Application of quinazoline and pyrido3,2-dpyrimidine templates to design multi-targeting agents in Alzheimer's disease

摘要

A quinazoline and pyrido3,2-d pyrimidine based compound library was designed, synthesized and evaluated as multi-targeting agents aimed at Alzheimer's disease (AD). The SAR studies identified compound 8h (8-chloro-N-2-isopropyl-N-4-phenethylquinazoline-2,4-diamine) as a potent inhibitor of A beta 40 aggregation (IC50 = 900 nM) which was 3.6-fold more potent compared to the reference agent curcumin (Ab40 IC50 = 3.3 mM). It also exhibited dual ChE inhibition (AChE IC50 = 8.6 mu M; BuChE IC50 = 2.6 mu M). Compound 9h (8-chloro-N-4-(3,4-dimethoxyphenethyl)-N-2-isopropylquinazoline-2,4-diamine) was identified as the most potent A beta 42 aggregation inhibitor (IC50 similar to 1.5 mu M). Transmission electron microscopy (TEM) imaging demonstrates their anti-A beta 40/A beta 42 aggregation properties. Compound 8e was identified as a potent BuChE inhibitor (BuChEIC(50) = 100 nM) which was 36-fold more potent compared to donepezil (BuChEIC(50) = 3.6 mM). The pyrido3,2-d pyrimidine bioisostere 10b (N-2-isopropyl- N-4-phenethylpyrido3,2-d pyrimidine-2,4-diamine) exhibited good anti-Ab activity (A beta 40 IC50 = 1.1 mM), dual ChE inhibition and iron-chelating properties (23.6 chelation at 50 mM). These investigations demonstrate the usefulness of either a quinazoline or a pyrido3,2-d pyrimidine based ring scaffold in the design of multi-targeting agents to treat AD.