title: Synthesis and Structure-Activity Relationships of Tambjamines and B-Ring Functionalized Prodiginines as Potent Antimalarials.
abstract: Synthesis and antimalarial activity of 94 novel bipyrrole tambjamines (TAs) and a library of B-ring functionalized tripyrrole prodiginines (PGs) against a panel of Plasmodium falciparum strains are described. The activity and structure-activity relationships demonstrate that the ring-C of PGs can be replaced by an alkylamine, providing for TAs with retained/enhanced potency. Furthermore, ring-B of PGs/TAs can be substituted with short alkyl substitutions at either 4-position (replacement of OMe) or 3- and 4-positions without impacting potency. Eight representative TAs and two PGs have been evaluated for antimalarial activity against multidrug-resistant P. yoelii in mice in the dose range of 5-100 mg/kg × 4 days by oral administration. The KAR425 TA offered greater efficacy than previously observed for any PG, providing 100% protection to malaria-infected mice until day 28 at doses of 25 and 50 mg/kg × 4 days, and was also curative in this model in a single oral dose (80 mg/kg). This study presents the first account of antimalarial activity in tambjamines.
authors: Department of Chemistry, Portland State University , Portland, Oregon 97201, United States.
authors: Papireddy
authors: P
authors: Kancharla
authors: Department of Chemistry, Portland State University , Portland, Oregon 97201, United States.|Veterans Affairs Medical Center , Portland, Oregon 97239, United States.
authors: Jane Xu
authors: JX
authors: Kelly
authors: Department of Chemistry, Portland State University , Portland, Oregon 97201, United States.
authors: Kevin A
authors: KA
authors: Reynolds
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011758:Pyrroles