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

Abstract：

: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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Tani N,Rahnasto-Rilla M,Wittekindt C,Salminen KA,Ritvanen A,Ollakka R,Koskiranta J,Raunio H,Juvonen RO

doi

10.1016/j.ejmech.2011.10.053

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

270-7

issue

1

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(11)00795-1

journal_volume

47

pub_type

杂志文章

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