New biologically potent benzimidazole‐based‐triazole derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors along with molecular docking study

Abstract

AbstractA series of fifteen hybrid analogs (1–15) based on benzimidazole bearing triazole skeleton were synthesized and were evaluated for in vitro AChE and BuChE inhibition profile. All the newly afforded scaffolds showed moderate to good AChE and BuChE activity having IC50 values ranging from 0.40 ± 0.05 to 19.60 ± 0.40 μM against AChE and 1.50 ± 0.10 to 23.30 ± 0.50 μM against BuChE in comparison to Donepezil (IC50 = 0.016 ± 0.12 μM for AChE), (IC50 = 4.5 ± 0.11 μM for BuChE) as reference drug. It was concluded from structure–activity relationship (SAR) studies that scaffolds bearing groups of strong e‐withdrawing nature (–NO2, –F and –Cl) at different position of aryl ring were found to be potent inhibitors of both targeted AChE and BuChE enzymes. Therefore, compounds 7 (bearing para‐NO2), 2 (bearing para‐fluoro), 6 (bearing meta‐NO2) and 8 (bearing meta‐fluoro) were identified as the most active on screening against AChE enzyme with IC50 values of 0.40 ± 0.05, 0.60 ± 0.05 and 0.80 ± 0.05 and 0.90 ± 0.05 μM. These scaffolds 7, 2, 6 and 8 also showed superior potency against BuChE enzyme with IC50 values of 1.50 ± 0.10, 2.10 ± 0.10, 2.60 ± 0.10 and 2.30 ± 0.10 μM. It was also observed that inhibition profile of synthesized scaffolds against both these targeted enzymes was greatly affected by altering either position or number/s of substituent around aryl ring. Moreover, it was noteworthy that scaffolds that hold substituent of bulky nature are unable to interact better with active site of targeted enzymes and hence, lower the enzymatic potentials against targeted enzymes. In addition, the active scaffolds such as 7 and 2 were further subjected to molecular docking studies and result obtained revealed that these active scaffolds interacts well both with AChE and BuChE enzymes and forms several key interactions (conventional hydrogen bond, π‐cation, π‐π stacking, π‐π T‐shaped, π‐sulfur and π‐alkyl) with active site of these targeted enzymes. Furthermore, newly afforded scaffolds were characterized by using various spectroscopic tools such as HR‐EI‐MS, 13C NMR and 1HNMR spectroscopy.