Bifonazole Explained

Bifonazole (trade name Canespor among others^[1]) is an imidazole antifungal drug used in form of ointments.

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.^[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.

Synthesis

Friedel-Crafts acylation between biphenyl (1) and benzoyl chloride (2) gives 4-phenylbenzophenone (3). Reduction with sodium borohydride gives the alcohol (4). Halogenation by thionyl chloride gives (5). Amination with imidazole (6) completes the synthesis of bifonazole.^{[7] [8] [9]}

Further reading

• Lackner TE, Clissold SP . Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses . Drugs . 38 . 2 . 204–225 . August 1989 . 2670516 . 10.2165/00003495-198938020-00004 . 195697559 .

Notes and References

1. Bifonazole.

2. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 502 . en.
3. Book: Austria-Codex. Canesten Bifonazol-Creme. Haberfeld H . Österreichischer Apothekerverlag. Vienna. 2015. German.
4. Trösken ER, Fischer K, Völkel W, Lutz WK . 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 . February 2006 . 16330141 . 10.1016/j.tox.2005.10.020 .
5. Egbuta C, Lo J, Ghosh D . Mechanism of inhibition of estrogen biosynthesis by azole fungicides . Endocrinology . 155 . 12 . 4622–4628 . December 2014 . 25243857 . 4239419 . 10.1210/en.2014-1561 .
6. Berg D, Regel E, Harenberg HE, Plempel M . Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole . Arzneimittel-Forschung . 34 . 2 . 139–146 . 1984 . 6372801 .
7. Regel E, Draber W, Buchel KH, Plempel M . Substituted azol-1-ylmethanes . US . 4118487 . 3 October 1978 . Bayer Aktiengesellschaft .
8. 10.1021/jo00112a023 . Chiral Azole Derivatives. 2. Synthesis of Enantiomerically Pure 1-Alkylimidazoles . 1995 . Corelli F, Summa V, Brogi A, Monteagudo E, Botta M . The Journal of Organic Chemistry . 60 . 7 . 2008–2015 .
9. Hu Q, Negri M, Jahn-Hoffmann K, Zhuang Y, Olgen S, Bartels M, Müller-Vieira U, Lauterbach T, Hartmann RW . Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17)--part II: Core rigidification and influence of substituents at the methylene bridge . Bioorganic & Medicinal Chemistry . 16 . 16 . 7715–7727 . August 2008 . 18674917 . 10.1016/j.bmc.2008.07.011 .