Synthesis and Structure-Activity Relationships of Side-Chain-Substituted Analogs of the Allylamine Antimycotic Terbinafine Lacking the Central Amino Function

Nußbaumer, Peter; Leitner, I.; Mraz, Karin; Stütz, Anton

doi:10.1021/jm00010a029

Cited by 106 publications

(47 citation statements)

References 5 publications

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“…Bacterial salicylate 1-monooxygenase catalyzes the formation of catechol from salicylate, an intermediate from naphthalene degradation (2). Thus, terbinafine, which has a naphthalene nucleus in its chemical structure (23)(24)(25)39), could be the substrate for a similar degradation pathway in fungi, generating salicylate or an analogous compound as substrate for the enzyme salicylate 1-monooxygenase in A. nidulans.…”

Section: Discussionmentioning

confidence: 99%

Terbinafine Resistance Mediated by Salicylate 1-Monooxygenase inAspergillus nidulans

Graminha

Rocha

Prade

et al. 2004

Antimicrob Agents Chemother

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Resistance to antifungal agents is a recurring and growing problem among patients with systemic fungal infections. UV-induced Aspergillus nidulans mutants resistant to terbinafine have been identified, and we report here the characterization of one such gene. A sib-selected, 6.6-kb genomic DNA fragment encodes a salicylate 1-monooxygenase (salA), and a fatty acid synthase subunit (fasC) confers terbinafine resistance upon transformation of a sensitive strain. Subfragments carrying salA but not fasC confer terbinafine resistance. salA is present as a single-copy gene on chromosome VI and encodes a protein of 473 amino acids that is homologous to salicylate 1-monooxygenase, a well-characterized naphthalene-degrading enzyme in bacteria. salA transcript accumulation analysis showed terbinafine-dependent induction in the wild type and the UV-induced mutant Terb7, as well as overexpression in a strain containing the salA subgenomic DNA fragment, probably due to the multicopy effect caused by the transformation event. Additional naphthalene degradation enzyme-coding genes are present in fungal genomes, suggesting that resistance could follow degradation of the naphthalene ring contained in terbinafine.

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Section: Discussionmentioning

confidence: 99%

Terbinafine Resistance Mediated by Salicylate 1-Monooxygenase inAspergillus nidulans

Graminha

Rocha

Prade

et al. 2004

Antimicrob Agents Chemother

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“…The synthesis of compounds 4a-d and 5a-d was carried out from the reaction of acetylene 1 with butyl lithium and the subsequent reaction with the corresponding electrophile agent 3, in the presence of 2 mol-equiv of BF 3 •OEt 2 (Scheme 1). Firstly, the lithium acetylenides were generated from the respective acetylenes 1,2 using BuLi in THF, at -20 °C for 30 min.…”

Section: Resultsmentioning

confidence: 99%

“…Firstly, the lithium acetylenides were generated from the respective acetylenes 1,2 using BuLi in THF, at -20 °C for 30 min. In a second step, the reaction between β-dimethylaminovinyl ketones 3 and lithium acetylenides was carried out using BF 3 •OEt 2 , -15 °C for 2 hours, and THF as solvent. The transformation was completed after being stirred at room temperature for 16 hours.…”

Section: Resultsmentioning

confidence: 99%

“…1 These moieties are found to be integral parts of highly potent antitumor, 2 and antifungal agents, 3 and first line components of antiretroviral therapy. 4 Terbinafine (Lamisil™) 3 is one example of an enyne derivative in clinical use. In addition, in many systems rigidification has been an efficient method used to increase the activity of a drug or to reduce its side-effects.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of novel conjugated enynes: a reaction of lithium acetylenides with β-dimethylaminovinyl ketones

Martins¹,

Rossatto²,

Rosa³

et al. 2007

Arkivoc

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“…Previous studies have variously reported the elimination half-life of terbinafine in humans to be 15 h (33), 26 h (27), 290 h (35), and 22 days (33,35,43). Terbinafine is extensively metabolized in the liver by oxidation or N demethylation of the three carbon atoms bound to the central nitrogen atom or of the nitrogen atom itself (2), and the metabolites lack the antimycotic activity of the parent drug (34).…”

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confidence: 99%

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

Hosseini-Yeganeh

McLachlan

2002

Antimicrob Agents Chemother

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The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n ‫؍‬ 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (V ss ) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the V ss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition.Terbinafine is an antifungal agent from the allylamine class that inhibits the fungal squalene epoxidase enzyme, leading to the intracellular accumulation of squalene, which causes the rapid death of fungi (36,37). It has demonstrated activity against most superficial fungal infections, including onychomycosis and dermatomycosis (11,17), and systemic fungal infections, such as histoplasmosis (1), Pneumocystis carinii infection, (8), and aspergillosis (39). Terbinafine is highly lipophilic and keratophilic, so it is extensively distributed throughout adipose tissue, dermis, epidermis, and nails in humans (12,19). The apparent volume of distribution in humans is relatively large and has been reported to be in the range of 780 to 2,000 liters (22,25,27,28,33). The large volume of distribution of terbinafine and its accumulation in peripheral tissue as well as the slow redistribution of the drug into blood are likely to significantly influence the half-life of terbinafine. Previous studies have variously reported the elimination half-life of terbinafine in humans to be 15 h (33), 26 h (27), 290 h (35), and 22 days (33,35,43). Terbinafine is extensively metabolize...

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Synthesis and Structure-Activity Relationships of Side-Chain-Substituted Analogs of the Allylamine Antimycotic Terbinafine Lacking the Central Amino Function

Cited by 106 publications

References 5 publications

Terbinafine Resistance Mediated by Salicylate 1-Monooxygenase inAspergillus nidulans

Terbinafine Resistance Mediated by Salicylate 1-Monooxygenase inAspergillus nidulans

Synthesis of novel conjugated enynes: a reaction of lithium acetylenides with β-dimethylaminovinyl ketones

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

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