In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

Abstract

TAK-456 is a novel oral triazole compound with potent and broad-spectrum in vitro antifungal activity and strong in vivo efficacy against Candida albicans and Aspergillus fumigatus. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/ml. TAK-456 showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and Cryptococcus neoformans, except for Candida glabrata. The MICs at which 90% of the isolates tested were inhibited byTAK-456, fluconazole, itraconazole, voriconazole, and amphotericin B were 0.25, 4, 0.5, 0.13, and 0.5 g/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 g/ml, respectively, for clinical isolates of A. fumigatus. Therapeutic activities of TAK-456 and reference triazoles against systemic lethal infections caused by C. albicans and A. fumigatus in mice were investigated by orally administering drugs once daily for 5 days, and efficacies of the compounds were evaluated by the prolongation of survival. In normal mice, TAK-456 and fluconazole were effective against infection caused by fluconazole-susceptible C. albicans at a dose of 1 mg/kg. In transiently neutropenic mice, therapeutic activity of TAK-456 at 1 mg/kg of body weight against infection with the same strain was stronger than those at 1 mg/kg of fluconazole. TAK-456 was effective against infections with two strains of fluconazole-resistant C. albicans at a dose of 10 mg/kg. TAK-456 also expressed activities similar to or higher than those of itraconazole against the infections caused by two strains of A. fumigatus in neutropenic mice at a dose of 10 mg/kg. These results suggest that TAK-456 is a promising candidate for development for the treatment of candidiasis and aspergillosis in humans.

Antifungal Activity of the Ethanol Extract from Flos Rosae Chinensis with Activity against Fluconazole‐Resistant Clinical Candida

“…Each group contained 15 mice. Immunosuppression was induced by intraperitoneal treatment with 80 mg/kg cyclophosphamide (Shionogi, Osaka, Japan) 3 days before infection [ 25 ]. Then, 1 × 10 5 cells were inoculated in the mouse lateral tail vein.…”

1-(4-Bromophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-1-one

“…Many compounds containing a triazole unit have good biological and pharmacological activities, such as antineoplastic, analgesic, antimicrobial and anticonvulsant (Almasirad et al, 2004;Konosu et al, 2001; Baraldi et al, 2002;Ruel et al, 2003). They are widely used in the fields of medication for various diseases and plant protection (Tsuchimori et al, 2002;Patchett & Nargund, 2000;Tafi et al, 2002;Sekimata et al, 2002). In a search for additional biologically active triazole compounds, the title compound, (I), was synthesized and its crystal structure was determined (Fig.…”

The (1H-Tetrazol-1-yl)arenediazonium Salts as Convenient Reagents for Quinones Arylation: Synthesis of 1,3-Benzoxathiol-2-ones and Naphtho[2,1-d][1,3]oxathiol-2-ones Bearing (1H-Tetrazol-1-yl)phenyl Motif

“…5 There is a number of promising tetrazole derivatives with a pronounced antifungal effect. For instance, compound C (TAK-456) bearing the 1,2,4-triazolyl and (tetrazol-1-yl)aryl moieties has shown a strong inhibitory effect on Candida spp., A. fumigatus, and Cryptococcus neoformans, 6 tetrazole-containing aminopyrimidines (compound D) 7 and 1-(4-(1H-tetrazole-1-yl)phenyl)-3-arylprop-2-en-1-one (compound E) 8 displayed high in vitro antifungal activity comparable to that of fluconazole, against C. albicans, S. cerevisiae, A. niger, and A. fumigatus. Several types of polynuclear heterocyclic compounds F and G containing tetrazolyl moieties are promising COX-1 and COX-2 inhibitors demonstrating anti-inflammatory activity comparable to that of the known drugs (diclofenac and indomethacin).…”