A molecular approach in DRUG DEVELOPMENT for the management of cognitive dysfunction in Alzheimer’s Disease.

Abstract

AbstractBackgroundCognitive decline is budding as one of the greatest health threats in the current scenario as it results in conditions like impaired attention, learning, memory, and problem solving incapability in the patient of Alzheimer’s disease. Neuroinflammation, neurodegradation and oxidative stress can lead to cognitive decline and neuronal loss. Currently, only four AChE inhibitors (tacrine, rivastigmine, donepezil and galantamine) 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. This instigated further development in the fields of AChEIs and antioxidants for cognitive decline as investigations in these fields seems promising and encouraging. A series of novel polyamino‐substituted‐1,4‐benzoquinone molecules were designed and synthesized against the target AChE and evaluated for their in vitro, in vivo, and ex vivo AChE inhibitory activity and antioxidant potential for the development of novel potent molecules for the management of cognitive decline.MethodSeries of novel amino‐substituted‐1,4‐benzoquinone derivatives have been designed and docked with the binding pocket of the enzyme AChE. These molecules were synthesized and evaluated for their selective in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential, and for antioxidant potential using DPPH and hydrogen peroxide radical scavenging protocols. Further these compounds have been evaluated against behavioral alterations using step down passive avoidance and escape learning protocol with reference to the standard donepezil. Subsequently, compounds were further subjected for their ex vivo AChE inhibition using mice brain homogenate as the source of enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione and catalase) has also been carried out to determine the role of the synthesized molecules on the scopolamine induced oxidative damage.ResultOur outcomes depicted that the anti‐amnesic effect of the synthesized conjugates on scopolamine‐induced memory impairment may be related to the mediation of cholinergic system and their effective antioxidant activity.ConclusionThe results obtained from pharmacological studies were found to be appreciable and provided promising leads which can be further explored structurally and pharmacologically, presenting a favorable scenario for the development of selective AChE inhibitors for the management of cognitive decline.