Page 40 - 《中国药科大学学报》2026年第1期

学报
34 Journal of China Pharmaceutical University 2026, 57(1): 34 − 45

·论 文·

乳酸脱氢酶 A 抑制剂的设计、合成与生物活性

邴天德 ，胡佳宝 ，张晓进 1,2*
1,2
1,2
（ 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）
1
2
摘 要 人乳酸脱氢酶 A（lactate dehydrogenase A, LDHA）是一种将丙酮酸转化为乳酸的 NADH 依赖型氧化还原酶，在肿
瘤细胞的有氧糖酵解中至关重要。此外，LDHA 在肝脏中还负责催化乙醛酸向草酸盐的转化，草酸盐过度累积会引发高草酸
尿症。目前报道的代表性 LDHA 抑制剂有 GNE-140、NCATS-SM1441 及 CHK-336 等。本研究以 NCATS-SM1441 为先导
物，在分析其与 LDHA 的共晶复合物结合模式基础上，保留关键的噻唑甲酸及芳环药效团，以结构简化的脲连接链替代原有
的取代吡唑连接链，设计并合成了 9 个脲类目标化合物。随后，在构效关系和分子对接研究基础上，进一步设计了 9 个三氮
唑类目标化合物。最终发现三氮唑类化合物 25 展现出最佳的体外 LDHA 酶抑制活性（IC 50 = 1.59 μmol/L）。分子动力学
模拟分析了化合物 25 与关键氨基酸残基的相互作用。最后，对化合物 25 进行了理化性质的预测和细胞毒性评价。本研究
为未来开发具有更优成药性的新型 LDHA 抑制剂提供了实验依据。
关键词 乳酸脱氢酶 A 抑制剂；抗肿瘤；高草酸尿症；分子对接；氧化还原酶
中图分类号 R914.2;R965 文献标志码 A 文章编号 1000−5048(2026)01−0034−12
doi：10.11665/j.issn.1000−5048.2025072101

引用本文 邴天德，胡佳宝，张晓进. 乳酸脱氢酶 A 抑制剂的设计、合成与生物活性 [J]. 中国药科大学学报，2026，57（1）：34-45.

Cite this article as: BING Tiande, HU Jiabao, ZHANG Xiaojin. Design, synthesis and biological evaluation of lactate dehydrogenase A
inhibitors[J]. J China Pharm Univ, 2026, 57(1): 34-45.

Design, synthesis and biological evaluation of lactate dehydrogenase A
inhibitors

1,2
1,2
BING Tiande , HU Jiabao , ZHANG Xiaojin 1,2*
1
Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing 211198;
2
Jiangsu Provincial Key Laboratory of Drug Design and Optimization, Nanjing 211198, China
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 (IC = 1.59 μmol/L) in
50
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.

收稿日期 2025-07-21 * 通信作者 E-mail：zxj@cpu.edu.cn