Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer's disease

Abstract

A quinazoline and pyrido[3,2-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-N²-isopropyl-N⁴-phenethylquinazoline-2,4-diamine) as a potent inhibitor of Aβ40 aggregation (IC₅₀ = 900 nM) which was 3.6-fold more potent compared to the reference agent curcumin (Aβ40 IC₅₀ = 3.3 μM). It also exhibited dual ChE inhibition (AChE IC₅₀ = 8.6 μM; BuChE IC₅₀ = 2.6 μM). Compound 9h (8-chloro-N⁴-(3,4-dimethoxyphenethyl)-N²-isopropylquinazoline-2,4-diamine) was identified as the most potent Aβ42 aggregation inhibitor (IC₅₀ ∼ 1.5 μM). Transmission electron microscopy (TEM) imaging demonstrates their anti-Aβ40/Aβ42 aggregation properties. Compound 8e was identified as a potent BuChE inhibitor (BuChE IC₅₀ = 100 nM) which was 36-fold more potent compared to donepezil (BuChE IC₅₀ = 3.6 μM). The pyrido[3,2-d]pyrimidine bioisostere 10b (N²-isopropyl-N⁴-phenethylpyrido[3,2-d]pyrimidine-2,4-diamine) exhibited good anti-Aβ activity (Aβ40 IC₅₀ = 1.1 μM), dual ChE inhibition and iron-chelating properties (23.6% chelation at 50 μM). These investigations demonstrate the usefulness of either a quinazoline or a pyrido[3,2-d]pyrimidine based ring scaffold in the design of multi-targeting agents to treat AD.