Lanoconazole and Its Related Optically Active Compound NND-502: Novel Antifungal Imidazoles with a Ketene Dithioacetal Structure
Imidazole antifungal agents have been successfully developed in medicine mainly for the treatment of superficial skin fungal infections. Through the screening for novel imidazole compounds, it was found that remarkable augmentation of in vitro antifungal activity is brought by the introduction of imidazole moiety to a unique structure ketene dithioacetal, and among these imidazole compounds (±)-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile (generic name: lanoconazole, CAS 101530-10-3) is now available as a topical drug used for the treatment of superficial skin fungal infections in Japan. Lanoconazole exerted 30-700 times more potent activity as measured by MICs (minimun inhibitory concentrations) against dermatophytes than did other antifungal imidazole compounds, bifonazole and clotrimazole. In therapeutic experiments using guinea pig models of infections, lanoconazole also exhibited excellent curative effect on two tinea models (tinea pedis and tinea corporis) and a cutaneous candidiasis model as compared to other reference agent, bifonazole, clotrimazole and / or tolnaftate, a thiocarbamate class of compound, in term of eradicating fungi from the infected loci. Since lanoconazole is a racemic compound and only the R-enantiomer was found to be active, extensive screening for optically active-related compound was further conducted. As a result, an optically active compound NND-502 was found to have more potent antifungal activity than lanoconazole and terbinafine, an allylamine class of antifungal agent. In an in vivo study with a guinea pig model of tinea pedis, short-term treatment regimen of topical NND-502 achieved a complete mycological cure, while that of topical lanoconazole and terbinafine did not. Furthermore, the potentiality of the compound for the oral and intravenous treatment of aspergillosis, one of the major deep-seated fungal infections, has been found out as well as for the topical treatment of dermatophytosis. The oral regimen of NND-502 in a murine model of systemic aspergillosis was apparently superior to that of itraconazole, a triazole compound, in terms of prolonging survival. Intravenous NND-502 also proved highly effective in a rat model of pulmonary aspergillosis compared with intravenous amphotericin B in terms of not only prolonging survival but also eradication of fungi from the lung. These encouraging results suggest that the related compounds of lanoconazole could bring considerable progress in the antifungal chemotherapy.
Keywords: antifungal agent, Imidazole, lanoconazole, nnd-502
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