prodigiosin and Malaria

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.

Topics: Animals; Antimalarials; Cell Line; Cell Survival; Female; Malaria; Mice; Plasmodium falciparum; Plasmodium yoelii; Prodigiosin; Structure-Activity Relationship

Heptyl prodigiosin was purified from a culture of alpha-proteobacteria isolated from a marine tunicate collected in Zamboanga, Philippines, as part of a program to screen natural products for antiparasitic activity. An in vitro antimalarial activity similar to that of quinine was found against the chloroquine-sensitive strain Plasmodium falciparum 3D7. The in vitro antimalarial activity was about 20 times the in vitro cytotoxic activity against L5178Y mouse lymphocytes. A single subcutaneous administration of 5 and 20 mg/kg significantly extended survival of P. berghei ANKA strain-infected mice but also caused sclerotic lesions at the site of injection. A single administration by gavage of 50 mg/kg did not increase survival time. The compound was not found to be mutagenic using in vitro micromethods for the Ames Salmonella typhimurium assay and the micronucleus assay using L5178Y mouse lymphoma cells.

Topics: Alphaproteobacteria; Animals; Antimalarials; Cell Line; Cell Survival; Disease Models, Animal; Malaria; Mice; Micronuclei, Chromosome-Defective; Micronucleus Tests; Mutation; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Prodigiosin; Salmonella typhimurium

An antimalarial drug testing system is described which utilizes trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys. The schizonticidal activity of standard antimalarial drugs in this system is reported. The system accurately predicted antimalarial activity in man of 8 of 9 compounds selected for clinical trials.

Topics: Amodiaquine; Animals; Antimalarials; Dapsone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Haplorhini; Macaca mulatta; Malaria; Phenanthrenes; Primaquine; Prodigiosin; Pyrimethamine; Quinine; Sulfadiazine; Sulfadimethoxine; Sulfalene; Trimethoprim

Two prodigiosin-like pigments from Streptomyces sp. were shown to be undecylprodiginine (i) and butylcycloheptylprodiginine (v). The antimalarial activity of five prodiginine pigments is given.

Topics: Animals; Antimalarials; Chemical Phenomena; Chemistry; Malaria; Mice; Plasmodium berghei; Prodigiosin; Streptomyces