Structure-activity relationship (SAR) from arginase inhibitors from Leishmania (Leishmania) amazonensis using natural and synthetic compounds

• Grant number: 14/02016-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): July 01, 2014
• Effective date (End): June 30, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Edson Roberto da Silva
• Grantee: Lucas Marinho Walter
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil

Abstract

Leishmaniasis is an anthropozoonosis that affect humans and domestic dogs. Dogs with leishmaniasis are sacrificed due to lack of proper treatment. The enzyme arginase from Leishmania is considered as a target for the development of drugs against the parasite. Our group works with medicinal plants that possess leishmanicidal activity in culture of promastigote forms of the parasite and that simultaneously exhibit inhibitory activity of arginase enzyme in vitro. Polyphenols and isolated flavonoids inhibit the arginase enzyme from Leishmania (Leishmania) amazonensis. Recently we have showed that flavonoids such as quercetin and flavanoids such as (+)-catechin are potent inhibitors of arginase and possess activity against Leishmania. Extracts enriched in anthocyanidins prepared from grape and jabuticada also have inhibitory activity against parasite arginase enzyme. So in this project we propose a study of the structure activity relationship (SAR) six anthocyanidins on the inhibition of arginase enzyme and also to carry out tests with 6 synthetic compounds that were synthesized as arginase inhibitors. We will determine the IC50, the inhibition constants (Ki) and the mechanism of enzyme inhibition. The mechanism of action promastigotes culture will be evaluated through supplementation with L-ornithine.