Division of Medicinal and Process Chemistry, CSIR- Central Drug Research Institute, Lucknow-226031, India.
Curr Top Med Chem. 2020;20(29):2723-2734. doi: 10.2174/1568026620666200903163515.
Tuberculosis (TB) is a major infectious disease caused by Mycobacterium Tuberculosis. As per the World Health Organization (WHO) report of 2019, there were 1.5 million deaths in the year 2018, mainly because of multi- and extensively drug-resistant tuberculosis (MDR & XDR-TB). Among several antitubercular drugs in clinical trials, bedaquiline (TMC207) is a highly promising drug that was approved by the FDA in 2012 and marketed in 2016 for the treatment of multidrug resistant TB in combination with other drugs. Bedaquiline acts on mycobacterial ATP synthase and is highly effective in replicating as well as on dormant mycobacteria. Several series of substituted quinolines have been reported with their antitubercular and ATP synthase inhibitory activity.
To understand the role of physicochemical parameters like hydrophobicity, electronic and steric factors in eliciting the biological response, the Quantitative structure-activity relationship (QSAR) studies have been carried out using the computed parameters as independent variable and activity (-log IC50/MIC) as the dependent variable.
The developed QSAR models in terms of positively contributing Molar Refractivity (MR) and negatively contributing Partition Coefficient (PC) and Connolly Molecular Area (CMA) parameters have high predictivity as also shown on external data set and the mean value of the computed 3D parameters of enantiomers may be used in QSAR analysis for racemic compounds.
These results are also substantiated by pharmacophore modeling. The similar dependence of antitubercular activity against whole-cell M.Tb.H37Rv on MR and CMA suggests ATP synthase as the main target for antitubercular activity and the QSAR models may be useful in the identification of novel antitubercular agents.
结核病（TB）是由结核分枝杆菌引起的主要传染病。根据世界卫生组织（WHO）2019 年的报告，2018 年有 150 万人死亡，主要是因为耐多药和广泛耐药结核病（MDR 和 XDR-TB）。在临床试验中的几种抗结核药物中，贝达喹啉（TMC207）是一种很有前途的药物，于 2012 年获得 FDA 批准，并于 2016 年上市，用于联合其他药物治疗耐多药结核病。贝达喹啉作用于分枝杆菌的 ATP 合酶，对复制期和休眠期分枝杆菌均高度有效。已经报道了几系列取代的喹啉类化合物，具有抗结核和 ATP 合酶抑制活性。
为了了解物理化学参数（如疏水性、电子和空间因素）在引发生物学反应中的作用，我们进行了定量构效关系（QSAR）研究，使用计算参数作为自变量，活性（-log IC50/MIC）作为因变量。
以正贡献摩尔折射度（MR）和负贡献分配系数（PC）和康诺利分子面积（CMA）参数为特征的开发的 QSAR 模型具有很高的预测性，也在外部数据集上得到了证明，并且外消旋化合物的手性 3D 计算参数的平均值可用于 QSAR 分析。
这些结果也得到了药效团模型的证实。抗结核活性对全细胞 M.Tb.H37Rv 的依赖与 MR 和 CMA 相似，表明 ATP 合酶是抗结核活性的主要靶标，QSAR 模型可用于鉴定新型抗结核药物。
