Investigations on the 2-thiazolylhydrazyne scaffold: Synthesis and molecular modeling of selective human monoamine oxidase inhibitors

A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and H-1 NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the C=N, displayed IC50 = 3.81 +/- 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the enzyme-inhibitor interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.