2. Academic Validation
  3. Discovery of C-3 nitrothiophene substituted thiochromone derivatives as potent and selective human monoamine oxidase B (hMAO-B) inhibitors for the treatment of atherosclerosis

Discovery of C-3 nitrothiophene substituted thiochromone derivatives as potent and selective human monoamine oxidase B (hMAO-B) inhibitors for the treatment of atherosclerosis

  • Bioorg Chem. 2025 Oct:165:108940. doi: 10.1016/j.bioorg.2025.108940.
Yuqing Lin 1,  Huiming Hu 2,  Xiongwang Li 1,  Siqi Li 1,  Qin Wang 2,  Pengbing Mi 3,  Jia-Jia Lang 4,  Ying-Wu Lin 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Hengyang Medicinal School, University of South China, Hengyang, Hunan 421001, China.
  • 2 The affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hunan 421001, China.
  • 3 School of Pharmaceutical Science, Hengyang Medicinal School, University of South China, Hengyang, Hunan 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address: geyynb@foxmail.com.
  • 4 Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan 421001, China; School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China. Electronic address: langjiajia@stu.scu.edu.cn.
  • 5 Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan 421001, China; School of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan 421001, China. Electronic address: ywlin@usc.edu.cn.
PMID: 40916299 DOI: 10.1016/j.bioorg.2025.108940
Abstract

Inhibition of human Monoamine Oxidase B (hMAO-B) to prevent both oxidative stress and lipid metabolism disorders, which are high-risk factors for pathogenesis of atherosclerosis, is a potential strategy for the treatment of atherosclerosis. In this study, we have explored a series of C-3 nitrothiophene substituted thiochromone analogues that showed good to excellent potency against hMAO-B. The strategy of introduction the nitro-group into thiophene linker, which contributes pivotal interactions with Cys172, significantly improved the potency and selectivity of these compounds. In our investigations, all compounds 6 (except 6a, 6c and 6 m) exhibited excellent activity against hMAO-B (IC50hMAO-B in the range of 1.4 ± 0.8 to 126.8 ± 13.2 nM) and remarkable selectivity for hMAO-B over hMAO-A (hMAO-B selectivity index in the range 109-fold to >90,909-fold). These compounds exhibited favorable cytotoxicity profiles in RAW264.7 cells. Moreover, compound 6e exhibited the ability to reverse the formation of foam cells in oxidized low-density lipoprotein (ox-LDL)-induced RAW264.7 macrophage foam cells and reduced the production of intracellular Reactive Oxygen Species (ROS) in RAW264.7 cells. These results indicated that C-3 nitrothiophene substituted thiochromone derivatives are potential leading compounds of high performance hMAO-B inhibitors for treatment of atherosclerosis.

Keywords

Atherosclerosis; Human monoamine oxidase B inhibitor; Nitro-group; Thiochromone.

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