2.12.1 Clotrimazole: Chemical and pharmaceutical aspects

Clotrimazole 2.61 [23593-75-1], one of the first azolyl antimycotic drugs, is still much prescribed and one of the standards against which new developments are compa-red.[2.366]

clotrimazole Canesten Bay b 5097



It combines good skin penetration with broad-spectrum activity against dermatophytes, yeasts,[2.367] Aspergillus, Malassezia furfur, and inhibits Corynebacte-rium minutissimum, Staphylococci, Streptococci which all may accompany myco-tic infections. In the treatment of tinea infections and cutaneous candidiasis of skin and mucous membranes such as vaginal candidiasis, clotrimazole can be used as a single dose.[2.366]

An account of the investigators has summarized the ideas and hypotheses along which optimization of structure was achived.[2.318] Curing rates of Candida infection of the mouse after systemic application are connected with

1. the hydrolysis rates of the C-N bond (carbocation formation),

2. the lipophilicity of the molecule (transport phenomena), and

3. its steric structure (fitting at the site of action); favorable influence of ortho-substitution (exaggeration of the trityl-propeller).

However, no clear-cut relationships could be worked out with the QSAR methods of Hansch and of Free-Wilson, since some of the mathematical properties of the biological results lacked sufficient precision. Rank correlations are useful and confirmed the superiority of ortho-substitution for antimycotic acticity. A more recent investigation demonstrated the relation of lipophilicity with maximum surface area (as expressed by chromatographic parameters).[2.368]

The importance of clotrimazole has challenged a world-wide search for improved and alternative synthetic methods [2.112, 2.369, 2.370, 2.371, 2.372, 2.373, 2.374, 2.375, 2.376, 2.377, 2.378, 2.379, 2.380, 2.381, 2.382, 2.383, 2.384, 2.385, 2.386, 2.387, 2.388, 2.389, 2.390, 2.391, 2.392, 2.393, 2.394, 2.395, 2.396] which have been reviewed recently.[2.397]

The low solubility of clotrimazole (5.5 |mmol/L)[2.331] has presented a challenge to find suitable galenic preparations for topical,[2.330, 2.398, 2.399, 2.400, 2.401, 2.402, 2.403, 2.404, 2.406, 2.407, 2.408] and vaginal applications,[2.324, 2.326, 2.409, 2.410, 2.411, 2.412], for aerosols in pulmonary treatment,[2.413] for the treatment of herpes labialis,[2.414] and in ophthalmology using its efficacy against Anthamoeba spp.[2.415]

New applications as antimycotic have been suggested by incorporation in shoe insoles or sandals,[2.416] for cellulose or synthetic fibers,[2.417, 2.418] and for finishing underwear and socks.[2.419]

2.12.2 Clotrimazole: microbiological activity

Clotrimazole displays activity against Gram-negative microorganisms such as Legio-nella.[2.316] The detection of trypanocidal activity in the complex RuCl2(clotrima-zole)2 has given hope for a new remedy for Chagas disease, endemic in South Ame-rica.[2.420] This observation stresses the importance of the stability constants of complexes of clotrimazole and other standard antimycotics with heavy metals.[2.421]

Clotrimazole, a potent inhibitor of epidermal metabolism of benzo[a]pyrene offers the chance to lower cancer risk caused by polycyclic aromatics in skin.[2.422, 2.423] It inhibits normal and cancer cell proliferation.[2.424] The drug has been recommended as a virucide in the treatment of Herpes simplex, [2.399] and shows promise in the treatment of sickle cell anemia.[2.425, 2.426, 2.427, 2.428] For this potential application, a HPLC assay has been developed to study pharmacokinetics after oral dose.[2.429] In this treatment, the effective agent seems to be the metabolite 2-chlorophenyl-bisphenylmethanol.[2.430]

Clotrimazole may serve as a novel antidiarrheal agent owing to its interference of K+ transport. [2.433]

The emergence of strains resistant to clotrimazole, certainly an undesirable development in harmful microorganisms, has been turned into an advantage. Such chemical mutagenesis of brewing yeast gives a clotrimazole-resistant variety which shows an advantage in industrial alcoholic fermentation.[2.431, 2.432]

2.12.3 Flutrimazole

It is surprizing that after 20 years of thorough investigation of clotrimazole and its related halogenated tritylimidazoles, the structurally similar flutrimazole 2.62 [11900677-8] with improved properties could be introduced.[2.434, 2.435, 2.436]

flutrimazole UR-4056



Here, the hope has been realized that with the appearance of fluorinated instead of chlorinated metabolites, embryotoxicity can be lowered further in comparison to clotrimazole and less irritation might be seen. In vitro activity of flutri-mazole seems to be equal or better than the standards, bioavailability is four-fold higher in dogs.[2.437] Flutrimazole was launched in 1995 as a topical antimyco-tic.[2.438] The drug also displays anti-inflammatory action.[2.439]


2.12.4 Further close analogs of clotrimazole

Flutrimazole must not be confused with fluotrimazole 2.63 [31251-03-3].[2.440] N-


Yet fluotrimazole with its somewhat limited fungicidal spectrum has been replaced by triadimefon (see section 4.7) with its much broader spectrum of antimicrobial activity.[2.440, 2.441, 2.442].

Another related compound, Bay d 6853, 2.64 [66642-47-5], shows a broad spectrum of antimicrobial activity, but suffers from insufficient absorption.[2.295]


Cure Your Yeast Infection For Good

Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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