Design, synthesis and biological evaluation of lactate dehydrogenase A inhibitors
10.11665/j.issn.1000-5048.2025072101
- VernacularTitle:乳酸脱氢酶A抑制剂的设计、合成与生物活性
- Author:
Tiande BING
1
;
Jiabao HU
;
Xiaojin ZHANG
Author Information
1. 中国药科大学理学院化学系, 南京211198;江苏省药物分子设计和成药性优化重点实验室, 南京211198
- Publication Type:Journal Article 期刊文章
- Keywords:
lactate dehydrogenase A inhibitor;
antitumor;
hyperoxaluria;
molecular docking;
oxidoreductase
- From:
Journal of China Pharmaceutical University
2026;57(1):34-45
- CountryChina
- Language:Chinese
-
Abstract:
Human lactate dehydrogenase A (LDHA) is an NADH-dependent oxidoreductase that catalyzes the conversion of pyruvate to lactate, playing a crucial role in the aerobic glycolysis of tumor cells. Additionally, LDHA is responsible for catalyzing the conversion of glyoxylate to oxalate in the liver, excessive accumulation of which leads to hyperoxaluria. Representative LDHA inhibitors reported to date include GNE-140, NCATS-SM1441, and CHK-336. In this study, NCATS-SM1441 was used as the lead compound. Based on the analysis of its cocrystal binding mode with LDH, the key carboxythiazole and aromatic pharmacophores were retained, while the original substituted pyrazole linker was replaced with urea linker moieties to simplify the structure. As a result, nine urea derivatives were designed and synthesized. Subsequently, on the basis of structure-activity relationship and molecular docking studies, nine target triazole compounds were further designed. Ultimately, triazole compound 25 was found to exhibit the most potent LDHA inhibitory activity (IC50 = 1.59 μmol/L) in vitro. Molecular dynamics simulations were employed to analyze the interactions between compound 25 and key amino acid residues. Finally, the prediction of physicochemical properties and the evaluation of cell viability were performed for compound 25. The study provides an experimental basis for future development of novel LDHA inhibitors with improved drugability.
