Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Malaria
remains one of the deadliest diseases in the world today.
Novel chemoprophylactic and chemotherapeutic antimalarials are needed
to support the renewed eradication agenda. We have discovered a novel
antimalarial acridone chemotype with dual-stage activity against both
liver-stage and blood-stage malaria. Several lead compounds generated
from structural optimization of a large library of novel acridones
exhibit efficacy in the following systems: (1) picomolar inhibition
of in vitro Plasmodium falciparum blood-stage
growth against multidrug-resistant parasites; (2) curative efficacy
after oral administration in an erythrocytic Plasmodium
yoelii murine malaria model; (3) prevention of in
vitro Plasmodium berghei sporozoite-induced
development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice.
This study offers the first account of liver-stage antimalarial activity
in an acridone chemotype. Details of the design, chemistry, structure–activity
relationships, safety, metabolic/pharmacokinetic studies, and mechanistic
investigation are presented herein.