Design and synthesis of benzimidazole analogs as a potent inhibitor of acetylcholinesterase and butyrylcholinesterase and their docking and MD simulation analysis

Benzimidazole derivatives play a significant role in medicinal chemistry due to their wide range of pharmacological activities. This study focuses on the design and synthesis of novel benzimidazole analogs with the aim of developing a potent inhibitor for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A series of benzimidazole analogs (1-15) was synthesized and evaluated for their inhibitory activities against acetylcholinesterase and butyrylcholinesterase enzymes. All these analogs showed varying degree of acetylcholinesterase and butyrylcholinesterase inhibition with IC₅₀ values ranging between 0.10 ± 0.01 to 4.10 ± 0.20 µM for BuChE when compared to the standard drug donepezil having an IC₅₀ value of 0.016 ± 0.01 µM for acetylcholinesterase and 0.30 ± 0.01µM for butyrylcholinesterase. Among these, six analogs showed better inhibition when compared with the standard drug donepezil having an IC₅₀ value of 0.016 ± 0.01 µM for acetylcholinesterase and 0.30 ± 0.010 µM for butyrylcholinesterase. From structure activity relationships (SAR) analysis, it was observed that the most potent analogs among the series are 1,2,5, 7 and 8 as they have (fluoro and trifluoro) on the phenyl ring. The analog 11 IC₅₀ (0.12 ± 0.1 to 0.15 ± 0.01 µM) showed good activity for both enzymes. The structures of the synthesized derivatives were confirmed using various spectroscopic techniques including ¹H-NMR, ¹³C-NMR, and HREI-MS. Molecular docking and simulation analysis were performed to confirm the binding interaction of the most potent analog and enzyme active site.