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Antimicrobial Agents and Chemotherapy, July 2008, p. 2442-2448, Vol. 52, No. 7
0066-4804/08/$08.00+0 doi:10.1128/AAC.01297-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Potent In Vitro Antifungal Activities of Naturally Occurring Acetylenic Acids
Xing-Cong Li,1*
Melissa R. Jacob,1
Shabana I. Khan,1
M. Khalid Ashfaq,1
K. Suresh Babu,1
Ameeta K. Agarwal,1
Hala N. ElSohly,1
Susan P. Manly,1 and
Alice M. Clark1,2*
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences,1 Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, Mississippi 386772
Received 8 October 2007/ Returned for modification 6 January 2008/ Accepted 26 April 2008
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 (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 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 activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various 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 MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 µM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 µmol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
* Corresponding author. Mailing address: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677. Phone for X.-C. Li: (662) 915-6742. Fax: (662) 915-7989. E-mail: xcli7{at}olemiss.edu. Phone for A. M. Clark: (662) 915-7482. Fax: (662) 915-7577. E-mail: amclark{at}olemiss.edu
Published ahead of print on 5 May 2008.
Antimicrobial Agents and Chemotherapy, July 2008, p. 2442-2448, Vol. 52, No. 7
0066-4804/08/$08.00+0 doi:10.1128/AAC.01297-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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