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 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.
Rossello
Armando
A
Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università degli Studi di Pisa, Via Bonanno, 6, 56100 Pisa, Italy.
Bertini
Simone
S
Lapucci
Annalina
A
Macchia
Marco
M
Martinelli
Adriano
A
Rapposelli
Simona
S
Herreros
Esperanza
E
Macchia
Bruno
B
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D002175:Candida / Q000187:drug effects / Q000201:enzymology; D003455:Cryptococcus neoformans / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship; D014249:Trichophyton / Q000187:drug effects
D000935:Antifungal Agents; D004987:Ethers; D007093:Imidazoles; D010091:Oximes; D011993:Recombinant Fusion Proteins; D003577:Cytochrome P-450 Enzyme System; C022155:oxiconazole; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase