hMAO-B Inhibitors 6e(University of South China)

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.