Synthesis, Qsar and Molecular Modeling Studies on Anti-Alzheimer Agents

Abstract

Alzheimer disease (AD) is a progressive deterioration of memory functioning in the brain that results in impaired thinking and behavior. It involves degeneration of neurons in the outer tissue layer, or cortex of the brain. People suffering from the disease have considerably less amounts of the enzyme, choline acetyltransferase, which is needed to produce acetylcholine (ACh). Currently, the only approved therapy for AD is based on the reduction of the cognitive deficits by enhancing cholinergic transmission through the inhibition of AChE, known as cholinergic hypothesis. These acetylcholinesterase (AChE) inhibitors include Tacrine, Galanthamine, Donepezil, and Rivastigmine, which have been shown to induce a moderate improvement in memory and cognitive function but do not appear to prevent or slow the progressive neurodegeneration. So, it has become a challenge for researchers to have in-depth look into the essential physicochemical and structure requirements for the discovery of candidate molecules which can cure the basic pathology of the AD. During the last century, pharmaceutical research has evolved from a random discovery dominated research to a more rational approach which can now result in the reduction in the risk and providence of the process and thereby a reduction in the time and cost of drug research. Thus in the current scenario of drug discovery and development, the rational approaches including computer-aided drug design (CADD), also called computer-assisted molecular design (CAMD) to drug design play an important role in both step of lead identification and optimization in the process of drug discovery research. Drug discovery and development is a long process with low rate of new therapeutic discovery (1 out of 10,000 compounds) in the 10-15 years. In CADD, attempts are made to find a ligand (the putative drug) which can bind with the receptor representing the target site and interact favorably in terms of hydrophobic, electrostatic, and van der Waals interactions. Therefore in the present work a systematic attempt has been made to indentify essential physicochemical and structure requirements for the design, synthesis of AChE inhibitors as anti- Alzheimer agents using the state of art of computer-aided drug design (CADD) approaches, organic synthesis and biological evaluation. The research work embodied in the thesis has been based on the above theme and is divided in to five chapters. The first chapter includes the brief introduction of Alzheimer’s disease, their characteristics, causes, about AChE structure with its active site and lastly the review literature of various AChE inhibitors and introduction of drug discovery process and computer-assisted drug design. The second chapter includes the 3D-QSAR (CoMFA and CoMSIA) studies on AChE inhibitors, in order to identify essential physicochemical and structural parameters. The third chapter deals with the 3D-pharmacophore model generation of the AChE inhibitors to find important pharmacophoric features for AChE inhibitory activity. In fourth chapter the virtual screening using both the pharmacophore-based virtual screening (PBVS) and structure-based virtual screening (SBVS) approaches for the identification of noval hits for AChE inhibitors from in-house virtual library are discussed. It is followed by the fifth and the last chapter which includes the synthesis and biological evaluation of noval hits obtained from virtual screening approaches. Some of these compounds have showed good AChE inhibitory activity as compare