Description
Miconazole is a widely used antifungal imidazole that acts by inhibiting the 14α-
demethylation of lanosterol, which consequently leads to the inhibition of ergosterol synthesis in fungal cell membranes.
1,2 Additionally, miconazole has been shown to induce reactive oxygen species in fungal biofilms, demonstrating a MIC value of ≥256 μM against
Candida spp.
3
Chemical Properties
White Solid
Originator
Daktarin,Janssen,Italy,1974
Manufacturing Process
Imidazole is reacted with ω-bromo-2,4-dichloroacetophenone and that product
reduced with sodium borohydride.
A suspension of 10.3 parts of the α-(2,4-dichlorophenyl)imidazole-1-ethanol
thus obtained and 2.1 parts of sodium hydride in 50 parts of dry
tetrahydrofuran is stirred and refluxed for 2 hours. After this reaction time,
the evolution of hydrogen is ceased. Then there are added successively 60
parts dimethylformamide and 8 parts of 2,4-dichlorobenzyl chloride and
stirring and refluxing are continued for another 2 hours. The tetrahydrofuran
is removed at atmospheric pressure. The dimethylformamide solution is
poured onto water.
The product, 1-[2,4-dichloro-β-(2,4 -dichlorobenzyloxy)phenethyl]imidazole, is
extracted with benzene. The extract is washed with water, dried, filtered and
evaporated in vacuo. From the residual oily free base, the nitrate salt is
prepared in the usual manner in 2-propanol by treatment with concentrated
nitric acid, yielding, after recrystallization of the crude solid salt from a
mixture of 2-propanol, methanol and diisopropyl ether, 1-[2,4-dichloro-β-
dichlorobenzyloxy)phenethyl]imidazole nitrate; melting point 170.5°C.
Brand name
M-Zole (Actavis); Monistat (Ortho-McNeil); Monistat (Personal Products); Monistat (Johnson & Johnson).
Therapeutic Function
Antifungal
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards. Miconazole nitrate is an imidazole derivative and a broad spectrum antifungal drug used in the management of fungal outbreak in humans and veterinary animals.
Biological Activity
Antifungal agent. Inhibits lanosterol demethylase and induces formation of reactive oxygen species.
Biochem/physiol Actions
Miconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for ergosterol biosynthesis. The inhibition of ergosterol results in increased cellular permeability causing leakage of cellular contents. Miconazole may also inhibit endogenous respiration, interact with phospholipids in the cell membrane, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and interfere with triglyceride and phospholipid biosynthesis.
Clinical Use
1-[2-(2,4-Dichlorophenyl)-2-[2,4-dichlorophenyl]-methoxy]ethyl]-1H-imidazole mononitrate (Monistat,Micatin) is a weak base with a pKa of 6.65. The nitric acidsalt occurs as white crystals that are sparingly soluble inwater and most organic solvents.
The free base is available in an injectable form, solubilized with polyethylene glycol and castor oil, and intended for the treatment of serious systemic fungal infections, such as candidiasis, coccidioidomycosis, cryptococcosis, petriellidiosis, and paracoccidioidomycosis. It may also be used for the treatment of chronic mucocutaneous candidiasis. Although serious toxic effects from the systemic administration of miconazole are comparatively rare, thrombophlebitis, pruritus, fever, and gastrointestinal upset are relatively common. Miconazole nitrate is supplied in various dosage forms (cream, lotion, powder, and spray) for the treatment of tinea infections and cutaneous candidiasis. Vaginal creams and suppositories are also available for the treatment of vaginal candidiasis. A concentration of 2% of the salt is used in most topical preparations.
References
[1] H VANDEN BOSSCHE. Biochemical approaches to selective antifungal activity. Focus on azole antifungals.[J]. Mycoses, 1989, 32 Suppl 1: 35-52. DOI:
10.1111/j.1439-0507.1989.tb02293.x[2] M S SAAG W E D. Azole antifungal agents: emphasis on new triazoles.[J]. Antimicrobial Agents and Chemotherapy, 1988, 32 1: 1-8. DOI:
10.1128/aac.32.1.1[3] NICOLAS DELATTIN Karin T Bruno P A Cammue. Reactive oxygen species-inducing antifungal agents and their activity against fungal biofilms.[J]. Future medicinal chemistry, 2014, 6 1: 77-90. DOI:
10.4155/fmc.13.189
