Antifungal activities of novel non-azole molecules against S. cerevisiae and C. albicans

• Published in: European journal of medicinal chemistry 2012, Vol.47 (1), p.270-277
• Main Authors: Tani, Niina, Rahnasto-Rilla, Minna, Wittekindt, Carsten, Salminen, Kaisa A., Ritvanen, Anniina, Ollakka, Riina, Koskiranta, Jenna, Raunio, Hannu, Juvonen, Risto O.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological and medical sciences; C. albicans; Candida albicans - drug effects; Candida albicans - enzymology; CYP enzyme; CYP51; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Liver - enzymology; Medical sciences; Models, Molecular; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology. Drug treatments; Protein Conformation; Reactive group; S. cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Sterol 14-Demethylase - chemistry; Sterol 14-Demethylase - metabolism; User-Computer Interface
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.10.053

Because of the increasing number of immunocompromised patients and due to problems with antifungal treatment, especially with the most widely used antifungals, azoles, there is an urgent need for new, potent and safe antifungals with fewer cytochrome P450 (CYP)-mediated interactions with other drugs. In the present study, 54 novel non-azole molecules were selected with the help of molecular modelling and virtual molecule database screening to identify new fungistatic or fungicidic compounds with functional groups that would produce reactive intermediates killing the yeast cells. Database screening and selection of tested compounds were based on the construction of two pharmacophores and docking hits to the active site of the CYP51 homology model. Inhibition potency of the compounds was tested against Saccharomyces cerevisiae and/or Candida albicans. Two new structured compounds, 2-({4-[(2-cyanoethyl)(methyl) amino]benzylidene} amino)-5-(3,4-dimethoxyphenyl)-4-methylthiophene-3-carbonitrile and 2-[([1,1′-biphenyl]-4-ylmethylene)amino]-5-(3,4-dimethoxyphenyl)-4-methylthiophene-3-carbonitrile were discovered to have promising antifungal properties based on bioassays. Inhibition screen of human hepatic CYP enzymes revealed that these two compounds did not inhibit potently five human recombinant CYP enzymes. The results of this study indicate that the functional groups of the two compounds may produce reactive intermediates when located at the active site of CYP51. [Display omitted] ► We identified novel non-azole inhibitors of yeast growth. ► Molecular modelling and virtual screening approaches were used. ► Of the 54 hit compounds, two had potent inhibitory activity towards S. cerevisiae and C. albicans. ► These two molecules are potential candidates for further development as antifungal agents.