Design, Synthesis, and Evaluation of 2-Amino-6-nitrobenzothiazole-Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group.

A series of 2-amino-6-nitrobenzothiazole-derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO-A/MAO-B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO-B isoform. N'-(5-Chloro-2-oxoindolin-3-ylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide (compound 31) showed the highest MAO-B inhibitory activity (IC50 =1.8±0.3 nm, selectivity index [SI]=766.67), whereas compound 6 [N'-(1-(4-bromophenyl)ethylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide] was found to be the most active MAO-A inhibitor (IC50 =0.42±0.003 μm). Kinetic studies revealed that compounds 6 and 31 exhibit competitive-type reversible inhibition against both MAO-A and MAO-B, respectively. Structure-activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO-B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π-π stacking and hydrogen bond interactions for effective stabilization of virtual ligand-protein complexes. Further optimization studies of compound 31, including co-crystallization of inhibitor-MAO-B complexes, are essential to develop these compounds as potential therapeutic agents for MAO-B-associated neurodegenerative diseases.