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Abstract : Eighteen compounds derived from two sub-series, (HC1–HC9) and (HF1–HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC50 value of 0.040 μM, followed by HC3 (IC50 = 0.049 μM), while compound HF4 most potently inhibited MAO-A (IC50 = 0.046 μM), followed by HF2 (IC50 = 0.075 μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC2H5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the –OC2H5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially –OC2H5 (HC4) > –OCH3 (HC3) > –F (HC7) > –CH3 (HC2) > –Br (HC8) > –H (HC1) in order. In MAO-A inhibition, the substituent 4-OC2H5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by –CH3 (HF2), –F (HF7), –Br (HF8), –OCH3 (HF3), and–H (HF1). In the enzyme kinetics and reversibility study, the Ki value of HC4 for MAO-B was 0.035 ± 0.005 μM, and that of HF4 for MAO-A was 0.035 ± 0.005 μM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders. Similar content being viewed by others