Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

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 IC value of 0.040 μM, followed by HC3 (IC = 0.049 μM), while compound HF4 most potently inhibited MAO-A (IC = 0.046 μM), followed by HF2 (IC = 0.075 μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OCH in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OCH substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OCH (HC4) > -OCH (HC3) > -F (HC7) > -CH (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OCH in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH (HF2), -F (HF7), -Br (HF8), -OCH (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the K 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.