#37 Design, synthesis and evaluation of the cholinesterase inhibitory potential of 5-chlorobenzimidazole derivatives for Alzheimer’s

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Pathak, S. .; Gurjar, A. .; Law, C. S. W. .; Yeong, K. Y. .; Vishwakarma, S. . #37 Design, Synthesis and Evaluation of the Cholinesterase Inhibitory Potential of 5-Chlorobenzimidazole Derivatives for Alzheimer’s. J Pharm Chem 2022, 8.


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to a decline in cognitive function and behavior. It is characterized by depletion in acetylcholine and butyrylcholine, presence of amyloid deposits, formation of neurofibrillary tangles in the brain. Donepezil, an acetylcholinesterase inhibitor remains the leading compound for symptomatic relief of AD patients. Thus, cholinesterase is a promising target to explore the therapeutic effect for AD. By blocking AChE peripheral anionic site, its co-localization with amyloid fibrils can be restricted and hence limiting plaques deposition in different regions of the brain. Extending study towards the development of cholinesterase inhibitors may eventually prevent precipitation of amyloid plaques and neurofibrillary tangles hence justifying its targeted interest. Nitrogen-containing heterocyclic scaffolds are known to possess potential activity towards AD targets. Hence, we intend to explore the therapeutic effect of substituted 5 chlorobenzimidazole derivatives as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors with their neuroprotective role. Ligands were sketched and minimized with LigPrep under the force field of OPLS-2005 (Schrödinger’s Maestro release 2018-1). QikProp v.5.5 (Schrödinger’s Maestro release 2018-1) was accessed for in-silco ADME. 5-chlorobenzimidazole derivatives were synthesized with benign synthetic methods. The purified derivatives were characterized by infrared spectroscopy (IR) and proton nuclear magnetic resonance (1H-NMR). The masses of the target compounds were confirmed through LC-MS (ESI). In-vitro LPO (lipid peroxidation) assay was performed on rat brain. Cholinesterase inhibition was carried out on the synthesized derivatives using Ellman’s method. All the derivatives exhibited favourable drug like properties and the results were complying with the QikProp recommended range. In-vitro LPO assay results were in the range from 2.80 – 31.68 μM depicting their neuroprotective potential with Bz–6 being the most effective. In-vitro cholinesterase inhibition assay indicated that BZ series potentially inhibited BuChE over AChE. Substituted Bz-10 with IC50 4.25 mM was the most potent BuChE inhibitor. 5-chlorobenzimidazole derivatives showed favourable ADME parameters, portraying neuroprotection and cholinesterase inhibition. Cholinesterase inhibition was found to be more promising against BuChE as compared to AChE at 10 µM. Hence, these can act as effective candidates for symptomatic treatment of AD.

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