Investigation of Thiazole Derivatives and Other Promising Compounds with Anti-Toxoplasma gondii Potential in Murine Models of Toxoplasmosis

• Grant number: 24/22547-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Juliana Quero Reimão Dalla Zanna
• Grantee: Ingrid de Oliveira Dias
• Host Institution: Faculdade de Medicina de Jundiaí (FMJ). Prefeitura Municipal de Jundiaí. Jundiaí , SP, Brazil
• Associated research grant: 18/18954-4 - Drug repurposing: evaluation of activity, selectivity and mechanism of action of new drug candidates against Toxoplasma gondii, AP.JP

Abstract

Introduction: Toxoplasmosis is an infection caused by the protozoan Toxoplasma gondii, which can lead to severe clinical manifestations, especially in immunocompromised individuals. Its cerebral form is among the most severe manifestations, resulting in central nervous system lesions. Although therapies are available, they are limited in controlling the chronic phase and present high toxicity for the host. Therefore, the search for new therapeutic options is essential. Privileged structures, such as thiazole derivatives, among others, have been explored in drug development due to their ability to generate potent ligands for various biological targets. Objective: This project aims to investigate the anti-T. gondii potential of compounds with privileged structures, such as thiazole derivatives, in experimental models of toxoplasmosis. Methodology: A screening of a compound library containing privileged structures, including dozens of thiazole derivatives, will be performed to evaluate their anti-T. gondii activity at nanomolar concentrations. Predictions of absorption, distribution, metabolism, excretion, and toxicity (ADMET) will be conducted using the SwissADME and OSIRIS platforms, aiming to select compounds with high gastrointestinal absorption, blood-brain barrier permeability, and no toxicity. Through in vitro assays using intracellular tachyzoites and human foreskin fibroblasts, the Effective Concentration 50% (EC50) against the parasite and Cytotoxic Concentration 50% (CC50) against host cells will be determined to identify the most selective compounds. The efficacy of the most promising compounds will be assessed in murine models of acute and chronic toxoplasmosis, employing real-time PCR. Ultrastructural changes induced in the parasite by the most promising compounds will be examined under transmission electron microscopy. Expected Results: Preliminary results indicated promising activity of these compounds against T. gondii tachyzoites. It is to identify those with selective activity and the ability to reach therapeutic levels in animal models, as well as to contribute to the understanding of the possible mechanisms of action of the most promising compounds. (AU)