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dc.contributor.authorMohamed, Tarek
dc.date.accessioned2011-08-30 19:05:22 (GMT)
dc.date.available2011-08-30 19:05:22 (GMT)
dc.date.issued2011-08-30T19:05:22Z
dc.date.submitted2011
dc.identifier.urihttp://hdl.handle.net/10012/6183
dc.description.abstractAlzheimer’s disease (AD) is a highly complex and rapidly progressive neurodegenerative disorder characterized by the systemic collapse of cognitive function and formation of dense amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). AD pathology is derived from the cholinergic, amyloid and tau hypotheses, respectively. Current pharmacotherapy with known anti-cholinesterases, such as Aricept ® and Exelon ®, only offer symptomatic relief without any disease-modifying effects (DMEs). It is now clear that in order to prevent the rapid progression of AD, new therapeutic treatments should target multiple AD pathways as opposed to the traditional “one drug, one target” approach. This research project employed medicinal chemistry tools to develop multifunctional small organic molecules against three key targets of AD pathology – the cholinesterases (AChE and BuChE), AChE-induced and self-induced Aβ1-40 aggregation and generation (β-secretase). A chemical library composed of 112 derivatives was generated to gather structure-activity relationship (SAR) data. The derivatives were based on a novel, non-fused, 2,4-disubstituted pyrimidine ring (2,4-DPR) template with substituents at the C-2 and C-4 position varying in size, steric and electronic properties. Molecular modeling was utilized to investigate their binding modes within the target enzymes and along with the acquired SAR, the chemical library was screened to identify lead multifunctional candidates.en
dc.language.isoenen
dc.publisherUniversity of Waterlooen
dc.subjectAlzheimer's diseaseen
dc.subjectMedicinal Chemistryen
dc.subjectCholinesteraseen
dc.subjectAmyloiden
dc.subjectPyrimidineen
dc.subjectBACE-1en
dc.titleDesign, Synthesis and Biological Evaluation of 2,4-Disubstituted Pyrimidine Derivatives: Multifunctional Candidates as Potential Treatment Options for Alzheimer’s Diseaseen
dc.typeMaster Thesisen
dc.pendingfalseen
dc.subject.programPharmacyen
uws-etd.degree.departmentSchool of Pharmacyen
uws-etd.degreeMaster of Scienceen
uws.typeOfResourceTexten
uws.peerReviewStatusUnrevieweden
uws.scholarLevelGraduateen


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