%0 Journal Article
%T Hybridization of Fluoro-amodiaquine (FAQ) with Pyrimidines: Synthesis and Antimalarial Efficacy of FAQ¨CPyrimidines
%J -
%D 2019
%R https://doi.org/10.1021/acsmedchemlett.8b00496
%X To evade the possible toxicity associated with the formation of quinone-imine metabolite in amodiaquine (AQ), the para-hydroxyl group was replaced with a £¿F atom, and the resulting 4¡ä-fluoro-amodiaquine (FAQ) was hybridized with substituted pyrimidines. The synthesized FAQ¨Cpyrimidines displayed better in vitro potency than chloroquine (CQ) against the resistant P. falciparum strain (Dd2), exhibiting up to 47.3-fold better activity (IC50: 4.69 nM) than CQ (IC50: 222 nM) and 2.8-fold better potency than artesunate (IC50: 13.0 nM). Twelve compounds exhibited better antiplasmodial activity than CQ against the CQ-sensitive (NF54) strain. Two compounds were evaluated in vivo against a P. berghei-mouse malaria model. Mechanistic heme-binding studies, computational docking studies against Pf-DHFR and in vitro microsomal stability studies were performed for the representative molecules of the series to assess their antimalarial efficacy
%U https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00496