Design, synthesis, structure activity relationship and molecular docking studies of thiophene-2-carboxamide Schiff base derivatives of benzohydrazide as novel acetylcholinesterase and butyrylcholinesterase inhibitors

Abstract

The novel hydrazone derivatives of thiophene-2-carboxamide based benzohydrazide were designed, synthesized, characterized and explored for their potential as cholinesterase inhibitors and as antioxidants by in vitro analysis. Methylanthralate (1) was derivitized to Methyl 2-(thiophene-2-carboxamido)benzoate (3) by reacting it with 2-thiophencarbonyl chloride. The compound 3 was further treated with hydrazine hydrate to get N-(2-(hydrazinecarbonyl)phenyl)thiophene-2-carboxamide (4). 4 was further reacted with various aldehydes to obtain the desired Schiff base derivatives (5–20) in good yield (>85%). All compounds (1–20) were characterized by using FTIR, NMR spectroscopies and Mass spectrometric analysis. The biological evaluation results clearly showed that most of the synthesized compounds (5–20) are effective dual inhibitors with varying% inhibition values against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. Remarkably, compound 13 was established as the most active inhibitor of both BChE (% inhibition = 90.16%) and AChE (% inhibition = 83.21%) amongst the series, relative to the standard Donepezil (% inhibition = 92.34% for BChE and 95.24% for AChE). Moreover, the derivatives 6 and 20 also exhibited good inhibition against AChE with% inhibition of 79.41 and 78.79, respectively and against BChE with%age inhibition of 88.98 and 82.93, respectively. While, compounds 10 and 20 were found to possess good antioxidant potential with% inhibition of 89.23% and 94.49%, respectively. Structure-activity relationship showed that para substitution of benzene ring with more electronegative groups enhanced the activities of compounds against the enzymes. Binding interactions of the ligands with the active site of the enzymes were explored by carrying out molecular docking studies.