Piperazine propanol derivative as a novel antifungal targeting 1,3-beta-D-glucan synthase.
Piperazine propanol derivative as a novel antifungal targeting 1,3-beta-D-glucan synthase.
复制标题
DOI：
10.1248/bpb.28.2138
复制
发表时间：
2005-11
影响因子：
2
通讯作者：
O. Kondoh;Yukiko Inagaki;H. Fukuda;E. Mizuguchi;Y. Ohya;M. Arisawa;N. Shimma;Y. Aoki;M. Sakaitani;Takahide Watanabe
中科院分区：
文献类型：
--
作者：
O. Kondoh;Yukiko Inagaki;H. Fukuda;E. Mizuguchi;Y. Ohya;M. Arisawa;N. Shimma;Y. Aoki;M. Sakaitani;Takahide Watanabe
1，3-β-D-葡聚糖合成酶（1，3-beta-D-Glucan synthase，1，3-β-D-Glucan synthase）是合成真菌细胞壁的主要成分之一，是抗真菌药物研究的重要靶点。为了鉴定1，3-β-D-葡聚糖合酶抑制剂的新化学类别，我们筛选了监测白色念珠菌1，3-β-D-葡聚糖合酶活性抑制的化学文库。哌嗪丙醇衍生物GSI 578 [（2，6-二氟-苯基）-氨基甲酸3-（4-苯并噻唑-2-基-哌嗪-1-基）-丙酯]被鉴定为针对1，3-β-D-葡聚糖合酶的有效抑制剂，IC 50值为0.16 μ M。GSI 578对常见的病原真菌具有体外抗真菌活性。白色念珠菌和烟曲霉。在酿酒酵母的Deltafks 2背景中，FKS 1基因的温度敏感性突变改变了对GSI 578的敏感性，其中FKS 1和FKS 2编码1，3-β-D-葡聚糖合酶的推定催化亚基。这表明哌嗪丙醇衍生物的抗真菌活性对1，3-β-D-葡聚糖合酶抑制有影响。我们的初步评价结果表明，哌嗪丙醇衍生物是一类抗真菌药物的新化学结构，通过抑制真菌1，3-β-D-葡聚糖合酶来抑制真菌细胞生长。
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.