A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Naturalproduct inhibitors of cell wall (

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The potent insecticidal agent nodulisporic acid A (1a), representative of a new class of indole terpenes, was isolated from fermentations of a Nodulisporium sp. Nodulisporic acid A was active against the larvae of the blowfly and mosquito at sub-part-per-million levels. The structure followed mainly from a consideration of spectroscopic evidence, including Dunkel's computerized 2D INADEQUATE analysis. The relative stereochemistry of the eastern and western hemispheres of 1a and its methyl ester, 1b, were independently determined on the basis of ROESY, NOESY, NOEDS, and J vic evidence. By employing the same methods, the complete relative stereochemistry was determined by analysis of suitable transformation products, using the reduced β-ketodihydropyrrole ring as a stereochemical bridge between the two zones. These results were confirmed by X-ray analysis of the 7-p-bromobenzoate methyl ester derivative, 1c. The absolute stereochemistry was established by application of the advanced Mosher method to methyl ester 1b. Of biogenetic interest is the presence of a unique isoprenylated indole moiety not previously found in other indole mycotoxins.