Imidazole Bifonazole

Topical azole derivatives include the imidazoles bifonazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, lanoconazole, flutrima-zole and sertaconazole. These drugs show activity against the dermatophytes Epidermophyton, Mi-crosporum and Trichophyton. They are also effective against the yeasts Candida albicans and Pityrospo-rum orbiculare. Local side effects include pruritus, erythema and local irritation. Allergic dermatitis is rare. 

Imidazoles Bifonazole, Butoconazole, Chlormidazole, Clotrimazole, Econazole, Fenticonazole, Isoconazole, Ketoconazole, Miconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole... 

Bifonazole (109) is claimed to be remarkably non-toxic and is marketed as a topical antifungal agent overseas. It can be conveniently synthesized in the by now familiar way by reduction of p-phenylbenzophenone (108) with borohydride, conversion to the chloride with thionyl chloride, and then imidazole displacement to bifonazole (109) [39]. 

C3H4N2 288-32-4) see Bifonazole Butoconazole Clotrimazole Eprosartan Fenticonazole Isoconazole Ketoconazole Miconazole Neticonazole hydrochloride Omoconazole nitrate Oxiconazole Ozagrel 1/f-imidazole lithium salt (C,H3LiN2 55986-39-5) see Flutrimazole 2-imidazolidinone... 

The topical antifungal bifonazole (60-2) dispenses with virtually all but the imidazole ring the intermediate (60-1) is obtained by sequential reduction of 4-phenyl-benzophenone and then reaction of the alcohol with thionyl chloride. Displacement of chlorine by imidazole gives (60-2) [65]. 

Apart from the triazole derivatives, a small group of imidazoles is active against plant pathogens (Figure 5). The most important compounds in this group are imazalil and prochloraz. However, most of the Important antimycotic EBI s originate from the imidazole series. Two of these antimycotics are bifonazole and clotrimazole, which resemble fluotrimazole. These two antimycotics will be dis-... 

Terbinafme (TBF) as an allylamine was purchased from Wako pure chemical (Osaka, Japan). Ciclopirox olamine (CPO), and four imidazole antimycotics, including miconazole (MCZ), bifonazole (BFZ), sulconazole (SCZ) and clotrimazole (CTZ) were purchased from Sigma (St. Louis, MO, USA). Amorolfin (AMF) was synthesized in our laboratories and identified by nuclear magnetic resonance. These agents were dissolved in dimethyl sulfoxide (DMSO) at various concentrations and added at a final concentration less than 1%. 

Because of their limited activity, small spectrum, and side effects, the older topical antimycotics have generally been surpassed by newer antimycotic chemotherapeutic agents. These newer antimycotics for topical use include the imidazole derivatives clotrimazole, miconazole, econazole, isoconazole, sulconazole, fenticonazole, oxiconazole, bifonazole, butoconazole, zinoconazole, tioconazole, and the triazole derivative, terconazole (Table 2) (5—7). The introduction of the azole derivatives represents a milestone in the treatment of mycoses. 

The inclusion of imidazole derivatives (bifonazole, clotrimazole, econazole, sul-conazole, miconazole, oxiconazole) with j8-CyD and hydroxypropyl-) -CyD (HP-) -CyD) was investigated over a wide range of column temperatures in RP-HPLC [44, 45]. Interestingly, at 20 °C the inclusion of imidazole derivatives in the HP-) -CD cavity was from 5 to 16 times weaker than in the p-CyD one. At 5 °C the six imidazole derivatives had nil stability constant with HP-y -CyD, whereas the stability constants with yS-CyD were in the range 21.5-185 M . ... 

Treatment of dermatophytoses is nowadays straightforward. The topical agents, including various imidazoles (econazole, tioconazole, isoconazole, bifonazole, etc.) are equally efficient and can be used in all forms of dermatophytosis except onychomycosis (due to lack of penetration). One daily application is considered adequate for 2-4 weeks. There is a tendency to use simultaneously systemic antimycotics, even in tinea corporis, when multiple lesions are present. 

Botta and coworkers have used the enyne metathesis in the synthesis of the enantiopure antifungal agent (5 )-bifonazole 130 [47]. In this work, the diene for the Diels-Alder reaction had to be synthesized from an alkyne. Reaction of alkyne (R)-131 with ethyl vinyl ether, in the presence of catalyst 2-Ru, thus afforded the desired diene 132 (Scheme 17.25) in an excellent yield of 88%. Next, the diene 132 was reacted with methyl vinyl ketone in a Diels-Alder reaction to afford compound 133. Exposure of compound 133 to acid and then DDQ yielded the aromatic product 134, where a newly formed benzene ring had been assembled. Further manipulations, including the formation of the required imidazole ring, allowed for the enantioselective synthesis of (S)-bifonazole 130. 

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