Department of Chemistry, Pondicherry University, Kalapet, Puducherry, India.
Department of Bioinformatics, Pondicherry University, Kalapet, Puducherry, India.
Drug Dev Res. 2023 May;84(3):470-483. doi: 10.1002/ddr.22039. Epub 2023 Feb 6.
In the quest to develop potent inhibitors for Mycobacterium tuberculosis, novel isoniazid-based pyridinium salts were designed, synthesized, and tested for their antimycobacterial activities against the H Rv strain of Mycobacterium tuberculosis using rifampicin as a standard. The pyridinium salts 4k, 4l, and 7d showed exceptional antimycobacterial activities with MIC at 1 µg/mL. The in vitro cytotoxicity and pharmacokinetics profiles of these compounds were established for the identification of a lead molecule using in vivo efficacy proof-of-concept studies and found that the lead compound 4k possesses LC value at 25 µg/mL. The in vitro antimycobacterial activity results were further supported by in silico studies with good binding affinities ranging from -9.8 to -11.6 kcal/mol for 4k, 4l, and 7d with the target oxidoreductase DprE1 enzyme. These results demonstrate that pyridinium salts derived from isoniazid can be a potentially promising pharmacophore for the development of novel antitubercular candidates.
在开发针对结核分枝杆菌的有效抑制剂的过程中，设计、合成了新型基于异烟肼的吡啶鎓盐，并使用利福平作为标准，对结核分枝杆菌 H37Rv 株进行了抗分枝杆菌活性测试。吡啶鎓盐 4k、4l 和 7d 表现出优异的抗分枝杆菌活性，MIC 值为 1μg/mL。这些化合物的体外细胞毒性和药代动力学特征已建立，用于通过体内疗效概念验证研究来鉴定先导分子，并发现先导化合物 4k 的 LC 值为 25μg/mL。体外抗分枝杆菌活性结果得到了计算机模拟研究的进一步支持，化合物 4k、4l 和 7d 与目标氧化还原酶 DprE1 酶的结合亲和力良好，范围在-9.8 至-11.6kcal/mol 之间。这些结果表明，异烟肼衍生的吡啶鎓盐可能是开发新型抗结核候选药物的有前途的药效团。
