title: 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.affiliation: Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. lmeerpoe@prdbe.jnj.com
authors.forename: Lieven
authors.initials: L
authors.lastname: Meerpoel
authors.forename: Leo J J
authors.initials: LJ
authors.lastname: Backx
authors.forename: Louis J E
authors.initials: LJ
authors.lastname: Van der Veken
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: David
authors.initials: D
authors.lastname: Corens
authors.forename: Alex
authors.initials: A
authors.lastname: De Groot
authors.forename: Frank C
authors.initials: FC
authors.lastname: Odds
authors.forename: Frans
authors.initials: F
authors.lastname: Van Gerven
authors.forename: Filip A A
authors.initials: FA
authors.lastname: Woestenborghs
authors.forename: Andre
authors.initials: A
authors.lastname: Van Breda
authors.forename: Michel
authors.initials: M
authors.lastname: Oris
authors.forename: Pascal
authors.initials: P
authors.lastname: van Dorsselaer
authors.forename: Gustaaf H M
authors.initials: GH
authors.lastname: Willemsens
authors.forename: Karen J P
authors.initials: KJ
authors.lastname: Vermuyten
authors.forename: Patrick J M G
authors.initials: PJ
authors.lastname: Marichal
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Vanden Bossche
authors.forename: Jannie
authors.initials: J
authors.lastname: Ausma
authors.forename: Marcel
authors.initials: M
authors.lastname: Borgers
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003879:Dermatologic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017964:Itraconazole / Q000494:pharmacology; D051379:Mice; D003904:Mitosporic Fungi / Q000187:drug effects / Q000302:isolation & purification; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology; D009281:Naphthalenes / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000077291:Terbinafine; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D003879:Dermatologic Agents; D007093:Imidazoles; D009281:Naphthalenes; D014230:Triazoles; D017964:Itraconazole; C482452:pramiconazole; D000077291:Terbinafine