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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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