Uses
An antifungal compound and CYP inhibitor
Uses
Clotrimazole is an antifungal agent.
Definition
ChEBI: A member of the class of imidazoles that is 1H-imidazole in which the hydrogen attached to a nitrogen is replaced by a monochlorotrityl group.
Description
Clotrimazole is an imidazole antifungal that is active against a wide variety of fungal forms and is effective in many types of fungal infections.
1,2,3,4 It tightly binds sterol 14-
α demethylase isoform B from
A. fumigatus (K
D = 103 nM) and, like other imidazoles, disturbs the fungal cell membrane.
5,4 In mammalian cells, clotrimazole potently inhibits the calcium-
dependent potassium channels K
v1.3 and IK-
1 (IC
50 = 6.0 and 0.07 μM, respectively).
6
Originator
Canesten,Bayer,UK,1973
Indications
Clotrimazole (Lotrimin, Gyne-Lotrimin, Mycelex) is a
broad-spectrum fungistatic imidazole drug used in the
topical treatment of oral, skin, and vaginal infections
with C. albicans. It is also employed in the treatment of
infections with cutaneous dermatophytes.
Topical use results in therapeutic drug concentrations
in the epidermis and mucous membranes; less
than 10% of the drug is systemically absorbed. Although
clotrimazole is generally well tolerated, local abdominal
cramping, increased urination, and transient
liver enzyme elevations have been reported.
Manufacturing Process
156.5 g (0.5 mol) o-chlorophenyldiphenylmethyl chloride and 34 g (0.5 mol)
imidazole are dissolved in 500 ml acetonitrile, with stirring, and 51 g (0.5
mol) triethylamine are added, whereupon separation of triethylamine
hydrochloride occurs even at room temperature. In order to complete the
reaction, heating at 50°C is carried out for 3 hours. After cooling, one liter of
benzene is added and the reaction mixture is stirred, then washed salt-free
with water. The benzene solution is dried over anhydrous sodium sulfate,
filtered and concentrated by evaporation; giving 167 g crude 1-(ochlorophenylbisphenylmethyl)-imidazole. By recrystallization from acetone,
115 g (= 71% of the theory) of pure 1-(o-chlorophenylbisphenylmethyl)-
imidazole of MP 154° to 156°C are obtained.
Brand name
Gyne-
Lotrimin (Schering-Plough); Gynix (Teva); Lotrimin
(Schering-Plough); Mycelex (Bayer).
Therapeutic Function
Antifungal
General Description
Chemical structure: imidazole
Biochem/physiol Actions
Clotrimazole is a specific inhibitor of Ca2+-activated K+ channels. It is an antifungal azole. Clotrimazole is a derivative of imidazole and has similar antimicrobial action and activity to ketoconazole. It inhibits cytochrome P450-dependent 14α-demethylase, which is critical to ergosterol biosynthesis. The accumulated 14α-methylated sterols change the membrane structure of sensitive fungi, altering cell membrane permeability.
Clinical Use
1-(o-Chloro-α,α-diphenylbenzyl)imidazole (Lotrimin, Gyne-Lotrimin, Mycelex) is a broad-spectrum antifungal drug thatis used topically for the treatment of tinea infections and candidiasis.It occurs as a white crystalline solid that is sparinglysoluble in water but soluble in alcohol and most organic solvents.It is a weak base that can be solubilized by dilute mineralacids.
Clotrimazole is available as a solution in polyethyleneglycol 400, a lotion, and a cream in a concentration of 1%.These are all indicated for the treatment of tinea pedis, tineacruris, tinea capitis, tinea versicolor, or cutaneous candidiasis.A 1% vaginal cream and tablets of 100 mg and 500 mgare available for vulvovaginal candidiasis. Clotrimazole isextremely stable, with a shelf life of more than 5 years.
Synthesis
Clotrimazole, 1-(o-chloro-α,α-diphenylbenzyl)imidazole (35.2.21), is synthesized by reacting 2-chlorotriphenylmethylchloride (35.2.20) with imidazole in the presence of triethylamine.
The starting substance 2-chlorotriphenylmethylchloride is made in various ways. In particular, chlorinating 2-chlorotoluene under light makes 2-chlorotrichloromethylbenzene (35.2.22), which is reacted with benzene in the presence of aluminum chloride to give 2-chlorotriphenylmethylchloride (35.2.20).
An alternative way of making 2-chlorotriphenylmethylchloride is a Grignard reaction between 2-chlorobenzolphenone and phenylmagnesium bromide, followed by substitution of the hydroxyl group in the resulting 2-chlorotriphenylmethylcarbinol (35.2.23) with a chlorine using thionyl chloride.
And finally, reacting phosphorous pentachloride with 2-chlorobenzophenone gives 2- chloro-1,1-dichlorodiphenylmethane (35.2.24), which is used for the alkylation of benzene in the presence of aluminum chloride and gives 2-chlorotriphenylmethylchloride (35.2.20).
Veterinary Drugs and Treatments
Topical clotrimazole has activity against dermatophytes and yeasts; it may be useful for localized lesions associated with Malassezia. It is
not very effective in treating dermatophytosis in cats.
Clotrimazole inhibits the biosynthesis of ergosterol, a component of fungal cell membranes leading to increased membrane permeability
and probable disruption of membrane enzyme systems.
