Benzofuro[3,2-d]pyrimidines inspired from cercosporamide CaPkc1 inhibitor: Synthesis and evaluation of fluconazole susceptibility restoration

  • Bioorg Med Chem Lett. 2018 Jul 15;28(13):2250-2255. doi: 10.1016/j.bmcl.2018.05.044.
Viet Hung Dao  1 ,  Isabelle Ourliac-Garnier  2 ,  Marc-Antoine Bazin  1 ,  Catherine Jacquot  2 ,  Blandine Baratte  3 ,  Sandrine Ruchaud  3 ,  Stéphane Bach  3 ,  Olivier Grovel  4 ,  Patrice Le Pape  2 ,  Pascal Marchand  5
Affiliations
  • 1. Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, EA1155 - IICiMed, Institut de Recherche en Santé 2, F-44200 Nantes, France.
  • 2. Université de Nantes, Nantes Atlantique Universités, Département de Parasitologie et Mycologie Médicale, EA1155 - IICiMed, Institut de Recherche en Santé 2, F-44200 Nantes, France.
  • 3. Sorbonne Université, CNRS, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), USR Protein Phosphorylation and Human Diseases, Station Biologique, Place Georges Teissier, F-29688 Roscoff, France.
  • 4. Université de Nantes, Nantes Atlantique Universités, EA2160 - Mer Molécules Santé, Faculté de Pharmacie, F 44035 Nantes, France.
  • 5. Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, EA1155 - IICiMed, Institut de Recherche en Santé 2, F-44200 Nantes, France. Electronic address: [email protected].
PMID: 29853332 DOI: 10.1016/j.bmcl.2018.05.044
Abstract

In a context of growing resistance to classical Antifungal therapy, the design of new drugs targeting alternative pathways is highly expected. Benzofuro[3,2-d]pyrimidine derivatives, derived from (-)-cercosporamide, were synthesized and evaluated as potential Candida albicans PKC inhibitors in the aim of restoring susceptibility to azole treatment. Co-administration assay of benzofuropyrimidinedione 23 and fluconazole highlighted a synergistic effect on inhibition of cell growth of a Candida albicans resistant strain.

Keywords
Antifungal activity; Benzofuro[3,2-d]pyrimidine; Candida albicans Pkc1; Cercosporamide; Fluconazole susceptibility restoration.