SYNTHESIS AND CHARACTERIZATION OF HYBRID GUANIDINES COMPOUNDS, THEIR PEPTIDE BIOCONJUGATES AND TETRAHYDROISOQUINOLINES FOR THE TREATMENT OF LEISHMANIASIS

• Grant number: 25/01056-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2025
• End date: February 28, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Eduardo Rene Perez Gonzalez
• Grantee: Luana Ribeiro dos Anjos
• Host Institution: Faculdade de Ciências e Tecnologia (FCT). Universidade Estadual Paulista (UNESP). Campus de Presidente Prudente. Presidente Prudente , SP, Brazil

Abstract

Leishmaniasis is a neglected disease that affects regions of greater vulnerability and poverty, both in Brazil and worldwide. The protozoan Leishmania has different species, characterizing different manifestation forms of the disease, the main ones being cutaneous, mucocutaneous and visceral leishmaniasis. In Brazil, the cutaneous and visceral forms have high rates of cases in the North, Northeast and Central-West regions. The current treatment of leishmaniasis is based on the administration of pentavalent antimonials and amphotericin B, however there are problems with efficacy and, mainly, toxicity. In this sense, studies for new drugs are necessary. Guanidines are a class of compounds that show promising results against leishmaniasis, which the compound LQOF-G2 achieved an IC50-AMA of 5.6 µM against L. amazonensis. Considering the promising results of guanidines already reported the aim is to synthesize hybrid guanidine compounds to increase efficacy and selectivity. This hybridization will be performed with acridines, which are compounds with several biological activities, such as antiparasitic, thus resulting in the acridine-guanidine hybrid compounds. In addition to hybridization, this work proposes bioconjugation with peptides. For bioconjugation, the guanidine compounds already reported in the literature will be functionalized with a carboxylic acid group. In addition to these molecules, the novel acridine-guanidine hybrid molecules will also be functionalized for coupling with peptides. To increase the stock of promising molecules for the treatment of leishmaniasis, the project aims to synthesize tetrahydroisoquinoline derivatives. These structures have already been reported against L. donovani, reaching IC50-PRO values of 0.28 µM. The synthesis of guanidine compounds and their hybrids will be carried out through the reaction of thioureas (which will also be previously synthesized) with benzylamine or 4-(aminomethyl) benzoic acid, catalyzed by Bi(NO3)3.5H2O. The tetrahydroisoquinoline derivatives will be synthesized by the Pictet-Spengler reaction catalyzed by phosphate. The characterization of the compounds will be performed by Mass Spectrometry and Nuclear Magnetic Resonance techniques. The in vitro activity will initially be investigated against promastigotes of Leishmania Viannia braziliensis. The compounds that present the best results will be evaluated against intramacrophagic amastigotes. In addition, tests on the production of cytokines, reactive oxygen species and NO will be performed.