title: Piperazine propanol derivative as a novel antifungal targeting 1,3-beta-D-glucan synthase.
abstract: 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.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd. (formerly Nippon Roche Research Center), Japan. kondoosm@chugai-pharm.co.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Kondoh
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuda
authors.forename: Eisaku
authors.initials: E
authors.lastname: Mizuguchi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohya
authors.forename: Mikio
authors.initials: M
authors.lastname: Arisawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakaitani
authors.forename: Takahide
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000254:growth & development; D052160:Benzothiazoles; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D041221:Candida glabrata / Q000187:drug effects / Q000254:growth & development; D054714:Echinocandins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004952:Esters / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D008565:Membrane Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013696:Temperature
chemical_list: C506343:(2,6-difluoro-phenyl)-carbamic acid 3-(4-benzothiazol-2-yl-piperazine-1-yl)-propyl ester; D000935:Antifungal Agents; D052160:Benzothiazoles; D054714:Echinocandins; D004791:Enzyme Inhibitors; D004952:Esters; D008565:Membrane Proteins; D010879:Piperazines; D029701:Saccharomyces cerevisiae Proteins; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; C091618:FKS1 protein, S cerevisiae