Bifonazole
Bifonazole (trade name Canespor among others[1]) is an imidazole antifungal drug used in form of ointments.
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| Trade names | Canespor, many others |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | Topical |
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| ECHA InfoCard | 100.056.651 |
| Chemical and physical data | |
| Formula | C22H18N2 |
| Molar mass | 310.400 g·mol−1 |
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| Chirality | Racemic mixture |
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It was patented in 1974 and approved for medical use in 1983.[2] There are also combinations with carbamide for the treatment of onychomycosis.
Adverse effects
The most common side effect is a burning sensation at the application site. Other reactions, such as itching, eczema or skin dryness, are rare.[3] Bifonazole is a potent aromatase inhibitor in vitro.[4][5]
Pharmacology
Mechanism of action
Bifonazole has a dual mode of action. It inhibits fungal ergosterol biosynthesis at two points, via transformation of 24-methylendihydrolanosterol to desmethylsterol, together with inhibition of HMG-CoA. This enables fungicidal properties against dermatophytes and distinguishes bifonazole from other antifungal drugs.[3][6]
Pharmacokinetics
Six hours after application, bifonazole concentrations range from 1000 μg/cm3 in the stratum corneum to 5 μg/cm3 in the papillary dermis.[3]
Synthesis
Friedel-Crafts acylation between limonene [92-52-4] (1) and benzoyl chloride [98-88-4] (2) gives 4-phenylbenzophenone [2128-93-0] (3). Reduction with borohydride gives the alcohol [7598-80-3] (4). Halogenation by thionyl chloride gives [7515-73-3] (5). Amination with imidazole (6) completed the synthesis of bifonazole (7).
References
- International Drug Names: Bifonazole.
- Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 502. ISBN 9783527607495.
- Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Canesten Bifonazol-Creme.
- Trösken ER, Fischer K, Völkel W, Lutz WK (February 2006). "Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation". Toxicology. 219 (1–3): 33–40. doi:10.1016/j.tox.2005.10.020. PMID 16330141.
- Egbuta C, Lo J, Ghosh D (December 2014). "Mechanism of inhibition of estrogen biosynthesis by azole fungicides". Endocrinology. 155 (12): 4622–4628. doi:10.1210/en.2014-1561. PMC 4239419. PMID 25243857.
- Berg D, Regel E, Harenberg HE, Plempel M (1984). "Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole". Arzneimittel-Forschung. 34 (2): 139–146. PMID 6372801.
- Serradell, MN; Blancafort, P.; Castaer, J.; Bifonazole. Drugs Fut 1982, 7, 2, 87.
- Erik Regel, Wilfried Draber, Karl Heinz Buchel, Manfred Plempel, U.S. patent 4,118,487 (1978 to Bayer Aktiengesellschaft).
- Corelli, Federico; Summa, Vincenzo; Brogi, Alessandra; Monteagudo, Edith; Botta, Maurizio (1995). "Chiral Azole Derivatives. 2. Synthesis of Enantiomerically Pure 1-Alkylimidazoles". The Journal of Organic Chemistry. 60 (7): 2008–2015. doi:10.1021/jo00112a023.
- Hu, Q., Negri, M., Jahn-Hoffmann, K., Zhuang, Y., Olgen, S., Bartels, M., Müller-Vieira, U., Lauterbach, T., Hartmann, R. W. (August 2008). "Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17)—Part II: Core rigidification and influence of substituents at the methylene bridge". Bioorganic & Medicinal Chemistry. 16 (16): 7715–7727. doi:10.1016/j.bmc.2008.07.011.