title: Inhibition of ergosterol synthesis by novel antifungal compounds targeting C-14 reductase.
abstract: The limited number of clinically available antifungal drugs for life-threatening fungal infections has produced an increased demand for new agents. In the course of our screening for novel antifungals, we identified aminopiperidine derivatives which exhibit antifungal activities against the major pathogenic yeasts. Thin layer chromatography (TLC) analysis of the extracted non-saponifiable lipids from Candida albicans showed that these compounds inhibited the ergosterol production in the late step of the synthesis pathway. The results of an LC/Q-Tof MS analysis showed that abnormal sterols including predicted ignosterol, which is known to be accumulated in C. albicans ERG24 deleted mutant, were accumulated in C. albicans treated with one of these derivatives (Compound 1b). Furthermore, the partial disruption of the cell membrane of C. albicans treated with compound 1b was observed by electron microscopy analysis, suggesting its inhibition of ergosterol synthesis. Additionally, a genetic approach demonstrated that ERG24 gene would be responsible for the resistance of Saccharomyces cerevisiae against Compound 1b, strongly indicating that the enzyme targeted by Compound 1b is Erg24p. From all these data, we concluded that these aminopiperidine derivatives are novel antifungal compounds inhibiting C-14 reduction in the ergosterol synthesis pathway.
authors.affiliation: Kasai R&D Center, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan. hata.masato.tu@daiichisankyo.co.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Hata
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishii
authors.forename: Eri
authors.initials: E
authors.lastname: Watanabe
authors.forename: Kouichi
authors.initials: K
authors.lastname: Uoto
authors.forename: Shozo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Otani
authors.forename: Akikazu
authors.initials: A
authors.lastname: Ando
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002855:Chromatography, Thin Layer; D004338:Drug Combinations; D025141:Drug Resistance, Fungal; D004875:Ergosterol / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008401:Gas Chromatography-Mass Spectrometry; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D009821:Oils; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010636:Phenols; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D009821:Oils; C027222:P & S Liquid; D010636:Phenols; D010088:Oxidoreductases; C022672:delta(14)-sterol reductase; D004875:Ergosterol