Synthesis and structure-activity relationships of phenyl-substituted benzylamine antimycotics: a novel benzylbenzylamine antifungal agent for systemic treatment

Nußbaumer, Peter; Dorfstätter, G; Grassberger, Maximilian A.; Leitner, I.; Meingassner, Josef G.; Thirring, K.; Stütz, Anton

doi:10.1021/jm00067a010

Cited by 38 publications

(21 citation statements)

References 8 publications

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“…17). A few drug candidates containing the primary benzylamine moiety have also been considered for development including antifungal agents [135], NK-1 receptor antagonists [136], factor Xa inhibitors [137] and analgesics [138]. However the development of many compounds (e.g., factor Xa inhibitors) were suspended because of toxicities observed in various preclinical species.…”

Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

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“…Further structure-activity relationship explorations, concentrating on the allyl side chain, led to the discovery of the homoproparglyamines (43,53) and the benzylamines (43). Within the latter derivatives, para substitution of the benzyl group is required for high antifungal activity, with butenafine being the preferred molecule (42). In butenafine, the "allylic" double bond is fixed in the E configuration and is an essential feature for maintaining high activity (52,53).…”

Section: Discussionmentioning

confidence: 99%

Experimental and Conformational Analyses of Interactions between Butenafine and Lipids

Mingeot‐Leclercq

Gallet

Flore

et al. 2001

Antimicrob Agents Chemother

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Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride) is an antifungal agent of the benzylamine class that has excellent therapeutic efficacy and a remarkably long duration of action when applied topically to treat various mycoses. Given the lipophilic nature of the molecule, efficacy may be related to an interaction with cell membrane phospholipids and permeabilization of the fungal cell wall. Similarly, high lipophilicity could account for the long duration of action, since fixation to lipids in cutaneous tissues might allow them to act as local depots for slow release of the drug. We have therefore used computer-assisted conformational analysis to investigate the interaction of butenafine with lipids and extended these observations with experimental studies in vitro using liposomes. Conformational analysis of mixed monolayers of phospholipids with the neutral and protonated forms of butenafine highlighted a possible interaction with both the hydrophilic and hydrophobic domains of membrane phospholipids. Studies using liposomes demonstrated that butenafine increases membrane fluidity [assessed by fluorescence polarization of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene and 1,6-diphenylhexatriene] and membrane permeability (studied by release of calcein from liposomes). The results show, therefore, that butenafine readily interacts with lipids and is incorporated into membrane phospholipids. These findings may help explain the excellent antifungal efficacy and long duration of action of this drug when it is used as a topical antifungal agent in humans.Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride), a broad-spectrum topical antifungal agent (21), shows excellent therapeutic efficacy in humans with dermatomycoses (13,22,34,36,44,50,54). In vitro, the MIC and the minimal fungicidal concentration of butenafine against Trichophyton mentagrophytes and Microsporum canis were 0.012 to 0.05 mg/liter, i.e., 4 to 130 times lower than those for naftifine, tolnaftate, clotrimazole, and bifonazole (13, 36), other well-known antifungal drugs. Of additional interest is the fact that, in contrast to imidazole and triazole antifungals, butenafine does not interact with cytochrome P450-dependent enzymes (13) and is, therefore, unlikely to cause toxicity via untoward drug-drug interactions.The efficacy of butenafine might be attributed to its ability to inhibit sterol synthesis by blocking squalene epoxidation (24,25). This would lead to depletion of ergosterol, an essential lipid component of the fungal membrane; accumulation of squalene; and alteration in membrane function. At high concentrations, the damaging effect of butenafine on the cell membrane might play a major role in its anticandidal activity (27).One of the major characteristics of butenafine is its ability to provide long-lasting antifungal activity. Topical application of butenafine produces residual fungicidal concentrations in the skin (and particularly in the stratum corneum) that remain for...

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“…A new generation of fungicidal agents, which includes naftifine, terbinafine, and butenafine, demonstrates considerably greater potency than the azole derivatives against common dermatophytes in vitro . 5–7 The newest of these more potent agents is butenafine, a benzylamine derivative. Butenafine has a potency superior to naftifine and similar to terbinafine, and is particularly active against dermatophytes, aspergilli, and dimorphic fungi.…”

Section: Discussionmentioning

confidence: 99%

Butenafine, a fungicidal benzylamine derivative, used once daily for the treatment of interdigital tinea pedis

Reyes

Beutner²,

Cullen³

et al. 1998

Int J Dermatology

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A multi‐center, randomized, double‐blind, placebo‐controlled trial was performed to evaluate the effectiveness of butenafine, a fungicidal benzylamine derivative, in the once daily treatment of interdigital tinea pedis. One hundred and fifty patients with interdigital tinea pedis characterized by a minimum erythema score of 2 and a minimum score of 2 for either pruritus or scaling (on a scale of 0–3, where ‘2’ defines moderate severity) were initially enrolled, pending confirmation by mycologic culture and KOH testing. Patients were excluded if the evaluation of tinea pedis might have been impaired by concomitant conditions, if they were hypersensitive to allylamines or ingredients of the study medications, or if they had clinically significant abnormal laboratory values. Women of childbearing potential were also excluded if they were pregnant, lactating, or not using adequate contraceptive measures. The patients were randomized and given study formulations in coded tubes containing either butenafine hydrochloride cream 1% (butenafine) or the vehicle. They were instructed to apply the formulation to all tinea pedis lesions one daily, for 4 weeks. They were evaluated after 1, 2, and 4 weeks of treatment, and again 4 weeks post‐treatment, using the following measures: (i) mycologic cure: negative fungal culture and KOH test; (ii) effective treatment: mycologic cure and investigator global assessment of 80% or more improvement in signs and symptoms; (iii) investigator global assessment of clinical response: cleared (100% improvement in signs and symptoms), excellent (80–99% improvement), good (50–79% improvement), fair (25–49% improvement), poor (less than 25% improvement), unchanged, or worse, (iv) patient’s assessment of change since baseline: 5=greatly improved, 4=somewhat improved, 3=the same, 2=somewhat worse, and 1=much worse. Mycologic cure and effective treatment were each analyzed using the Cochran–Mantel–Haenszel (CMH) test of response by treatment partialled on investigator. Patient perceptions and investigator evaluations of global response were analyzed as ordered categorical data using the CMH mean score test with uniform scores.

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Synthesis and structure-activity relationships of phenyl-substituted benzylamine antimycotics: a novel benzylbenzylamine antifungal agent for systemic treatment

Cited by 38 publications

References 8 publications

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Experimental and Conformational Analyses of Interactions between Butenafine and Lipids

Butenafine, a fungicidal benzylamine derivative, used once daily for the treatment of interdigital tinea pedis

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