Synthesis and evaluation of novel antifungal agents-quinoline and pyridine amide derivatives

Nakamoto, Kazutaka; Tsukada, Itaru; Tanaka, Keigo; Matsukura, Masayuki; Haneda, Toru; Inoue, Satoshi; Murai, Norimoto; Abe, Shinya; Ueda, Norihiro; Miyazaki, Mamiko; Watanabe, Naoaki; Asada, Makoto; Yoshimatsu, Kentaro; Hata, Katsura

doi:10.1016/j.bmcl.2010.06.005

Cited by 36 publications

(34 citation statements)

References 19 publications

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“…YW3548, a natural product, is thought to inhibit the addition of phosphoethanolamine (EtNP) to the first mannose of GPI, but it inhibits both yeast and mammalian GPI-EtNP transferases, although EtNP modification of the first mannose is not essential for the surface expression of GPI-anchored proteins on mammalian cells (22,58). We have modified the prototype compound BIQ (38,59,63) and developed E1210, which possesses potent antifungal activity (19,34). In this study, E1210 was shown to inhibit C. albicans and A. fumigatus Gwt1ps, which are suggested to be involved in the inositol acylation of GlcN-PI in the GPI biosynthesis pathway (36,63,64), but not human Pig-Wp.…”

Section: Discussionmentioning

confidence: 99%

“…In our efforts to improve the efficacy of this prototype-inhibitor BIQ (38,59), we next developed E1210, 3-(3-{4-[(pyridin-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-amine (34). This compound showed potent in vitro antifungal activity against a broad range of pathogenic fungi, including Candida spp., Aspergillus spp., and other molds, such as Fusarium and Scedosporium spp., although its action was fungistatic (34), and subsequently showed high therapeutic efficacy in several representative in vivo models of invasive fungal infections (19).…”

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confidence: 99%

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E1210, a New Broad-Spectrum Antifungal, Suppresses Candida albicans Hyphal Growth through Inhibition of Glycosylphosphatidylinositol Biosynthesis

Watanabe

Miyazaki

Horii

et al. 2012

Antimicrob Agents Chemother

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Continued research toward the development of new antifungals that act via inhibition of glycosylphosphatidylinositol (GPI) biosynthesis led to the design of E1210. In this study, we assessed the selectivity of the inhibitory activity of E1210 against Candida albicans GWT1 (Orf19.6884) protein, Aspergillus fumigatus GWT1 (AFUA_1G14870) protein, and human PIG-W protein, which can catalyze the inositol acylation of GPI early in the GPI biosynthesis pathway, and then we assessed the effects of E1210 on key C. albicans virulence factors. E1210 inhibited the inositol acylation activity of C. albicans Gwt1p and A. fumigatus Gwt1p with 50% inhibitory concentrations (IC 50 s) of 0.3 to 0.6 M but had no inhibitory activity against human Pig-Wp even at concentrations as high as 100 M. To confirm the inhibition of fungal GPI biosynthesis, expression of ALS1 protein, a GPIanchored protein, on the surfaces of C. albicans cells treated with E1210 was studied and shown to be significantly lower than that on untreated cells. However, the ALS1 protein levels in the crude extract and the RHO1 protein levels on the cell surface were found to be almost the same. Furthermore, E1210 inhibited germ tube formation, adherence to polystyrene surfaces, and biofilm formation of C. albicans at concentrations above its MIC. These results suggested that E1210 selectively inhibited inositol acylation of fungus-specific GPI which would be catalyzed by Gwt1p, leading to the inhibition of GPI-anchored protein maturation, and also that E1210 suppressed the expression of some important virulence factors of C. albicans, through its GPI biosynthesis inhibition.T he incidence of life-threatening fungal infections has increased steadily over the past 2 decades as a result of an increase in the number of susceptible immunosuppressed patients (39, 68). However, there are a limited number of antifungals available that can safely and effectively treat serious invasive fungal infections in humans. Drugs available for human invasive fungal infections are represented principally by four classes of compounds-polyenes, fluorinated pyrimidines, azoles, and echinocandins-but they each have limited usefulness because of their limited spectrum of antifungal activity, adverse effects, drug-drug interactions, variable pharmacokinetics (often requiring therapeutic drug monitoring), and/or only one type of formulation (12). Resistance is also becoming an increasing problem, particularly among members of the azole class (33,44,45,47,66). Therefore, new antifungal drugs with novel mechanisms of action which show no crossresistance to existing antifungals are desirable for the treatment of serious invasive fungal infections.We have also focused our attention on ways to interfere with the expression of virulence factors that are associated with the establishment of fungal infections in order to design an optimal novel antifungal agent. Microorganisms must first attach to host cell surfaces in order to establish infections; this is followed by colonization and replication on...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

E1210, a New Broad-Spectrum Antifungal, Suppresses Candida albicans Hyphal Growth through Inhibition of Glycosylphosphatidylinositol Biosynthesis

Watanabe

Miyazaki

Horii

et al. 2012

Antimicrob Agents Chemother

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130

135

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“…We have discovered a key compound, 1-(4-butylbenzyl) isoquinoline (BIQ) that inhibits the surface expression of glycosylphosphatidylinositol (GPI)-anchored proteins in Saccharomyces cerevisiae, resulting in inhibition of fungal growth, and then identified the GWT1 (GPI-anchored wall protein transfer 1) gene, the target molecule of BIQ, which encodes a new acyltransferase involved in an early step in the GPI biosynthetic pathway of fungi (39,40). We have performed exploratory syntheses of many different compounds designed to enhance the antifungal activity of BIQ and finally discovered a candidate compound likely to be effective as a new antifungal (27,38).…”

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confidence: 99%

Efficacy of Oral E1210, a New Broad-Spectrum Antifungal with a Novel Mechanism of Action, in Murine Models of Candidiasis, Aspergillosis, and Fusariosis

Hata

Horii

Miyazaki

et al. 2011

Antimicrob Agents Chemother

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110

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E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.

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“…It may be that yeast Gwt1p differs from mammalian PIG-W in some molecular characteristics, although the membrane topology is apparently the same. For instance, binding efficiency of Gwt1p/PIG-W to a compound, BIQ, shows species specificity (34). In fact, we selected these two different inositol acyltransferases, yeast Gwt1p and mammalian PIG-W, in the hope of developing species-specific inhibitors of inositol acyltransferase.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, we selected these two different inositol acyltransferases, yeast Gwt1p and mammalian PIG-W, in the hope of developing species-specific inhibitors of inositol acyltransferase. Results from these types of experiments are described elsewhere (34). Further alanine substitution analysis may provide clues that can lead to the development of antifungal reagents that may be useful in treating mycoses.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Membrane Topology and Identification of Essential Residues for the Yeast Endoplasmic Reticulum Inositol Acyltransferase Gwt1p

Sagane

Umemura

Ogawa-Mitsuhashi

et al. 2011

Journal of Biological Chemistry

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Glycosylphosphatidylinositol (GPI) is a post-translational modification that anchors cell surface proteins to the plasma membrane, and GPI modifications occur in all eukaryotes. Biosynthesis of GPI starts on the cytoplasmic face of the endoplasmic reticulum (ER) membrane, and GPI precursors flip from the cytoplasmic side to the luminal side of the ER, where biosynthesis of GPI precursors is completed. Gwt1p and PIG-W are inositol acyltransferases that transfer fatty acyl chains to the inositol moiety of GPI precursors in yeast and mammalian cells, respectively. To ascertain whether flipping across the ER membrane occurs before or after inositol acylation of GPI precursors, we identified essential residues of PIG-W and Gwt1p and determined the membrane topology of Gwt1p. Guided by algorithmbased predictions of membrane topology, we experimentally identified 13 transmembrane domains in Gwt1p. We found that Gwt1p, PIG-W, and their orthologs shared four conserved regions and that these four regions in Gwt1p faced the luminal side of the ER membrane. Moreover, essential residues of Gwt1p and PIG-W faced the ER lumen or were near the luminal edge of transmembrane domains. The membrane topology of Gwt1p suggested that inositol acylation occurred on the luminal side of the ER membrane. Rather than stimulate flipping of the GPI precursor across the ER membrane, inositol acylation of GPI precursors may anchor the precursors to the luminal side of the ER membrane, preventing flip-flops.

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Synthesis and evaluation of novel antifungal agents-quinoline and pyridine amide derivatives

Cited by 36 publications

References 19 publications

E1210, a New Broad-Spectrum Antifungal, Suppresses Candida albicans Hyphal Growth through Inhibition of Glycosylphosphatidylinositol Biosynthesis

E1210, a New Broad-Spectrum Antifungal, Suppresses Candida albicans Hyphal Growth through Inhibition of Glycosylphosphatidylinositol Biosynthesis

Efficacy of Oral E1210, a New Broad-Spectrum Antifungal with a Novel Mechanism of Action, in Murine Models of Candidiasis, Aspergillosis, and Fusariosis

Analysis of Membrane Topology and Identification of Essential Residues for the Yeast Endoplasmic Reticulum Inositol Acyltransferase Gwt1p

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