Design Synthesis And Evaluation Of Donepezil Resagiline Based Compounds As Multipotent Inhibitors For The Treatment Of Alzheimers Disease

Abstract

iv newlineABSTRACT newline Design, Synthesis and Evaluation of Donepezil-Rasagiline Based Compounds newlineas Multipotent Inhibitors for the Treatment of Alzheimer s Disease newlineName of student : Bhupinder Kumar newlineRegistration Number : 15phdphm02 newlineDegree for which submitted : Ph. D (Pharmaceutical Sciences) newlineSupervisor : Dr. Vinod Kumar newlineCo-supervisor : Dr. Jyoti Parkash newlineDepartment : Pharmaceutical Sciences and Natural Products newlineSchool of Studies : Basic and Applied Sciences newlineKey words: Alzheimer s disease, MAO inhibitors, Diphenylpyrimidine, newlineAcetylcholinesterase inhibitors, Dual inhibitors, Neuroprotective agents newlineAlzheimer s disease (AD) is multifactorial in nature and different enzymes including newlineMAO, AChE, and amyloid beta are implicated in its pathogenesis. The pathomechanism newlineof AD is complex in nature and single target drugs proved to be ineffective for the newlinetreatment of the disease. With an aim of developing dual/multipotent inhibitors, 4,6- newlinediphenylpyrimidines were optionally substituted with propargyl group and an ethyl chain newlinecontaining a cyclic or acyclic tertiary nitrogen atom newline(piperidine/morpholine/pyrrolidine/N,N-dimethyl) as potential pharmacophores for MAO newlineand AChE enzymes. Compound VB1 was found to be the most potent MAO-A (IC50 newlinevalue of 18.34 ± 0.38 nM) inhibitor and VB8 was found to be the most potent AChE newline(IC50 value of 9.54 ± 0.07 nM) inhibitor. Compound VB3 was another promising newlinecompound in series-I with IC50 values of 28.33 ± 3.22 nM and 18.92 ± 0.29 nM against newlineMAO-A and AChE, respectively and displayed very high selectivity index (103) for AChE newlineover BuChE. These compounds were found to be reversible inhibitors of MAO and newlineAChE enzymes and non-toxic to the human neuroblastoma SH-SY5Y cells. Based on newlinestructure-activity relationship analysis of the first series of compounds, second series of newlinethe compounds were designed by fixing the position of piperidine/morpholine ethyl chain newlineat the para position of one of the phenyl rings. In the second series, compound VP15 newlinev newlinewas found to be a multi-potent inhibitor of MAO-B and AChE with I