Tetrahydrophthalazinone Inhibitor of Phosphodiesterase with In Vitro Activity against Intracellular Trypanosomatids

Antimicrob Agents Chemother. 2021 Feb 17;65(3):e00960-20. doi: 10.1128/AAC.00960-20. Print 2021 Feb 17.

Abstract

The phosphodiesterase inhibitor tetrahydrophthalazinone NPD-008 was explored by phenotypic in vitro screening, target validation, and ultrastructural approaches against Trypanosoma cruzi NPD-008 displayed activity against different forms and strains of T. cruzi (50% effective concentration [EC50], 6.6 to 39.5 μM). NPD-008 increased cAMP levels of T. cruzi and its combination with benznidazole gave synergistic interaction. It was also moderately active against intracellular amastigotes of Leishmania amazonensis and Leishmania infantum, confirming a potential activity profile as an antitrypanosomatid drug candidate.

Keywords: L. amazonensis; L. infantum; T. cruzi; cAMP; in vitro activity; phosphodiesterase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiprotozoal Agents* / therapeutic use
  • Chagas Disease* / drug therapy
  • Humans
  • Leishmania mexicana*
  • Phosphoric Diester Hydrolases
  • Trypanosoma cruzi*

Substances

  • Antiprotozoal Agents
  • Phosphoric Diester Hydrolases