Potent In Vitro Antifungal Activity of Naturally Occurring Acetylenic Acids

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, and Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA

^* To whom correspondence should be addressed. Email: xcli7{at}olemiss.edu. amclark{at}olemiss.edu.

	Abstract

Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C16 to C20: 6-hexadecynoic acid (1), 6-heptadecynoic acid (2), 6-octadecynoic acid (3), 6-nonadecynoic acid (4), and 6-icosynoic acid (5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activity against Candida albicans, C. glabrata, C. krusei, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, A. flavus, A. niger, Trichophyton mentagrophytes, and T. rubrum by comparing with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. They showed varying degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MIC values comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (6) and 5,8,11,14-eicosatetraynoic acid (7) in the in vitro antifungal testing further demonstrated that the antifungal activity of the acetylenic acids was associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that 1-5 were not toxic at concentrations up to 32 µM. Furthermore, 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 µmoles/kg administered intraperitoneally. Taking into account the low in vitro and in vivo toxicity and significant antifungal potency, these 6-acetylenic acids may be excellent leads for further preclinical studies.