Evaluation of 2-amino-6-nitrobenzothiazole derived hydrazones as acetylcholinesterase inhibitors: in vitro assays, molecular docking and theoretical ADMET prediction

Acetylcholinesterase (AChE) is an important target for the treatment of neurodegenerative disorders. A library of 2-amino-6-nitrobenzothiazole-derived hydrazones was evaluated as inhibitors of AChE. The compounds inhibited AChE with IC50 values in nanomolar to micromolar range. N'-(5-chloro-2-oxoindolin-3-ylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide (35) showed strong inhibitory activity against AChE (IC50 = 0.0035 +/- 0.005 A mu M), which was found to be similar to 0.6-fold active compared to donepezil and similar to 6.43-fold stronger compared to tacrine. Kinetic studies revealed that compound 35 exhibited a mixed type and reversible mode of enzyme inhibition. SAR studies disclosed several structural aspects significant for potency of these analogs. Molecular docking simulations and binding pose analysis of docked conformations revealed the significance of cumulative effects of hydrogen bonding and pi-pi interactions for effective stabilization of virtual ligand-AChE complexes. Conformational analysis of lead AChE inhibitor molecules led to the proposal of a five-point pharmacophore model essential for the AChE inhibition. Further, compound 35 presented antioxidant activity higher than ascorbic acid in the in vitro DPPH radical scavenging assay. Additionally, in silico molecular and ADMET properties of the synthesized compounds were predicted to explore their drug likeness for potential oral use as antineurodegenerative agents.