Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis, molecular modelling and in-silico ADME evaluation

A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydra zide with different (un) substituted 3-formylchromones. All compounds had IC50 values in lower micromolar range (IC50 = 0.33-7.14 mu M for MAO-A, and 1.12-3.56 mu M for MAO-B). The most active MAO-B inhibitor was N'-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl) methylidene]-4-methylbenzenesulfonohydra zide (3e) with IC50 value of 1.12 +/- 0.02 mu M, and N'-[(E)-(6-chloro-4-oxo-4H-chromen-3-yl) methyli dene]-4-methylbenzenesulfonohydrazide (3f) was the most active MAO-A inhibitor with IC50 value of 0.33 +/- 0.01 mu M. From enzyme kinetic studies, the mode of inhibition against MAO-B was found to be competitive, whereas against MAO-A, it was found to be non-competitive. Molecular docking studies indicated a new binding pocket for non-competitive MAO-A inhibitors. The activity of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability. (C) 2017 Elsevier Inc. All rights reserved.