文献类型：期刊文献

英文题名：Discovery of Novel MDH2 Inhibitor 28i by Secondary Development of Glibenclamide with Potent Antiaging Activities

作者：Wu, Lingyu[1,2];Zeng, Ru[1,2];Huang, Shuman[3];Wu, Jiale[1,2];Ai, Yu[1,2];Mao, Zhifan[3];Yang, Zhiguo[1,2,4];Liu, Dan[4];Huang, Yi-You[1,2];Li, Jian[1,2,3,5];Liu, Wenwen[1,2];Hu, Zelan[3];Li, Baoli[1,2]

机构：[1]Hainan Univ, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China;[2]Hainan Univ, Hainan Engn Res Ctr Drug Screening & Evaluat, Sch Pharmaceut Sci, Haikou 570228, Peoples R China;[3]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai Key Lab New Drug Design,Shanghai Frontier, Sch Pharm,State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]Shenyang Pharmaceut Univ, Key Lab Struct Based Drugs Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China;[5]Shihezi Univ, Sch Pharm, Key Lab Xinjiang Phytomed Resource & Utilizat, Minist Educ, Shihezi 832003, Peoples R China

年份：2026

卷号：69

期号：3

起止页码：2400

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001670797400001)】；

基金：We gratefully appreciate the financial support from the National Natural Science Foundation of China (grants 22437002 to J.L., 22467010 to B.L., 22277028 to Z.H., and 22207026 to W.L.), the Scientific Research Foundation of Hainan University (KYQD(ZR)-22010 to B.L.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

语种：英文

摘要：Aging is a major public health challenge that urgently requires effective pharmacological interventions. We previously identified mitochondrial malate dehydrogenase 2 (MDH2) as a regulator of aging and discovered that the approved drug glibenclamide (Gli) can inhibit MDH2 and delay aging, but is limited by weak potency and hypoglycemia. Herein, we employed a rational secondary development strategy to optimize Gli and discovered compound 28i, a potent MDH2 inhibitor that extended lifespan and improved healthspan in Caenorhabditis elegans. In multiple mammalian cell models, 28i significantly reduced senescence markers, and in both doxorubicin-induced and naturally aged mice, it alleviated tissue aging and suppressed SASP factors. Importantly, 28i displayed low acute toxicity (LD50 > 1000 mg/kg), minimal hERG channel inhibition (IC50 > 40 mu M), and lacked hypoglycemic effect in oral glucose tolerance tests. Collectively, these findings validate 28i as a highly promising nonhypoglycemic MDH2 inhibitor for future clinical translation as a gerotherapeutic candidate.