Dihydroquinazolinone Inhibitors of Proliferation of Blood and Liver Stage Malaria Parasites

作者：Derbyshire Emily R; Min Jaeki; Guiguemde W Armand; Clark Julie A; Connelly Michele C; Magalhaes Andreia D; Guy R Kiplin; Clardy Jon^*

来源：Antimicrobial Agents and Chemotherapy, 2014, 58(3): 1516-1522.

DOI：10.1128/AAC.02148-13

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(1H)-one with 50% effective concentrations (EC(50)s) of 0.46 mu M and 0.34 mu M 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.

• 出版日期2014-3