Bindra_2026_Chem.Biodivers_23_e71405

Twenty semicarbazone and thiosemicarbazone derivatives (T1-T20) were synthesized and evaluated for their inhibition of monoamine oxidases and cholinesterases. Most compounds showed stronger inhibition of MAO-B than MAO-A. Among the synthesized compounds, T6 most strongly inhibited MAO-B (IC(50) = 6.45 microM), followed by T17 (IC(50) = 9.46 microM). T6 and T17 exhibited the highest selectivity index values (3.60 and >4.23, respectively) for MAO-B as compared with MAO-A. T6 was a competitive MAO-B inhibitor. Regarding structure-activity relationship, the thiosemicarbazone T1 (IC(50) = 20.74 microM) showed >1.93 times better MAO-B inhibition than the semicarbazone T5 (IC(50) >40 microM); a similar pattern was observed for T6 vs. T10, T11 vs. T15, and T16 vs. T20, indicating that the thiosemicarbazone derivatives exhibited better MAO-B inhibition than the semicarbazone derivatives when the terminal -NH(2) group was free. All the compounds showed less than 50% inhibition of acetylcholinesterase at 10 microM. Comparatively, compounds T3 and T12 exhibited 70.65 and 61.94% inhibition of butyrylcholinesterase at 10 microM, respectively. Docking studies of the MAO-B inhibition of the most promising molecules were performed using MzDOCK. Collectively, thiosemicarbazone derivatives, specially T6 and T17, warrant further investigation as the promising candidates for the development of novel therapeutics targeting MAO-B-related disorders.