2. Academic Validation
  3. Discovery of Novel MDH2 Inhibitor 28i by Secondary Development of Glibenclamide with Potent Antiaging Activities

Discovery of Novel MDH2 Inhibitor 28i by Secondary Development of Glibenclamide with Potent Antiaging Activities

  • J Med Chem. 2026 Feb 12;69(3):2400-2423. doi: 10.1021/acs.jmedchem.5c02243.
Lingyu Wu 1,  Ru Zeng 1,  Shuman Huang 2,  Jiale Wu 1,  Yu Ai 1,  Zhifan Mao 2,  Zhiguo Yang 1 3,  Dan Liu 3,  Yi-You Huang 1,  Jian Li 1 2 4,  Wenwen Liu 1,  Zelan Hu 2,  Baoli Li 1
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 2 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China.
PMID: 41572571 DOI: 10.1021/acs.jmedchem.5c02243
Abstract

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 μM), 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.

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