Design, synthesis and pharmacological evaluation of some 1,4‐benzoquinone‐piperazine hybrids for the management of cognitive dysfunction in Alzheimer’s disease

Abstract

AbstractBackgroundCognitive dysfunction is one of the testimonial indications of neurological disorder like Alzheimer’s disease. Based on the causative factors four main hypotheses have facilitated to draw sketch of real situation of AD, i.e. cholinergic misbalance, neurofibrillary tangles, senile plaques, and oxidative stress. The inhibition of acetylcholinesterase (AChE) has been a promising target for the management of AD which is mainly associated with the decreased level of acetylcholine (ACh). Currently, only four AChE inhibitors (tacrine, rivastigmine, donepezil and galanthamine) have been approved by the FDA for the symptomatic treatment of AD. However, these acetylcholinesterase inhibitors are not devoid of side effects and have lesser CNS permeability. A series of 1,4‐benzoquinone‐piperazine hybrid molecules were designed and synthesized based on the best pharmacophoric features against the target AChE and evaluated for their AChE inhibitory activity for the development of novel potent molecules for the management of cognitive decline in AD.MethodAtom based 3D QSSR study of 1,4‐benzoquinone hybrids as acetylcholinesterase inhibitors for its selective binding with AChE was performed. Molecules were designed on the basis of the best model features and were docked with 3D crystal structure of AChE with the target. These designed hybrid molecules of 1,4‐benzoquinone and piperazine moiety were synthesized and evaluated as acetylcholinesterase inhibitors.ResultThe best 3D‐QSSR model displayed acceptable values of statistical parameters. The designed molecules showed good binding interactions with the important amino acids of the target protein. These molecules were synthesized and evaluated for their cognition improvements abilities. Out of all the synthesized compounds, few were selected for passive avoidance memory elevator test based on their in vitro AChE inhibitory activity. These molecules showed comparable improvement in the memory with that of the standard drug donepezil.ConclusionThe statistical measures of the best model clearly indicate that the generated model has satisfactory prediction power for new molecules. Out of all the synthesized molecules, some compounds showed significant in vitro AChE activity along with improved memory function during step down passive avoidance studies. Hence the present study facilitates the process of designing, synthesis and development of new potent and selective AChE inhibitors.