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ACS Med Chem Lett. 2012 Sep 7;3(10):814-7. doi: 10.1021/ml300173e. eCollection 2012 Oct 11.

Antifungal spectrum, in vivo efficacy, and structure-activity relationship of ilicicolin h.

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1
Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.

Abstract

Ilicicolin H is a polyketide-nonribosomal peptide synthase (NRPS)-natural product isolated from Gliocadium roseum, which exhibits potent and broad spectrum antifungal activity, with sub-μg/mL MICs against Candida spp., Aspergillus fumigatus, and Cryptococcus spp. It showed a novel mode of action, potent inhibition (IC50 = 2-3 ng/mL) of the mitochondrial cytochrome bc1 reductase, and over 1000-fold selectivity relative to rat liver cytochrome bc1 reductase. Ilicicolin H exhibited in vivo efficacy in murine models of Candida albicans and Cryptococcus neoformans infections, but efficacy may have been limited by high plasma protein binding. Systematic structural modification of ilicicolin H was undertaken to understand the structural requirement for the antifungal activity. The details of the biological activity of ilicicolin H and structural modification of some of the key parts of the molecule and resulting activity of the derivatives are discussed. These data suggest that the β-keto group is critical for the antifungal activity.

KEYWORDS:

Gliocadium roseum; antifungal activity; broad spectrum; cytochrome bc1 reductase inhibitor; ilicicolin H; in vivo efficacy

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