Synthesis And Biological Assessment Of Pyrimidotacrines As Promising Agents For Alzheimer'S Disease Therapy

Considering the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSMs) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. Thus, new Pyrimidotacrines were designed and synthesized by merging pyrimidine scaffold and tacrine. Among them, 4-(4-nitrophenyl)-2-phenyl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-5-amine (4 j) was identified as less hepatotoxic than tacrine at high concentration, a submicromolar inhibitor against both acetylcholinesterase (AChE) (IC50=677 +/- 28 nM) and butyrylcholinesterase (BuChE) (IC50=756 +/- 41 nM) showing potent antioxidant properties (2.43 TE) and displaying a strong neuroprotection effect against hydrogen peroxide (H2O2) and Oligomycin Rotenone. Consequently, 4 j is a potential new hit-ligand for AD therapy for further biological exploration