Synthesis, antifungal activity, and molecular modeling studies of new inverted oxime ethers of oxiconazole.

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Rossello A, Bertini S, Lapucci A, Macchia M, Martinelli A, Rapposelli S, Herreros E, Macchia B

Synthesis, antifungal activity, and molecular modeling studies of new inverted oxime ethers of oxiconazole.

J Med Chem. 2002 Oct 24;45(22):4903-12.

PubMed ID

12383016 [ View in PubMed

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Abstract

Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, C=N-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-alpha-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, C=N-O, of 6, obtaining new imidazoles possessing good antifungal properties.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Bifonazole	Cytochrome P450 51	Protein	Yeast	Yes	Inhibitor	Details
Oxiconazole	Cytochrome P450 51	Protein	Yeast	Yes	Inhibitor	Details