Executive Summary : | Alzheimer's disease is a neurological disorder that is generally caused by over expression of monoamine oxidase enzyme, declined levels of acetylcholine, accumulation of amyloid-b and oxidative stress. A few acetylcholinesterase inhibitors such as Tacrine, Donepezil, Rivastigmine have been developed, but suffer with multiple limitations mainly due to the multifactorial nature of Alzheimer disease. Therefore multi-target-directed ligand approach, based on the “one molecule-multiple target” has been proposed. Recently, some heterocyclic scaffolds containing propargylic moiety have been explored as monoamine oxidases (MAO) and acetylcholinesterases (AChE) inhibitors with great success. In this context, transition metal catalysed coupling of Aldehydes, Amines and Alkynes known as A³-coupling is one of the most facile approach to generate substituted propargylamines, a versatile building blocks for the rapid synthesis of drug-like molecules. Hence, this research proposal envisage the development of novel protocols for the construction of propargyl amine derived anti-alzheimer agents via A³- coupling. The synthesized compounds generated thereof will be screened for MAO-A, MAO-B and AChE inhibitory activities and lead compounds will be identified for further studies. The compounds with multipotent profile and drug like characteristics will be evaluated in vivo in the animal models of Alzheimer’s disease. The novelty content of the proposal lies in the facts that there exists un-limited scope to develop novel cascade transformations using A³-coupling afforded propargyl amines as a template while multifunctional substrates in term of aldehyde and alkyne remain less explored. Therefore A³-coupling will be explored with bifunctional building blocks with can enter into successive cascade cyclisation reactions to generate novel heterocyclic scaffolds Asymmetric synthesis will be performed through A³-coupling using chiral ligands and transition metal as cooperative catalysis which remain in the infant stage Investigation of A³-coupling in combination with sulphur as a sulfurating agent in C-H insertion/heterocyclisation reactions with propargylamine intermediates will be carried out Screening of the synthesized compounds against MAO and AChE enzymes will be carried out and structure activity relationship studies for lead optimization will be performed |