Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 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 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/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.
Li
Xing-Cong
XC
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. xcli7@olemiss.edu
Jacob
Melissa R
MR
Khan
Shabana I
SI
Ashfaq
M Khalid
MK
Babu
K Suresh
KS
Agarwal
Ameeta K
AK
Elsohly
Hala N
HN
Manly
Susan P
SP
Clark
Alice M
AM
D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005658:Fungi / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010946:Plants, Medicinal / Q000737:chemistry; D019666:Rubiaceae / Q000737:chemistry; D014249:Trichophyton / Q000187:drug effects
D000480:Alkynes; D000935:Antifungal Agents; D005231:Fatty Acids, Unsaturated