Bifonazole

Chemical compound
  • D01AC10 (WHO)
Legal statusLegal status
  • In general: Over-the-counter (OTC)
Identifiers
  • (RS)-1-[Phenyl(4-phenylphenyl)methyl]-1H-imidazole
CAS Number
  • 60628-96-8 checkY
PubChem CID
  • 2378
DrugBank
  • DB04794 checkY
ChemSpider
  • 2287 checkY
UNII
  • QYJ305Z91O
KEGG
  • D01775 checkY
ChEBI
  • CHEBI:31286 ☒N
ChEMBL
  • ChEMBL277535 checkY
CompTox Dashboard (EPA)
  • DTXSID9045631 Edit this at Wikidata
ECHA InfoCard100.056.651 Edit this at WikidataChemical and physical dataFormulaC22H18N2Molar mass310.400 g·mol−13D model (JSmol)
  • Interactive image
ChiralityRacemic mixture
  • n1ccn(c1)C(c3ccc(c2ccccc2)cc3)c4ccccc4
InChI
  • InChI=1S/C22H18N2/c1-3-7-18(8-4-1)19-11-13-21(14-12-19)22(24-16-15-23-17-24)20-9-5-2-6-10-20/h1-17,22H checkY
  • Key:OCAPBUJLXMYKEJ-UHFFFAOYSA-N checkY
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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.[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

Thieme ChemDrug Synthesis:[7] Patent:[8] ~95%:[9] ~11%:[10]

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

  1. ^ International Drug Names: Bifonazole.
  2. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 502. ISBN 9783527607495.
  3. ^ a b c Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Canesten Bifonazol-Creme.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ Serradell, MN; Blancafort, P.; Castaer, J.; Bifonazole. Drugs Fut 1982, 7, 2, 87.
  8. ^ Erik Regel, Wilfried Draber, Karl Heinz Buchel, Manfred Plempel, U.S. patent 4,118,487 (1978 to Bayer Aktiengesellschaft).
  9. ^ 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.
  10. ^ 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.

Further reading

  • Lackner TE, Clissold SP (August 1989). "Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses". Drugs. 38 (2): 204–225. doi:10.2165/00003495-198938020-00004. PMID 2670516. S2CID 195697559.
  • v
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Wall/
membrane
Ergosterol
inhibitors
Azoles (lanosterol 14α-
demethylase inhibitors)
Imidazoles
Triazoles
Thiazoles
Polyene antimycotics
(ergosterol binding)
Squalene monooxygenase
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Allylamines
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Others
β-glucan synthase
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Intracellular
Pyrimidine analogues/
thymidylate synthase inhibitors
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