Tuberculosis continues to wreak havoc worldwide and caused around 1.4 million deaths in 2019. Hence, in our pursuit of developing novel antitubercular compounds, we are reporting the e-Pharmacophore-based design of DprE1 (decaprenylphosphoryl-ribose 2′-oxidase) inhibitors. In the present work, we have developed a four-feature e-Pharmacophore model based on the receptor–ligand cavity of DprE1 protein (PDB ID 4P8C) and mapped our previous reported library of compounds against it. The compounds were ranked on phase screen score, and the insights obtained from their alignment were used to design some novel compounds. The designed compounds were docked with DprE1 protein in extra-precision mode using Glide module of Maestro, Schrodinger. Some derivatives like B1, B2, B4, B5 and B12 showed comparable docking score (docking score > − 6.0) with respect to the co-crystallized ligand. The designed compounds were synthesized and characterized. In vitro antitubercular activity was carried out on Mycobacterium tuberculosis H37Rv (ATCC27294) strain using the agar dilution method, and minimum inhibitory concentration (MIC) was determined. The compound B12 showed a MIC value of 1.56 μg/ml which was better than the standard drug ethambutol (3.125 μg/ml). Compounds B7 and B11 were found to be equipotent with ethambutol. Cytotoxicity studies against Vero cell lines proved that these compounds were non-cytotoxic. Molecular dynamic simulation study also suggests that compound B12 will form a stable complex with DprE1 protein and will show the crucial H-bond interaction with LYS418 residue. Further in vitro enzyme inhibition studies are required to validate these findings.

结核病继续在世界范围内肆虐，2019 年造成约 140 万人死亡。 因此，在我们追求开发新型抗结核化合物的过程中，我们报告了基于 e-Pharmacophore 的 DprE1（癸烯基磷酰核糖 2'-氧化酶）抑制剂设计。在目前的工作中，我们开发了一个基于 DprE1 蛋白受体 - 配体腔（PDB ID 4P8C）的四特征 e-Pharmacophore 模型，并将我们之前报道的化合物库映射到它上面。这些化合物按阶段筛选分数排名，从它们的比对中获得的见解用于设计一些新化合物。使用 Maestro, Schrodinger 的 Glide 模块以超精密模式将设计的化合物与 DprE1 蛋白对接。一些衍生品如 B1、B2、B4、B5 和 B12 显示出可比的对接分数（对接分数 > − 6。0) 关于共结晶的配体。合成并表征了设计的化合物。体外抗结核活性在结核分枝杆菌H37Rv（ATCC27294）菌株采用琼脂稀释法，测定最小抑菌浓度（MIC）。化合物B12的MIC值为1.56 μg/ml，优于标准药物乙胺丁醇（3.125 μg/ml）。发现化合物 B7 和 B11 与乙胺丁醇等效。针对 Vero 细胞系的细胞毒性研究证明这些化合物是无细胞毒性的。分子动力学模拟研究还表明，化合物 B12 将与 DprE1 蛋白形成稳定的复合物，并将显示与 LYS418 残基的关键 H 键相互作用。需要进一步的体外酶抑制研究来验证这些发现。