Rational drug design, synthesis, and study of the structure-activity relationship of Leishmania amazonensis arginase enzyme inhibitors for the development of new drugs

• Grant number: 19/23769-4
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2020
• End date: February 28, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Edson Roberto da Silva
• Grantee: Edson Roberto da Silva
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil
• Associated researchers: Beatriz Simonsen Stolf ; Claudia do Carmo Maquiaveli ; Marcos André Vannier dos Santos

Abstract

Over the past ten years, our group has described the interaction of natural and synthetic compounds with the enzyme Leishmania amazonensis arginase (La-Arg). To date, we have identified at least three pharmacophoric groups required for La-Arg inhibition: catechol, thiosemicarbazide, and phenylhydrazine. The first moiety identified was the catechol group from studies with the medicinal plant Cecropia pachystachya and a series of flavonoids and flavanoids. The thiosemicarbazide has been identified by the screening of synthetic compounds designed to inhibit the enzyme and finally prospecting new compounds we have identified the phenylhydrazide group. The study of the plant Stachytarpheta cayennensis, used in the Brazilian Amazon for the treatment of Leishmaniasis and its most abundant active compound, verbascoside, made it possible to correlate the use of S. cayennensis in the treatment of Leishmaniasis with selective inhibition of La-Arg. These studies highlighted arginase as a therapeutic target and enabled the creation of partnerships with laboratories for the synthesis of new compounds from various countries. In this project, we propose to continue with the prospecting of new arginase inhibitors through planned synthesis from Structure-Activity Relationship (SAR) studies. At least four series of compounds will be studied: 1) a series of semisynthetic compounds of caffeic acid esters produced in Belgium; 2) a series of about 280 (hydrazones and oxadiazoles) group-containing compounds produced in France; 3) a series of phenylhydrazides produced by Farmanguinhos laboratory (FIOCRUZ-RJ) and finally a new series planned at UFRJ as arginase inhibitors that in preliminary tests showed potential against Leishmania. With this, we hope to advance the development of synthetic and semi-synthetic compounds in order to develop a new drug for the treatment of human and canine Leishmaniasis. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAQUIAVELI, CLAUDIA DO CARMO; DA SILVA, EDSON ROBERTO; DE JESUS, BARBARA HILD; MONTEIRO, CAIO EDUARDO OLIVEIRA; NAVARRO, TIAGO RODRIGUES; BRANCO, LUIZ OCTAVIO PEREIRA; DOS SANTOS, ISABELA SOUZA; REIS, NANASHARA FIGUEIREDO; PORTUGAL, ARIELI BERNARDO; WANDERLEY, JOAO LUIZ MENDES; et al. Design and Synthesis of New Anthranyl Phenylhydrazides: Antileishmanial Activity and Structure-Activity Relationship. PHARMACEUTICALS, v. 16, n. 8, p. 10-pg., 2023-08-01. (19/23769-4)

DA SILVA, EDSON ROBERTO; COME, JULIO ABEL ALFREDO DOS SANTOS SIMONE; BROGI, SIMONE; CALDERONE, VINCENZO; CHEMI, GIULIA; CAMPIANI, GIUSEPPE; OLIVEIRA, TRICIA MARIA FERRREIRA DE SOUSA; PHAM, THANH-NHAT; PUDLO, MARC; GIRARD, CORINE; et al. Cinnamides Target Leishmania amazonensis Arginase Selectively. Molecules, v. 25, n. 22, NOV 2020. (19/23769-4)