Molecular modeling, synthesis, and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory activities of novel benzimidazole-bearing thiadiazole derivatives

Abstract

A new series of benzimidazole-based thiadiazole hybrids analogues (6a–p) as effective Alzheimer's inhibitors were synthesized and then evaluated for their inhibition profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes as compared to Donepezil as standard drug. All the synthesized benzimidazole-based thiadiazole analogues showed varied range of inhibitory potentials against targeted AChE & BuChE enzymes with IC50 values ranging from 1.32 ± 0.10 µM to 19.26 ± 0.60 µM (for AChE) and 1.94 ± 0.10 µM to 21.33 ± 0.70 µM (for BuChE) when compared to standard Donepezil (IC50 = 2.16 ± 0.050 µM for AChE) & 4.50 ± 0.10 µM for BuChE). As structure-activity relationship (SAR) studies revealed that the analogues 4d (bearing ortho‑hydroxy and para-NO2 on N-aryl ring along with ortho-NO2 substitution on another aryl ring) and 6k (that holds ortho‑hydroxy ¶-NO2 substitutions on N-aryl ring and 3,4-diCl moieties on another aryl ring) were emerged as the most potent analogues of AChE & BuChE enzymes having IC50 values of 1.32 ± 0.10 µM & 1.84 ± 0.20 µM (against AChE) and 1.94 ± 0.10 µM & 2.23 ± 0.20 µM (against BuChE) respectively. Furthermore, the active analogues were subjected to molecular docking studies in order to explore the binding interactions possess by potent analogues with the active sites of amino acids of targeted AChE & BuChE enzymes and result obtained shows that these active analogues furnished that several key interactions with targeted enzymes active sites. Additionally, all the synthesized analogues were elucidated structurally using variety of spectroscopic (1H NMR & 13C NMR) and spectrometric (HREI-MS) analysis.