Cinnamides Target Leishmania amazonensis Arginase Selectively

Author(s):Show less -

da Silva, Edson Roberto ^[1] ; Come, Julio Abel Alfredo dos Santos Simone ^{[1, 2]} ; Brogi, Simone ^[3] ; Calderone, Vincenzo ^[3] ; Chemi, Giulia ^{[4, 5]} ; Campiani, Giuseppe ^[4] ; Oliveira, Tricia Maria Ferrreira de Sousa ^[1] ; Pham, Thanh-Nhat ^[6] ; Pudlo, Marc ^[6] ; Girard, Corine ^[6] ; Maquiaveli, Claudia do Carmo ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Zootecnia & Engn Alimentos, Dept Med Vet, Lab Farmacol & Bioquim LFBq, BR-13635900 Pirassununga, SP - Brazil

^[2] Univ Eduardo Mondlane, Fac Vet, Dept Preclin, Av Mocambique, Km 1-5, Maputo 257 - Mozambique

^[3] Univ Pisa, Dept Pharm, Via Bonanno 6, I-56126 Pisa - Italy

^[4] Univ Siena, DoE Dept Excellence 2018 2022, Dept Biotechnol Chem & Pharm, Via Aldo Moro 2, I-53100 Siena - Italy

^[5] Univ Dundee, Wellcome Ctr Antiinfect Res, Drug Discovery Unit, Div Biol Chem & Drug Discovery, Dundee DD1 5EH - Scotland

^[6] Univ Bourgogne Franche Comte, PEPITE EA4267, F-25000 Besancon - France

• Document type: Journal article
• Source: Molecules; v. 25, n. 22 NOV 2020.
• Web of Science Citations: 1

Abstract

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 +/- 7.8 mu M) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 +/- 0.7 mu M). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 mu M, and where the most active was compound 15 (IC50 = 1.3 +/- 0.1 mu M). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 mu M). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors. (AU)

• FAPESP's process: 19/23769-4 - Rational drug design, synthesis, and study of the structure-activity relationship of Leishmania amazonensis arginase enzyme inhibitors for the development of new drugs
• Grantee: Edson Roberto da Silva
• Support Opportunities: Regular Research Grants