Piperazine Propanol Derivative as a Novel Antifungal Targeting 1,3-.BETA.-D-Glucan Synthase
| Autor: | Takahide Watanabe, Nobuo Shimma, Yoshikazu Ohya, Hiroshi Fukuda, Osamu Kondoh, Mikio Arisawa, Eisaku Mizuguchi, Yuko Aoki, Yukiko Inagaki, Masahiro Sakaitani |
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| Rok vydání: | 2005 |
| Předmět: |
Antifungal Agents
Saccharomyces cerevisiae Proteins Stereochemistry Chemical structure Pharmaceutical Science Candida glabrata Microbial Sensitivity Tests Saccharomyces cerevisiae Piperazines Chemical library Aspergillus fumigatus Propanol Echinocandins chemistry.chemical_compound Candida albicans Benzothiazoles Enzyme Inhibitors Pharmacology biology ATP synthase Temperature Membrane Proteins Esters General Medicine biology.organism_classification Piperazine 1 3-Beta-glucan synthase chemistry Biochemistry Glucosyltransferases biology.protein |
| Zdroj: | Biological and Pharmaceutical Bulletin. 28:2138-2141 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.28.2138 |
| Popis: | 1,3-beta-D-Glucan synthase, which synthesizes a main component of fungal cell wall, is one of the promising targets for antifungal agents. In order to identify novel chemical classes of 1,3-beta-D-glucan synthase inhibitors, we screened a chemical library monitoring inhibition of the Candida albicans 1,3-beta-D-glucan synthase activity. The piperazine propanol derivative GSI578 [(2,6-difluoro-phenyl)-carbamic acid 3-(4-benzothiazol-2-yl-piperazine-1-yl)-propyl ester] was identified as a potent inhibitor against 1,3-beta-D-glucan synthase with an IC50 value of 0.16 microM. GSI578 exhibited in vitro antifungal activity against pathogenic fungi including C. albicans and Aspergillus fumigatus. Temperature-sensitive mutations of the FKS1 gene in the Deltafks2 background of Saccharomyces cerevisiae, where FKS1 and FKS2 encode putative catalytic subunits of 1,3-beta-D-glucan synthase, altered sensitivity to GSI578. This suggests that the antifungal activity of the piperazine propanol derivative has an effect on 1,3-beta-D-glucan synthase inhibition. Results of our initial evaluation suggest that the piperazine propanol derivative is a novel chemical structure of the class of antifungals which inhibit fungal cell growth by inhibiting fungal 1,3-beta-D-glucan synthase. |
| Databáze: | OpenAIRE |
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