New azole antifungals with a fused triazinone scaffold.,European Journal of Medicinal Chemistry

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New azole antifungals with a fused triazinone scaffold.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-20 , DOI: 10.1016/j.ejmech.2020.112082
David Montoir ₁ , Rémi Guillon ₁ , Sophie Gazzola ₂ , Isabelle Ourliac-Garnier ₂ , Kossi Efouako Soklou ₁ , Alain Tonnerre ₁ , Carine Picot ₂ , Aurélien Planchat ₃ , Fabrice Pagniez ₂ , Patrice Le Pape ₂ , Cédric Logé ₁

Affiliation

We identified a new series of azole antifungal agents bearing a pyrrolotriazinone scaffold. These compounds exhibited a broad in vitro antifungal activity against pathogenic Candida spp. (fluconazole-susceptible and fluconazole-resistant) and were 10- to 100-fold more active than voriconazole against two Candida albicans isolates with known mechanisms of azole resistance (overexpression of efflux pumps and/or specific point substitutions in the Erg11p/CYP51 enzyme). Our lead compound 12 also displayed promising in vitro antifungal activity against some filamentous fungi such as Aspergillus fumigatus and the zygomycetes Rhizopus oryzae and Mucor circinelloides and an in vivo efficiency against two murine models of lethal systemic infections caused by Candida albicans.

中文翻译：

具有融合的三嗪酮支架的新型唑类抗真菌药。

我们鉴定了带有吡咯烷嗪酮支架的一系列新的唑类抗真菌剂。这些化合物对病原假丝酵母具有广泛的体外抗真菌活性。（对氟康唑敏感且对氟康唑有抗药性），并且对两种具有已知吡咯抗药性的白色念珠菌分离株（外排泵的过表达和/或Erg11p / CYP51酶的特定点取代）具有比伏立康唑高10至100倍的活性。。我们的先导化合物12还显示出对某些丝状真菌（如烟曲霉和米果合子菌和米科圆环菌）的体外抗真菌活性，以及对两种由白色念珠菌致死的系统性感染鼠模型的体内有效性。

更新日期：2020-01-21

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