American Society for Microbiology, Antimicrobial Agents and Chemotherapy, 3(58), p. 1516-1522, 2014
DOI: 10.1128/aac.02148-13
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ABSTRACT Drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds—dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles—with promising activity against the liver stage. Focused structure-activity studies on the dihydroquinazolinone scaffold revealed several molecules with excellent potency against both blood and liver stages. One promising early lead with dual activity is 2-( p -bromophenyl)-3-(2-(diethylamino)ethyl)-2,3-dihydroquinazolin-4(1 H )-one with 50% effective concentrations (EC 50 s) of 0.46 μM and 0.34 μM against liver stage Plasmodium berghei ANKA and blood stage Plasmodium falciparum 3D7 parasites, respectively. Structure-activity relationships revealed that liver stage activity for this compound class requires a 3-dialkyl amino ethyl group and is abolished by substitution at the ortho -position of the phenyl moiety. These compounds have minimal toxicity to mammalian cells and are thus attractive compounds for further development.