Synthesis and Antifungal Activity of Butenafine Hydrochloride (KP-363), a New Benzylamine Antifungal Agent

The mechanism of action of a new benzylamine antimycotic, butenafine hydrochloride, was studied in Candida albicans by using the thiocarbamate antimycotic tolnaftate as a reference drug. Butenafine completely inhibited the growth of a test strain of C. albicans at 25 ,g/ml and was cidal at 50 ,ug/ml. Tolnaftate did not show any growth-inhibitory activity up to 100 ,ug/ml. Both butenafine and tolnaftate inhibited squalene epoxidation in C. albicans, with 50% inhibitory concentrations being 0.057 and 0.17 i.g/ml, respectivel. Butenafine, but not tolnaftate, induced the release of appreciable amounts of Pi from C. albicans cells at 12.5 ,ug/ml. This effect of butenafine was augmented when the cells were pretreated with tolnaftate. The results suggest that the direct membrane-damaging effect of butenafine may play a major role in its anticandidal activity and that the drug-induced alteration in the cellular sterol composition renders the cell membrane more susceptible to the membrane-damaging effect of this drug.Butenafine, a new benzylamine antimycotic agent, has potent in vitro activity against a wide range of pathogenic fungi, including dermatophytes, yeasts such as Candida and Cryptococcus spp., and dimorphic fungi (13). In experimental studies with animal models of dermatophytosis and candidiasis and in subsequent clinical studies designed for application to humans with these superficial dermatomycoses, it has proved to have excellent therapeutic efficacy (2, 3, 7).The mechanisms of antifungal action of butenafine were investigated by Hiratani et al. (8,9), using a susceptible dimorphic fungus, Sporothrix schenckii, in the yeast phase of growth, and they demonstrated that it primarily inhibits ergosterol biosynthesis in the fungus; at low concentrations, butenafine specifically inhibited the conversion of squalene into 2,3-oxidosqualene catalyzed by squalene epoxidase, ultimately resulting in the lack of ergosterol, which is an indispensable lipid component of fungal cell membranes. This research also demonstrated that butenafine has a direct damaging effect on the cell membranes of this fungus at higher concentrations (8,9).Tolnaftate, a thiocarbamate antimycotic agent which has potent antidermatophytic activity, has been used for the topical treatment of dermatophytosis and is also known to inhibit selectively the fungal squalene epoxidase reaction in a manner similar to that of the allylamines naftifine and terbinafine (4,10,11,(14)(15)(16)(17)(18)(19). Although butenafine and tolnaftate appear to share a common mechanism of action, they are different in their antimicrobial spectra; butenafine is active against Candida albicans in vitro and in vivo, while tolnaftate is not.The present study was performed to examine possible differences in the mechanisms of anticandidal action between butenafine and tolnaftate. MATERIALS AND METHODS Drugs

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Two mechanisms of butenafine action in Candida albicans

Iwatani

Arika

Yamaguchi

1993

“…Antifungal drugs such as lanoconazole, butenafine, terbinafine, and amorolfine developed in recent years have potent in vitro antidermatophyte activity (11,14,18,28) in the horny layer and nails at high levels when topically applied (1,15,19,29). In our previous study with a guinea pig tinea pedis model (26), we demonstrated that the therapeutic efficacy of lanoconazole was not correctly assessed by the conventional culture method because of a carryover of the drug remaining in the treated skin tissues to the culture media for detecting fungi.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of Topically Applied KP-103 against Experimental Tinea Unguium in Guinea Pigs in Comparison with Amorolfine and Terbinafine

Tatsumi

Yokoo

Senda

et al. 2002

Self Cite

The therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation of Trichophyton mentagrophytes SM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine against T. mentagrophytes SM-110 were 8-and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.

“…In recent years, an imidazole (lanoconazole) (20) and three classes of antifungal compounds, a benzylamine (butenafine) (17), an allylamine (terbinafine) (27), and a morpholine (amorolfine) (32), have been successfully developed and introduced into clinical use. These newer drugs are more highly active than the former imidazoles against dermatophytes in vitro (17,20,27,32) and in vivo in guinea pig models of dermatophytosis (2,3,4,5,25,26,29,38).…”

mentioning

confidence: 99%

In Vitro Antifungal Activity of KP-103, a Novel Triazole Derivative, and Its Therapeutic Efficacy against Experimental Plantar Tinea Pedis and Cutaneous Candidiasis in Guinea Pigs

Tatsumi

Yokoo

Arika

et al. 2001

Self Cite

The in vitro activity of KP-103, a novel triazole derivative, against pathogenic fungi that cause dermatomycoses and its therapeutic efficacy against plantar tinea pedis and cutaneous candidiasis in guinea pigs were investigated. MICs were determined by a broth microdilution method with morpholinepropanesulfonic acidbuffered RPMI 1640 medium for Candida species and with Sabouraud dextrose broth for dermatophytes and by an agar dilution method with medium C for Malassezia furfur. KP-103 was the most active of all the drugs tested against Candida albicans (geometric mean [GM] MIC, 0.002 g/ml), other Candida species including Candida parapsilosis and Candida glabrata (GM MICs, 0.0039 to 0.0442 g/ml), and M. furfur (GM MIC, 0.025 g/ml). KP-103 (1% solution) was highly effective as a treatment for guinea pigs with cutaneous candidiasis and achieved mycological eradication in 8 of the 10 infected animals, whereas none of the imidazoles tested (1% solutions) was effective in even reducing the levels of the infecting fungi. KP-103 was as active as clotrimazole and neticonazole but was less active than lanoconazole and butenafine against Trichophyton rubrum (MIC at which 80% of isolates are inhibited [MIC 80 ], 0.125 g/ml) and Trichophyton mentagrophytes (MIC 80 , 0.25 g/ml). However, KP-103 (1% solution) exerted therapeutic efficacy superior to that of neticonazole and comparable to those of lanoconazole and butenafine, yielding negative cultures for all samples from guinea pigs with plantar tinea pedis tested. This suggests that KP-103 has better pharmacokinetic properties in skin tissue than the reference drugs. Because the in vitro activity of KP-103, unlike those of the reference drugs, against T. mentagrophytes was not affected by hair as a keratinic substance, its excellent therapeutic efficacy seems to be attributable to good retention of its antifungal activity in skin tissue, in addition to its potency.