Isolation, Synthesis and Optimization of Natural Aromatic Compounds as New Pharmaceutical Prototypes for Chagas Disease

• Grant number: 24/16243-4
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: André Gustavo Tempone Cardoso
• Grantee: André Gustavo Tempone Cardoso
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Cledir Rodrigues Santos ; João Henrique Ghilardi Lago ; Marcelo Visentini Kitahara

Abstract

Among the main goals of the National Health Plan (PNS 2024-2027) of the Ministry of Health is the elimination of Chagas disease (CD). CD affects 7 million people worldwide and is endemic in Latin America, especially among socioeconomically disadvantaged populations. Since the 1960s, only two drugs have been made available, and in Brazil, only benznidazole is available, highlighting the urgent need for new treatments. Despite this, research into new drugs for CD has not advanced significantly due to the complexity, resistance, and pathogenicity of Trypanosoma cruzi. Among the drugs approved by the FDA as antiparasitics and antimicrobials, over 50% have natural prototypes in their structures. Thus, the search for diverse chemical structures in nature is a key aspect of drug discovery for selecting more potent and selective compounds, which is the goal of this project. This diversity may be even richer in marine microorganisms as well as extremophiles, which produce a variety of differentiated metabolites due to adaptations to physical, chemical, geological, and nutritional conditions. This project aims to study the pharmacological potential of natural aromatic compounds of microbial origin (marine and extremophiles) and venoms from snakes of the genus Bothrops against Trypanosoma cruzi. Additionally, compounds synthesized based on natural products will be studied to optimize these prototypes. For this purpose, marine bacteria and extremophiles will be isolated from sediments and marine invertebrates in the southeastern region of São Paulo and extreme environments in Chile, such as saline lakes and glaciers. Microorganisms with anti-T. cruzi potential will be identified by MALDI-TOF/MS or genetic sequencing. Microbial secondary metabolites with anti-T. cruzi potential will be isolated using various chromatographic techniques with biomonitoring fractionation. Spectrometric (LC-MS/MS) and spectroscopic (13C and 1H NMR) techniques will be employed for molecular dereplication (GNPS platform) and structural elucidation of the compounds. In silico platforms will be used to analyze the compounds' pharmacokinetic properties and "drug-likeness". Pure isolated compounds will be evaluated against the trypomastigote and intracellular amastigote forms of T. cruzi, and cytotoxicity will be assessed in mammalian cells. The bioenergetic alterations of T. cruzi caused by the active compounds will be assessed to identify possible lethal mechanisms. Through national and international partnerships with the University of Oxford (UK), Universidad La Frontera (Chile), UFABC, and CEBIMar/USP, we will carry out a multidisciplinary project aimed at discovering new therapeutic candidates for Chagas disease. (AU)