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

J Med Chem. 2002 Oct 24;45(22):4903-12. doi: 10.1021/jm020980t.

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.

MeSH terms

  • Antifungal Agents / chemical synthesis*
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology
  • Aspergillus fumigatus / drug effects
  • 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
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Oxidoreductases / chemistry
  • Oxidoreductases / genetics
  • Oximes / chemical synthesis*
  • Oximes / chemistry
  • Oximes / pharmacology
  • Recombinant Fusion Proteins / chemistry
  • Sterol 14-Demethylase
  • Structure-Activity Relationship
  • Trichophyton / drug effects

Substances

  • Antifungal Agents
  • Ethers
  • Imidazoles
  • Oximes
  • Recombinant Fusion Proteins
  • Cytochrome P-450 Enzyme System
  • oxiconazole
  • Oxidoreductases
  • Sterol 14-Demethylase