Speaker: Dr. Praveen Nekkar
(Assistant Professor, Pharmaceutical Science, The School of Pharmacy, University of Waterloo)
Title of Seminar: "Development of Agents to Treat Alzheimer's Disease (AD)"
[Host: Dr. D. Spafford]
All are welcome!
Abstract: AD is a complex, debilitating, neurodegenerative disorder that affects thought, memory and language leading to dementia. It is now threatening to become a global menace in the coming years due to an increase in aging population and life span across the globe. According to the World Health Organization (WHO), by 2025 the total number of AD patients will be around 34 million worldwide. The current pharmacotherapy based on small molecule inhibitors of the enzyme acetylcholinesterase (AChE) provides symptomatic relief and are ineffective as AD progresses. This mandates the need to develop novel small molecule therapies to treat AD. Toward this direction, some strategies include development of dual cholinesterase enzyme (AChE and butyrylcholinesterase; BuChE) inhibitors and beta-amyloid aggregation inhibitors. We have designed, synthesized and evaluated a library of heterocyclic molecules as cholinesterase (ChE) inhibitors with beta-amyloid aggregation inhibition. The steric and electronic properties at various positions of the heterocyclic ring scaffold ring were varied to investigate their effect on ChE inhibitory potency and selectivity. The ability of the synthesized compounds to inhibit the cholinesterase enzymes and beta-amyloid aggregation was evaluated. In addition, the ligand-enzyme binding interactions of potent and selective ChE inhibitors were investigated by molecular modeling studies. The structure-activity relationship (SAR) data obtained combined with computational experiments will guide the development of a pharmacophore model to develop novel ChE inhibitors with beta-amyloid aggregation inhibition. In summary, the current study proposes that (i) novel heterocyclic rings can be developed as dual ChE inhibitors with beta-amyloid aggregation inhibition properties; (ii) the inhibitory potency and selectivity are sensitive to substituent steric and electronic effects and (iii) the SAR data combined with molecular modeling studies provide new drug-design concepts in ChE/beta-amyloid inhibitor development.
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