PYRIMIDINE ANALOGUES AS ANTI NEURO DEGENERATIVE AGENTS

Abstract

, Neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS) altogether comprise one neurodegenerative mechanisms involved in the disease development. This dissertation attempts to investigate the possibility of using the pyrimidine derivatives as neuroprotective agents, particularly emphasizing on their polypharmacology profiles. Pyrimidine, a heteroaromatic compound with six members containing a nitrogen atom, is well known for its chemical diversity, brain penetration, favorable physiochemical properties, and ability to interact with different biological receptors related to neurodegeneration. Among the important pathologic processes that have been considered in this research project are aggregation of amyloid-β, tau protein hyperphosphorylation, neurotransmitter imbalance (cholinergic and dopaminergic systems), oxidative stress associated with monoamine oxidase B (MAO-B) and chronic neuroinflammation. A systematic SAR study was conducted with a view to finding out how structural variations in certain positions in the pyrimidine scaffold affected the enzymes' binding affinity, lipophilicity, selectivity towards various types of receptors and central nervous system penetration. Functional groups examined within the context of this work included amino groups, diamino groups, styryl groups and electron donating/withdrawing substituents as regards their effects on the inhibitory activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidase B (MAO-B). Experimental work entailed in silico molecular docking of some selected pyrimidines against three neurodegeneration-related protein targets: monoamine oxidase B (PDB: 2BYB), acetyl-cholinesterase (PDB: 4BDT) and butyrylcholinesterase (PDB: 6QAB). In silico docking was done using recognized computational software, while docking scores were determined based on molecular interaction between the proteins and ligands. Among the selected pyrimidines, compound numbers 19 and 22 exhibited remarkable binding to MAO-B, while compounds 10 and 22 had favourable docking scores against acetylcholinesterase and butyryl-cholinesterase respectively. This study has established an excellent computational platform that will guide the future development of drugs based on pyrimidine compounds to target the highly complicated neurodegenerative pathways.