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.

In Vitro Profiling of Pramiconazole and In Vivo Evaluation in Microsporum canis Dermatitis and Candida albicans Vaginitis Laboratory Models

“…The in vitro IC 50 s for reference drugs were comparable to the ranges in literature (2,5,20), and available data on pramiconazole were also confirmed (16,17) (Table 1). TRB performs marginally better against dermatophytes.…”

“…Although current treatment options may suffice, new antifungals would still be acceptable to improve treatment compliance or reduce adverse effects and drug interactions. The triazole pramiconazole shows good in vitro and clinical activity against dermatophytes and yeasts (12,16,17) and Malassezia infections (10,11,19). Laboratory data always refer to oral treatment of mice and guinea pigs (16,17); however, no data on topical application are available.…”

“…The triazole pramiconazole shows good in vitro and clinical activity against dermatophytes and yeasts (12,16,17) and Malassezia infections (10,11,19). Laboratory data always refer to oral treatment of mice and guinea pigs (16,17); however, no data on topical application are available. No data have yet been published on pramiconazole in VVC in comparison with reference drugs, although it is in clinical de- a For MRC-5 cells, the CC 50 (the concentration at which 50% of the MRC-5 cells are killed) is given.…”

Activity of the Triazole Antifungal R126638 as Assessed by Corneofungimetry

“…The more pronounced in vivo effect of R126638 compared to itraconazole corroborated a 5-fold and 3-fold higher plasma and skin levels in mice [29] . These promising results from animal models were in line with the present data in humans, showing a clear antifungal activity of R126638 in the stratum corneum.…”

Synthesis and Biological Activity of 1,2,4-Triazolo-[3,4-b]Thiadiazole as Antimicrobial Agents

“…During the last two decades, the chemistry of 1,2,4-triazole and 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole and their derivatives have received considerable attention owing to their synthetic and effective biological importance [3][4][5]. 1,2,4-Triazoles and their derivatives occupy a essential position in medicinal chemistry because of their potential biological activities such as antibacterial [6], antifungal [7], antitubercular [8], anti-inflammatory [9] etc. The 1,2,4-triazole ring is an integral part found in various drugs such as rizatriptan, ribavirin, and fluconazole ( Fig.1), which find a wide range of applications in pharmaceutical industry [10][11][12].…”