| Summary: | A set of structurally related <i>O</i>-methylated flavonoid natural products isolated from <i>Senecio roseiflorus</i> (<b>1</b>), <i>Polygonum senegalense</i> (<b>2</b> and <b>3</b>), <i>Bhaphia macrocalyx</i> (<b>4</b>), <i>Gardenia ternifolia</i> (<b>5</b>), and <i>Psiadia punctulata</i> (<b>6</b>) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds <b>1</b>, <b>2</b>, and <b>5</b> showed selective inhibition of MAO-A, while <b>4</b> and <b>6</b> showed selective inhibition of MAO-B. Compound <b>3</b> showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds <b>1</b>–<b>3</b> and <b>5</b> with MAO-A, and compounds <b>3</b> and <b>6</b> with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by <b>1</b> and <b>3</b>, while a partially-reversible mixed-type inhibition by <b>5</b>. Similarly, enzyme inhibition-kinetics analysis with compounds <b>3</b>, <b>4</b>, and <b>6</b>, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that <b>1</b> selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the <i>O</i>-methylated flavonoids (<b>1</b> and <b>4</b>–<b>6</b>) and chalcones (<b>2</b> and <b>3</b>) to MAO-A matched closely with the trend in the experimental IC<sub>50′</sub>s. Analysis of the binding free-energies suggested better interaction of <b>4</b> and <b>6</b> with MAO-B than with MAO-A. The natural <i>O</i>-methylated flavonoid (<b>1</b>) with highly potent inhibition (IC<sub>50</sub> 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.
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