title: Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.
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(1H)-one with 50% effective concentrations (EC50s) 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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Derbyshire
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.forename: Julie A
authors.initials: JA
authors.lastname: Clark
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Andreia D
authors.initials: AD
authors.lastname: Magalhães
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000097:blood / Q000188:drug therapy / Q000469:parasitology; D010961:Plasmodium / Q000187:drug effects* / Q000254:growth & development; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011799:Quinazolines / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011799:Quinazolines