title: Antimalarial activity of natural and synthetic prodiginines.
abstract: Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds. Herein we describe the in vitro antimalarial activity of four natural (IC(50) = 1.7-8.0 nM) and three sets of synthetic prodiginines against Plasmodium falciparum. Set 1 compounds replaced the terminal nonalkylated pyrrole ring of natural prodiginines and had diminished activity (IC(50) > 2920 nM). Set 2 and set 3 prodiginines were monosubstituted or disubstituted at either the 3 or 5 position of the right-hand terminal pyrrole, respectively. Potent in vitro activity (IC(50) = 0.9-16.0 nM) was observed using alkyl or aryl substituents. Metacycloprodiginine and more potent synthetic analogues were evaluated in a P. yoelii murine patent infection using oral administration. Each analogue reduced parasitemia by more than 90% after 25 (mg/kg)/day dosing and in some cases provided a cure. The most favorable profile was 92% parasite reduction at 5 (mg/kg)/day, and 100% reduction at 25 (mg/kg)/day without any evident weight loses or clinical overt toxicity.
authors: Department of Chemistry, Portland State University, Portland, Oregon 97207-0751, United States.
authors: Kancharla
authors: K
authors: Papireddy
authors: Martin
authors: M
authors: Smilkstein
authors: Jane Xu
authors: JX
authors: Kelly
authors: Shweta
authors: Shaimaa M
authors: SM
authors: Salem
authors: Mamoun
authors: M
authors: Alhamadsheh
authors: Stuart W
authors: SW
authors: Haynes
authors: Gregory L
authors: GL
authors: Challis
authors: Kevin A
authors: KA
authors: Reynolds
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii / Q000187:drug effects; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; C010307:prodiginine; D011353:Prodigiosin