A total of 18 heterocyclic derived conjugated dienones (CD1-CD18) were evaluated for their potential monoamine oxidase (MAO)-A/-B inhibitory activity. Among the analyzed molecules, CD11 and CD14 showed notable inhibitory potentials against MAO-B, with half-maximal inhibitory concentration (IC50) values of 0.063 ± 0.001 μM and 0.036 ± 0.008 μM, respectively. In contrast, CD1, CD2 and CD3 showed comparable inhibitory activities toward MAO-A, with IC50 values of 3.45 ± 0.07, 3.23 ± 0.24, and 3.15 ± 0.10 μM, respectively. Derivatives of thiophene (CD13-CD17) exhibited selectivity indices greater than 250 for MAO-B. Both lead compounds exhibited similar potencies to safinamide and were more potent than pargyline. According to kinetic analysis, CD11 and CD14 exhibited competitive inhibition of MAO-B activity, with K i values of 12.67 ± 3.85 nM and 4.5 ± 0.62 nM, respectively. Furthermore, the reversibility test results indicated that the inhibitions were reversible. Molecular docking and molecular dynamics simulation studies can provide insights into the probable binding interactions of CD11 and CD14 with MAO-B. CD11 demonstrated a bipartite contact with Tyr326 and Phe343, whereas CD14 showed contact with Pro102 and Tyr435 via aromatic hydrogen bonds. These results indicated that both compounds have high-affinity binding interactions ( -10.13 and -9.90 kcal mol-1, respectively) at the active site of MAO-B. Furthermore, we used SwissADME to estimate ADME, and both lead compounds demonstrated blood-brain barrier penetration. The study results indicated that all the compounds evaluated demonstrated potent inhibition of MAO-B activity, which was comparable to the efficacy of reference medications. It is necessary to do further investigations on the lead molecules to see whether they may be used to treat different neurodegenerative illnesses.
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