Marine natural products as prototypes for new antitoxoplasmal and antimalarial agents

The continuing potential for novel drug discovery from marine-derived compounds remains virtually untapped. The world's oceans cover at least two-thirds of the Earth's surface. Marine organisms are a prolific source of structurally diverse bioactive secondary metabolites.; In a program targeted at the discovery of new bioactive agents from marine invertebrates, especially sponges, crude extracts, chromatographic column fractions, and pure isolated compounds were tested in antiprotozoal, antiviral, antimicrobial and anticancer assays. Plakortolide (28) and plakortolide G (30) were shown to have potent activity in vitro against Toxoplasma gondii. Another isolated, plakortolide F (29) displayed no in vitro antitoxoplasmal activity and low toxicity to human cells. This indicated that within the peroxylactone class some have better selectivity for inhibitory activity against the parasite. Plakortolide displayed inhibitory activity in vivo against mice infected orally with T. gondii cysts. This is the first reported T. gondii inhibitory activity from a marine natural product from this class of compounds.; Plakortolide G (30) showed inhibitory in vitro activity against D6 and W2 clones of the malarial parasite Plasmodium falciparum, with a selectivity for W2 clone. 3,4-Diepiplakortolide C (32) exhibited inhibitory activity against P. falciparum in both the D6 Clone and W2 Clone. Plakortolide H (31), jamaic acid (33), and onkopyranone (34) were inactive, but displayed no significant cytotoxicity to mammalian cells.; The absolute configuration of Plakortolide (28), plakortolide G (30) and diepiplakortolide C (32) (3R ,4R,6R,8S) were determined by spectroscopic and ab initio optical rotation computations using a coupled Hartree-Fock (CHF) method implemented in CADPAC. The relative stereochemistry of plakortolide F (29) and plakortolide H (31) were established using NOE techniques.; Manzamine A (40) inhibitory potential against mice infected orally with T. gondii was demonstrated by a lapse of 9 days between the end of treatment and the first deaths in the treated group. This suggests the relevant observation that significant prolongation of life was afforded to treated mice. This is the first reported T. gondii inhibitory activity from this class of compounds. Manzamine A (40) has potent in vitro activity against D6 and W2 clones of the malarial parasite Plasmodium falciparum.; A conventional high performance liquid chromatography method was developed for the separation of natural products and included C₁₈ and NH ₂ stationary phases gradient elution. The Sepbox®-system was also employed in the separation of manzamine alkaloids.