Hybridization of Fluoro-amodiaquine (FAQ) with Pyrimidines: Synthesis and Antimalarial Efficacy of FAQ-Pyrimidines.

To evade the possible toxicity associated with the formation of quinone-imine metabolite in amodiaquine (AQ), the -hydroxyl group was replaced with a -F atom, and the resulting 4'-fluoro-amodiaquine (FAQ) was hybridized with substituted pyrimidines. The synthesized FAQ-pyrimidines displayed better potency than chloroquine (CQ) against the resistant strain (Dd2), exhibiting up to 47.3-fold better activity (IC: 4.69 nM) than CQ (IC: 222 nM) and 2.8-fold better potency than artesunate (IC: 13.0 nM). Twelve compounds exhibited better antiplasmodial activity than CQ against the CQ-sensitive (NF54) strain. Two compounds were evaluated against a -mouse malaria model. Mechanistic heme-binding studies, computational docking studies against -DHFR and microsomal stability studies were performed for the representative molecules of the series to assess their antimalarial efficacy.