Antifungal Activities and Cytotoxicity Studies of Six New Azasordarins

Abstract

GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 are members of a new family of sordarin derivatives called azasordarins. The in vitro activities of these compounds were evaluated against clinical isolates of yeasts, including Candida albicans, Candida non-albicans, and Cryptococcus neoformans strains. Activities against Pneumocystis carinii, Aspergillus spp., less common molds, and dermatophytes were also investigated. Azasordarin derivatives displayed significant activities against the most clinically important Candida species, with the exception of C. krusei. Against C. albicans, including fluconazole-resistant strains, MICs at which 90% of the isolates tested are inhibited (MIC 90 s) were 0.002 g/ml with GW 479821, 0.015 g/ml with GW 515716 and GW 587270, and 0.06 g/ml with GW 471552, GW 471558, and GW 570009. The MIC 90 s of GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 were 0.12, 0.12, 0.03, 0.06, 0.12, and 0.06 g/ml, respectively, against C. tropicalis and 4, 0.25, 0.06, 0.25, 0.5, and 0.5 g/ml, respectively, against C. glabrata. In addition, some azasordarin derivatives (GW 479821, GW 515716, GW 570009, and GW 58720) were active against C. parapsilosis, with MIC 90 s of 2, 4, 4, and 1 g/ml, respectively. The compounds were extremely potent against P. carinii, showing 50% inhibitory concentrations of <0.001 g/ml. However Cryptococcus neoformans was resistant to all compounds tested (MIC > 16 g/ml). These azasordarin derivatives also showed significant activity against emerging fungal pathogens, which affect immunocompromised patients, such as Rhizopus arrhizus, Blastoschizomyces capitatus, and Geotrichum clavatum. Against these organisms, the MICs of GW 587270 ranged from 0.12 to 1 g/ml, those of GW 479821 and GW 515716 ranged from 0.12 to 2 g/ml, and those of GW 570009 ranged from 0.12 to 4 g/ml. Against Fusarium oxysporum, Scedosporium apiospermum, Absidia corymbifera, Cunninghamella bertholletiae, and dermatophytes, GW 587270 was the most active compound, with MICs ranging from 4 to 16 g/ml. Against Aspergillus spp., the MICs of the compounds tested were higher than 16 g/ml. The in vitro selectivity of azasordarins was investigated by cytotoxicity studies performed with five cell lines and primary hepatocytes. Concentrations of compound required to achieve 50% inhibition of the parameter considered (Tox 50 s) of GW 570009, GW 587270, GW 479281, and GW 515716 in the cell lines ranged from 60 to 96, 49 to 62, 24 to 36, and 16 to 38 g/ml, respectively. The cytotoxicity values of GW 471552 and GW 471558 were >100 g/ml for all cell lines tested. Tox 50 s on hepatocytes were in the following order: GW 471558 > GW 471552 > GW 570009 > GW 587270 > GW 515716 > GW 479821, with values ranging from higher than 100 g/ml to 23 g/ml. The cytotoxicity results obtained with fully metabolizing rat hepatocytes were in total agreement with those obtained with cell lines. In summary, the in vitro activities against important pathogenic fungi and the selectivity demonstrated in mam...

Antifungal Activities of R-135853, a Sordarin Derivative, in Experimental Candidiasis in Mice

“…On the other hand, R-135853 exhibited weak or no activity against C. parapsilosis, C. krusei, and Aspergillus spp. These in vitro characteristics of R-135853 are similar to those of other sordarins reported previously (16,17). It is remarkable that R-135853 exhibited potent activities against C. albicans, whether or not the strains showed resistance to FLC.…”

“…This multiple interaction may explain the high degree of selectivity of this class of compounds between fungal and mammalian cells (12). Some pharmaceutical companies have reported that sordarin derivatives exhibit potent antifungal activities with relatively broad-spectrum activities in vitro and that some compounds exhibit good efficacies in vivo (2,7,15,16,17,25,26). We also synthesized sordarin derivatives from zofimarin, a sordarin-related natural product which was isolated from the fungus Zopfiella marina (32).…”

Sordarin Inhibits Fungal Protein Synthesis by Blocking Translocation Differently to Fusidic Acid

“…Their spectrum includes most fungal pathogens that affect immunocompromised patients, i.e. Candida spp., Cryptococcus neoformans, Pneumocystis carinii, and several endemic American fungi as well as dermatophytes (2). These compounds exert their antifungal activity by selectively inhibiting the elongation step of protein synthesis in the target organisms, but not in higher eukaryotes (3).…”

Therapeutic Efficacies of GW471552 and GW471558, Two New Azasordarin Derivatives, against Pneumocystosis in Two Immunosuppressed-Rat Models

“…In addition, the low toxicity of GW471552 and GW471558 has been demonstrated in vitro (13) and confirmed by preliminary mouse toxicity tests [E. Herreros, A. Martínez, M. J. Almela, E. Jiménez, S. Lozano, M. J. Pérez, and D. GargalloViola, Abstr. 40th Intersci.…”

“…A further evolution of this class of compounds has led to a new family of substances, azasordarins, that have a similar biological profile but easier chemical synthesis. Azasordarins have demonstrated excellent in vitro activity against key fungal pathogens, including P. carinii (13), and therapeutic efficacy in experimental rodents of oral and vulvovaginal candidiasis (21).…”