Synthesis and Antimalarial Activity of Novel 3-Substituted Chloroquine Derivatives

The synthesis and characterization of a series of new 3-substituted chloroquine (CQ) derivatives is reported along with their anti-malarial activity against CQ sensitive, 3D7, and CQ resistant, Dd2, strains of Plasmodium falciparum. The new CQ derivatives stem from the aroylation of 3-aminochloroquine which in turn is prepared in four efficient steps from 4,7-dichloroquinoline. Variation of the aroylation substituents and ring substitution patterns reveal that 4-substitution with electron-withdrawing moieties results in the lowest IC50 values, both in the same order of magnitude as CQ itself for the 3D7 strain. Given its activity against the resistant Dd2 strain, the 4-chlorobenzamido-CQ derivative is chosen as the lead compound for potential use in combination therapy.