2,6‐hexadecadiynoic acid and 2,6‐nonadecadiynoic acid: Novel synthesized acetylenic fatty acids as potent antifungal agents

Abstract

The hitherto unknown 2,6-hexadecadiynoic acid, 2,6-nonadecadiynoic acid, and 2,9-hexadecadiynoic acid were synthesized in two steps and in 11-18% overall yields starting from either 1,5-hexadiyne or 1,8-nonadiyne. Among all the compounds 2,6-hexadecadiynoic acid displayed the best overall antifungal activity against both the fluconazole-resistant Candida albicans strains ATCC 14053 and ATCC 60193, with a minimum inhibitory concentration (MIC of 11 microM), and against Cryptococcus neoformans ATCC 66031 (MIC < 5.7 microM). 2,9-Hexadecadiynoic acid did not display any significant cytotoxicity against the fluconazole-resistant C. albicans strains, but it showed fungitoxicity against C. neoformans ATCC 66031 with a MIC value of < 5.8 microM. Other FA, such as 2-hexadecynoic acid, 5-hexadecynoic acid, 9-hexadecynoic acid, and 6-nonadecynoic acid were also synthesized and their antifungal activities compared with those of the novel acetylenic FA. 2-Hexadecynoic acid, a known antifungal FA, exhibited the best antifungal activity (MIC = 9.4 microM) against the fluconazole-resistant C. albicans ATCC 14053 strain, but it showed a MIC value of only 100 microM against C. albicans ATCC 60193. 2,6-Hexadecadiynoic acid and 2-hexadecynoic acid also displayed a MIC of 140-145 microM toward Mycobacterium tuberculosis H37Rv in Middlebrook 7H12 medium. In conclusion, 2,6-hexadecadiynoic acid exhibited the best fungitoxicity profile compared with other analogues. This diynoic FA has the potential to be further evaluated for use in topical antifungal formulations.

Potent In Vitro Antifungal Activities of Naturally Occurring Acetylenic Acids

“…While the reason for this discrepancy is unclear at this time, it is possible that other experimental conditions (such as inoculum size, incubation time, etc.) could account for these differences (6,7). To assess potential toxicity, the compounds were evaluated for in vitro cytotoxicity (39) Naturally occurring acetylenic acids are widely distributed in nature and are found in terrestrial plants, fungi, microorganisms, and marine organisms (3,11).…”

“…Several studies have also shown that natural and synthetic acetylenic acids have activity against human and agricultural fungal pathogens (5,9,14,16,17,24). As with the antibacterial activity, their antifungal activity is generally associated with their chain length and positional triple bond (6,16,22,28). For example, 4-, 5-, and 6-octynoic acids and 9-undecynoic acid are antifungal against T. mentagrophytes, with the last being the most active compound and slightly less potent than undecylenic acid (9).…”

“…Their strong fungicidal activities against T. mentagrophytes and T. rubrum indicates that they may quickly eradicate these pathogens and thus may reduce the chance of developing drug resistance in the treatment of topical infections. In addition, the synthetic methodologies for this class of compounds are available in the literature (6,7,26). Taking into account their antifungal potencies, low toxicities, synthetic accessibilities, and good pharmaceutical properties (similar to those of UDA), these 6-acetylenic acids may be excellent leads for further preclinical studies on their use as topical antifungal drug candidates to manage oral candidiasis and dermatomycosis.…”

“…In our ongoing effort to search for prototype natural product antifungal leads (1), the plant Sommera sabiceoides, which, along with P. gigantifolia, is a member of the family Rubiaceae, was selected for bioassayguided fractionation due to the potent antifungal activity of its crude methanol extract against C. albicans ATCC 90028 (50% inhibitory concentration [IC 50 ], Ͻ20 g/ml). As a result, five antifungal acetylenic acids, 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), compound 3, compound 4, and 6-icosynoic acid (compound 5), were isolated. Compounds 2 and 5 are newly isolated natural products.…”

A Single Amino Acid Substitution in One of the Lipases of Aspergillus nidulans Confers Resistance to the Antimycotic Drug Undecanoic Acid

“…Their inhibitory action on sensitive fungi is possibly the result of nonspecific interactions with cellular components that may lead to the disorganization of structural proteins and/or inactivation of enzymes (Walters et al 2004;Carballeira et al 2006). Undecanoic acid (UDA), a medium-chain fatty acid, is the most fungitoxic in the C 7:0 -C 18:0 series, inhibiting vegetative growth, conidial germination, and cellular respiration as well as fatty acid and phospholipid metabolism in the ubiquitous dermatophyte Trichophyton rubrum (Das and Banerjee 1982;Garg and Muller 1993).…”