Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, CN−O, of oxiconazole 6 is in an inverted atomic sequence, were synthesized and tested for their antifungal activities. Among them, the type 7 compounds, such as the N-ethoxy-morpholino-substituted derivatives 7l−o (Table 1), showed good antifungal properties against the Candida strains tested, with minimum inhibitory concentration (MIC) values similar to those of the reference drug 6. A remarkable result was obtained with these types of azoles, which had shown a cidal character against Candida albicans, while the reference drug oxiconazole was only fungistatic in the same tests. This fact may be seen from a comparison of the MIC values with those of the minimum fungicidal concentration (MFC) values for most of the type 7 compounds assayed that have shown differences between the MIC and the MFC, which are lower than three double diluitions. A simple molecular modeling of the P450 14-α-sterol demethylase from C. albicans (Candida P450DM) was built in order to understand how the structural differences between type 7 compounds and oxiconazole 6 can induce different antifungal profiles. The results of this work seem to confirm that it is possible to reverse the atomic sequence of the methyleneaminoxy group, CN−O, of 6, obtaining new imidazoles possessing good antifungal properties.

Synthesis, Antifungal Activity, and Molecular Modeling Studies of New Inverted Oxime Ethers of Oxiconazole

ROSSELLO, ARMANDO;BERTINI, SIMONE;LAPUCCI, ANNALINA;MACCHIA, MARCO;MARTINELLI, ADRIANO;RAPPOSELLI, SIMONA;
2002

Abstract

Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, CN−O, of oxiconazole 6 is in an inverted atomic sequence, were synthesized and tested for their antifungal activities. Among them, the type 7 compounds, such as the N-ethoxy-morpholino-substituted derivatives 7l−o (Table 1), showed good antifungal properties against the Candida strains tested, with minimum inhibitory concentration (MIC) values similar to those of the reference drug 6. A remarkable result was obtained with these types of azoles, which had shown a cidal character against Candida albicans, while the reference drug oxiconazole was only fungistatic in the same tests. This fact may be seen from a comparison of the MIC values with those of the minimum fungicidal concentration (MFC) values for most of the type 7 compounds assayed that have shown differences between the MIC and the MFC, which are lower than three double diluitions. A simple molecular modeling of the P450 14-α-sterol demethylase from C. albicans (Candida P450DM) was built in order to understand how the structural differences between type 7 compounds and oxiconazole 6 can induce different antifungal profiles. The results of this work seem to confirm that it is possible to reverse the atomic sequence of the methyleneaminoxy group, CN−O, of 6, obtaining new imidazoles possessing good antifungal properties.
Rossello, Armando; Bertini, Simone; Lapucci, Annalina; Macchia, Marco; Martinelli, Adriano; Rapposelli, Simona; E., Herreros; B., Macchia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/178325
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