Synthesis and in vitro and in vivo structure-activity relationships of novel antifungal triazoles for dermatology.
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.
Meerpoel
Lieven
L
Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. lmeerpoe@prdbe.jnj.com
Backx
Leo J J
LJ
Van der Veken
Louis J E
LJ
Heeres
Jan
J
Corens
David
D
De Groot
Alex
A
Odds
Frank C
FC
Van Gerven
Frans
F
Woestenborghs
Filip A A
FA
Van Breda
Andre
A
Oris
Michel
M
van Dorsselaer
Pascal
P
Willemsens
Gustaaf H M
GH
Vermuyten
Karen J P
KJ
Marichal
Patrick J M G
PJ
Vanden Bossche
Hugo F
HF
Ausma
Jannie
J
Borgers
Marcel
M
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
D000935:Antifungal Agents; D003879:Dermatologic Agents; D007093:Imidazoles; D009281:Naphthalenes; D014230:Triazoles; D017964:Itraconazole; C482452:pramiconazole; D000077291:Terbinafine