Synthesis, biological evaluation and structure–activity correlation study of a series of imidazol-based compounds as Candida albicans inhibitors

• Published in: European journal of medicinal chemistry Vol. 83; pp. 665 - 673
• Main Authors: Moraca, Francesca, De Vita, Daniela, Pandolfi, Fabiana, Di Santo, Roberto, Costi, Roberta, Cirilli, Roberto, D’Auria, Felicia Diodata, Panella, Simona, Palamara, Anna Teresa, Simonetti, Giovanna, Botta, Maurizio, Scipione, Luigi
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 18.08.2014; Elsevier
• Subjects: Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Azole derivatives; Candida albicans - drug effects; Candida albicans - enzymology; Cell Line; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Enantioselective synthesis; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - toxicity; Life Sciences & Biomedicine; Ligand-based drug design; Models, Molecular; Pharmacology & Pharmacy; Protein Conformation; Science & Technology; Sterol 14-Demethylase - chemistry; Sterol 14-Demethylase - metabolism; Structure-Activity Relationship; UTLIWAZSOYEKIX-UHFFFAOYSA-N; Antifungal; ARRHNUBWPABKMP-UHFFFAOYSA-N; Azole derivatives; WCEDXUNAAFEGHV-UHFFFAOYSA-N; ULTWFVLLKPONPF-UHFFFAOYSA-N; YNQKQNLALVYYHR-UHFFFAOYSA-N; Enantioselective synthesis; DYHUDZCDPDORKL-UHFFFAOYSA-N; GCXOJSSBLOSPBR-UHFFFAOYSA-N; XXRMPOPREBBDOA-UHFFFAOYSA-N; STEKVBCDKBFAFO-UHFFFAOYSA-N; Ligand-based drug design; NIBZKROZQXTODK-UHFFFAOYSA-N; ANTIFUNGAL AGENTS; DERIVATIVES; ANTICANDIDA ACTIVITY; FUNGAL-INFECTIONS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.07.001

A new series of 2-(1H-imidazol-1-yl)-1-phenylethanol derivatives was synthesized. The antifungal activity was evaluated in vitro against different fungal species. The biological results show that the most active compounds possess an antifungal activity comparable or higher than Fluconazole against Candida albicans, non-albicans Candida species, Cryptococcus neoformans and dermathophytes. Because of their racemic nature, the most active compounds 5f and 6c were tested as pure enantiomers. For 6c the (R)-enantiomer resulted more active than the (S)-one, otherwise for 5f the (S)-enantiomer resulted the most active. To rationalize the experimental data, a ligand-based computational study was carried out; the results of the modelling study show that (S)-5f and (R)-6c perfectly align to the ligand-based model, showing the same relative configuration. Preliminary studies on the human lung adenocarcinoma epithelial cells (A549) have shown that 6c, 5e and 5f possess a low cytotoxicity. [Display omitted] •New 2-(1H-imidazol-1-yl)-1-phenylethanols were synthesized and evaluated as antifungal.•The most active compounds possess an antifungal activity comparable or higher than Fluconazole.•The most active compounds were synthesized and tested as pure enantiomers.•A ligand-based computational study was carried out to rationalize the experimental data.•Active compounds possess a low cytotoxicity on the human lung adenocarcinoma epithelial cells (A549).