Biological study with molecular mechanism of imidazothiazole based Schiff bases as anti-Alzheimer agent: Insight into the role of synthesis, molecular docking and ADMET analysis.

• Design and target synthesis of novel imidazothiazole derived Schiff base hybrid derivatives (1–17). • Isolated compounds were evaluated for in vitro acetylcholinesterase and butyrylcholinesterase. • A number of the compounds exhibited excellent activity, some better than the reference standards. • A molecular docking and ADMET study was used to determine the binding interactions of the potent compounds with the enzymes active sites and their toxicity respectively. The current study aims to develop synthetic route and biological evaluation regarding a series of fused imidazothiazole derived Schiff base hybrid derivatives (1–17), synthesized by treating imidazothiazole bearing ester with hydrazine. The first intermediate imidazothiazole bearing hydrazide upon treating with ammonium thiocyanate was cyclized in the presence of 1,2-dioxane and potassium carbonate to second intermediate fused imidazothiazole bearing 2-aminothiadiazole. This intermediate was then mixed substituted benzaldehyde to afford fused imidazothiazole derived Schiff base hybrid derivatives. The current study revealed that the synthesized derivatives were examined and found with high inhibition profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in-comparison with marketed drug donepezil (IC 50 = 7.20 ± 0.10 and 7.80 ± 0.20 µM for AChE and BuChE). Among all the derivatives, analog 11 (IC 50 = 2.10 ± 0.30 and 2.80 ± 0.20 µM) was the one having highest inhibitory profile against both enzymes due to attachment of highly active tri-fluoromethyl group and hence regarded as potent analog. Furthermore, analog 7, 8, 9, 12 and 14 were also studied to exhibit excellent activity due to the attachment of electron donating groups and were found modest in contrast with the standard marketed drug. Protein-ligand interactions were observed through in-silico docking studies and their drug likeness properties were studied through ADMET analysis. [ABSTRACT FROM AUTHOR]