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

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 )...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-10, Vol.45 (22), p.4903-4912
Main Authors: Rossello, Armando, Bertini, Simone, Lapucci, Annalina, Macchia, Marco, Martinelli, Adriano, Rapposelli, Simona, Herreros, Esperanza, Macchia, Bruno
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antifungal agents
Antifungal Agents - chemical synthesis
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
Aspergillus fumigatus - drug effects
Biological and medical sciences
Candida - drug effects
Candida - enzymology
Cryptococcus neoformans - drug effects
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - genetics
Ethers - chemical synthesis
Ethers - chemistry
Ethers - pharmacology
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Medical sciences
Microbial Sensitivity Tests
Models, Molecular
Oxidoreductases - chemistry
Oxidoreductases - genetics
Oximes - chemical synthesis
Oximes - chemistry
Oximes - pharmacology
Pharmacology. Drug treatments
Recombinant Fusion Proteins - chemistry
Sterol 14-Demethylase
Structure-Activity Relationship
Trichophyton - drug effects
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Summary: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 ), 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, CN−O, of 6, obtaining new imidazoles possessing good antifungal properties.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020980t