2. Academic Validation
  3. New azole antifungals with a fused triazinone scaffold

New azole antifungals with a fused triazinone scaffold

  • Eur J Med Chem. 2020 Mar 1;189:112082. 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 4
Affiliations

Affiliations

  • 1 Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED- EA1155, Institut de Recherche en Santé 2, F-44200, Nantes, France.
  • 2 Université de Nantes, Nantes Atlantique Universités, Département de Parasitologie et Mycologie Médicale, Cibles et Médicaments des Infections et du Cancer, IICIMED- EA1155, Institut de Recherche en Santé 2, F-44200, Nantes, France.
  • 3 Université de Nantes, Nantes Atlantique Universités, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, Faculté des Sciences et Techniques, F-44322, Nantes, France.
  • 4 Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED- EA1155, Institut de Recherche en Santé 2, F-44200, Nantes, France. Electronic address: [email protected].
PMID: 32000050 DOI: 10.1016/j.ejmech.2020.112082
Abstract

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.

Keywords

3H-pyrrolo[1,2-d][1,2,4]triazin-4-one; Antifungal agents; Azoles; Candida; Filamentous fungi; Invasive fungal infections.

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