Synthesis and in vitro and in vivo structure-activity relationships of novel antifungal triazoles for dermatology.

Abstract

In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in animal models. This panel of azoles was studied in vitro and compared with itraconazole and terbinafine for their antifungal activity using a panel of 24 Candida spp. and 182 dermatophyte isolates. Three azoles (1c, 2c, and 4c) showed in vitro antifungal potency equivalent to itraconazole, but superior to terbinafine, against a panel of 24 Candida spp. with comparable or lower activity than that of itraconazole and terbinafine against 182 dermatophyte isolates and only rare activity against other pathogenic fungi. However, in vivo 1c and 4c, both given orally, demonstrated antifungal activity at least three times greater than itraconazole and were superior compared to terbinafine in M. canis infected guinea pigs. In a mouse model infected by T. mentagrophytes, again 4c, but not 1c, showed 5-fold superior activity over itraconazole and terbinafine. Compound 2c was effective in both models but less effective than itraconazole in these models. On the basis of these promising results, 4c is currently being clinically investigated for its potential as a novel antifungal agent against dermatophytosis.

• Authors: Lieven Meerpoel, Leo J J Backx, Louis J E Van der Veken, Jan Heeres, David Corens, Alex De Groot, Frank C Odds, Frans Van Gerven, Filip A A Woestenborghs, Andre Van Breda, Michel Oris, Pascal van Dorsselaer, Gustaaf H M Willemsens, Karen J P Vermuyten, Patrick J M G Marichal, Hugo F Vanden Bossche, Jannie Ausma, Marcel Borgers
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 6 Pg. 2184-93 (Mar 24 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15771461 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Dermatologic Agents
• Imidazoles
• Naphthalenes
• Triazoles
• Itraconazole
• pramiconazole
• Terbinafine

Topics

• Animals
• Antifungal Agents (chemical synthesis, chemistry, pharmacology)
• Dermatologic Agents (chemical synthesis, chemistry, pharmacology)
• Guinea Pigs
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Itraconazole (pharmacology)
• Mice
• Mitosporic Fungi (drug effects, isolation & purification)
• Mycoses (drug therapy, microbiology)
• Naphthalenes (pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Terbinafine
• Triazoles (chemical synthesis, chemistry, pharmacology)