Coumarin-thiazole and -oxadiazole derivatives: Synthesis, bioactivity and docking studies for aldose/aldehyde reductase inhibitors

Abstract In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase(ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin- thiazole6(a–o) and coumarin- oxadiazole11(a–h) hybrids and screened for their inhibitory activity against aldose reductase(ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c , 11d , and 11g were selective inhibitors of ALR2. Whereas, ( E )-3-(2-(2-(2-bromobenzylidene)hydrazinyl) thiazol-4-yl)-2 H -chromen-2-one 6c yielded the lowest IC 50 value of 0.16 ± 0.06 μM for ALR2. Moreover, compounds ( E )-3-(2-(2-benzylidenehydrazinyl) thiazol-4-yl)-2 H -chromen-2-one ( 6a ; IC 50 = 2.94 ± 1.23 μM for ARL1 and 0.12 ± 0.05 μM for ARL2) and ( E )-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl) thiazol-4-yl)-2 H -chromen-2-one ( 6e ; IC 50 = 1.71 ± 0.01 μM for ARL1 and 0.11 ± 0.001 μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i , 6k , 6m , and 11b were found to be selective inhibitors for ALR1, among which ( E )-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl) thiazol-4-yl)-2 H -chromen-2-one ( 6m ) was most potent (IC 50 = 0.459 ± 0.001 μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazoleseries lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazoleand oxadiazolederivatives could act as potential ALR1/ALR2 inhibitors.