Synthesis and antifungal properties of alpha-methoxy and alpha-hydroxyl substituted 4-thiatetradecanoic acids.
4-thiatetradecanoic acid exhibited weak antifungal activities against Candida albicans (ATCC 60193), Cryptococcus neoformans (ATCC 66031), and Aspergillus niger (ATCC 16404) (MIC=4.8-12.7 mM). It has been demonstrated that alpha-methoxylation efficiently blocks beta-oxidation and significantly improve the antifungal activities of fatty acids. We examined whether antifungal activity of 4-thiatetradecanoic acid can be improved by alpha-substitution. The unprecedented (+/-)-2-hydroxy-4-thiatetradecanoic acid was synthesized in four steps (20% overall yield), while the (+/-)-2-methoxy-4-thiatetradecanoic acid was synthesized in five steps (14% overall yield) starting from 1-decanethiol. The key step in the synthesis was the hydrolysis of a trimethylsilyloxynitrile. In general, the novel (+/-)-2-methoxy-4-thiatetradecanoic acid displayed significantly higher antifungal activities against C. albicans (ATCC 60193), C. neoformans (ATCC 66031), and A. niger (ATCC 16404) (MIC=0.8-1.2 mM), when compared with 4-thiatetradecanoic acid. In the case of C. neoformans the (+/-)-2-hydroxy-4-thiatetradecanoic acid was more fungitoxic (MIC=0.17 mM) than the alpha-methoxylated analog, but not as effective against A. niger (MIC=5.5 mM). The enhanced fungitoxicity of the (+/-)-2-methoxy-4-thiatetradecanoic acid, as compared to decylthiopropionic acid, might be the result of a longer half-life in the cells due to a blocked beta-oxidation pathway which results in more time to exert its toxic effects. Thus, these novel fatty acids may have applications as probes to study fatty acid metabolic routes in human cells.
Carballeira
Néstor M
NM
Department of Chemistry, University of Puerto Rico, P.O. Box 23346, San Juan 00931-3346, Puerto Rico. nmcarballeira@uprrp.edu
O'Neill
Rosann
R
Parang
Keykavous
K
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001234:Aspergillus niger / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D003455:Cryptococcus neoformans / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008826:Microbial Sensitivity Tests; D009227:Myristic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D009227:Myristic Acids