FR290581, a novel sordarin derivative: Synthesis and antifungal activity

Hanadate, Tadaatsu; Tomishima, Masaki; Shiraishi, Nobuo; Tanabe, Daisuke; Morikawa, Hiroshi; Barrett, David; Matsumoto, Satoru; Ohtomo, Kazumi; Maki, Katsuyuki

doi:10.1016/j.bmcl.2009.01.051

Cited by 36 publications

(25 citation statements)

References 26 publications

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“…The sordarins target fungal elongation factor 2 (EF-2), rapidly blocking translation. Nonetheless, because they display a poor pharmacokinetic profile, sordarin derivatives have not entered clinical use (28).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis

Mircus

Albert

Ben-Yaakov

et al. 2015

Antimicrob Agents Chemother

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cInvasive mycotic infections have become more common during recent decades, posing an increasing threat to public health. However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory and are limited to a small number of antifungals. The aim of this study was to identify novel fungal cell wall inhibitors from a library of small chemical compounds using a conditional protein kinase C (PKC)-expressing strain of Aspergillus nidulans sensitive to cell wall-active agents. Eight "hit" compounds affecting cell wall integrity were identified from a screen of 35,000 small chemical compounds. Five shared a common basic molecular structure of 4-chloro-6-arylamino-7-nitro-benzofurazane (CANBEF). The most potent compound, CANBEF-24, was characterized further and was shown to inhibit the growth of pathogenic Aspergillus, Candida, Fusarium, and Rhizopus isolates at micromolar concentrations but not to affect the growth of mammalian cell lines. CANBEF-24 demonstrated strong synergy in combination with caspofungin, an antifungal that inhibits cell wall biosynthesis. Genetic and biochemical analyses with Aspergillus nidulans and Saccharomyces cerevisiae indicated that CANBEFs selectively inhibit fungal rRNA maturation and protein synthesis, suggesting that their effect on the cell wall is indirect. CANBEFs were nontoxic in insect (Galleria mellonella, Drosophila melanogaster) and mouse models of fungal infection. Preliminary evidence showing no therapeutic benefit in these models suggests that further cycles of optimization are needed for the development of this novel class of compounds for systemic use.T he number of life-threatening invasive fungal infections has risen dramatically over the past 30 years (1, 2). The vast majority of these infections are caused by species of the genera Candida, Aspergillus, Cryptococcus, and Coccidioides (3). Invasive aspergillosis has now overtaken candidiasis as the most frequent invasive fungal infection found after death in Europe and the United States (4, 5). Today, as many as 4% of all patients dying in modern tertiary care hospitals have invasive aspergillosis caused by fungal pathogen species that belong to the genus Aspergillus, while as many as 2% of these patients suffer from invasive candidiasis caused by Candida species (4, 6). However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory.There are three main classes of antifungal drugs in common clinical use for the treatment of systemic mycoses: the polyene amphotericin B, which binds fungal membrane ergosterol, leading to cell lysis; azoles, which inhibit ergosterol biosynthesis (fluconazole, itraconazole, voriconazole [VRC], and posaconazole); and the newly introduced echinocandins, such as caspofungin (CAS), which inhibit fungal glucan biosynthesis. Most of these current systemic antifungal treatments interact unfavorably with other medications, have resistance problems, a narrow spectrum of activity, and limited formulations, and are fungistatic rather...

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis

Mircus

Albert

Ben-Yaakov

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…This sordarin derivative also can be administered orally, with peak concentration of 1 μg/mL and half-life of 3.4 hours following a dose of 2 mg/kg [68]. The in vitro potency and favorable pharmacokinetic parameters of FR290581 translate into in vivo potency, as tissue fungal burden was signifi cantly reduced in mice infected with systemic candidiasis caused by C. albicans.…”

Section: In Vivo Effi Cacymentioning

confidence: 97%

“…This stabilization prevents ribosomal translocation, thereby inhibiting protein synthesis [67]. However, signifi cant in vivo activity has not been observed with sordarin because of unfavorable pharmacokinetic characteristics (short half-life and low concentrations) and limited in vitro activity against pathogenic fungi [68]. To overcome these issues, several synthetic sordarin derivatives have been synthesized with modifi cations to the chemical structure that have increased in vitro potency and more favorable pharmacokinetic characteristics in vivo [68][69][70].…”

Section: Mechanism Of Action and In Vitro Activitymentioning

confidence: 99%

“…When the in vitro activity was evaluated against Candida species, the MICs of FR290581 ranged from 0.5 to 1 μg/mL against C. albicans, C. glabrata, and C. tropicalis, and 8 μg/mL against C. parapsilosis [68]. Furthermore, this activity was maintained against a C. albicans isolate that was resistant to fl uconazole (MIC 0.5 μg/mL) [68]. However, diminished potency was observed when tested against C. neoformans (4 μg/mL) and A. fumigatus (128 μg/mL).…”

Section: Mechanism Of Action and In Vitro Activitymentioning

confidence: 99%

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Pharmacology, in vitro activity, and in vivo efficacy of new antifungal agents

Wiederhold

2009

Curr Fungal Infect Rep

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“…Conversion of the aldehyde into a cyano group furnishes compounds with equal or greater potency ( Figure 2). 25 Research groups at Merck, 25 GSK, 26,27 Bristol-Myers-Squibb, 28,29 Sankyo, 30,31 and Astellas (formerly Fujisawa) 32 …”

Section: Introductionmentioning

confidence: 99%