged by molecular docking studies.
Statistically significant QSAR models generated by the SA-MLR method for 2D QSAR exhibited r = 0.852, q = 0.811, whereas 3D QSAR with SA-kNN showed q = 0.77. The synthesized compounds exhibited MIC in the range of 1.38-14.59(μg/ml). These compounds showed some crucial interaction with MTB ATPase.
The present study has shown some promising results which can be further explored for lead generation.
二芳基喹啉类药物如贝达喹啉通过抑制分枝杆菌 ATP 酶表现出有前景的抗结核活性。
通过计算化学工具（如 QSAR 和组合文库生成）探索一系列喹啉衍生物具有良好抗结核活性所需的结构特征。在本研究中，基于分子建模研究，设计并合成了 3-氯-4-(2-巯基喹啉-3-基)-1-取代苯基氮杂环丁烷-2-酮衍生物作为抗结核药物。
使用二维和三维 QSAR 分析设计具有喹啉骨架的化合物。合成的化合物针对结核分枝杆菌（MTB）H37Ra 和牛分枝杆菌 BCG 的活性和休眠菌株进行了评估。还通过 MTT 测定法评估了化合物对 MCF-7、A549 和 Panc-1 细胞系的细胞毒性。通过分子对接研究评估了设计化合物的结合亲和力。
SA-MLR 方法生成的二维 QSAR 统计上显著的 QSAR 模型显示 r = 0.852，q = 0.811，而 SA-kNN 的三维 QSAR 显示 q = 0.77。合成的化合物的 MIC 范围为 1.38-14.59(μg/ml)。这些化合物与 MTB ATP 酶表现出一些关键相互作用。
本研究显示出一些有希望的结果，可以进一步探索用于产生先导化合物。
