Structure-activity relationships of novel N-imidazoylpiperazines with potent anti-Trypanosoma cruzi activity

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Espinoza-Chavez, Rocio Marisol ; de Oliveira Rezende Jr, Celso ; de Souza, Mariana Laureano ; Pauli, Ivani ; Valli, Marilia ; Ferreira, Leonardo Luiz Gomes ; Chelucci, Rafael Consolin ; Michelan-Duarte, Simone ; Krogh, Renata ; da Silva, Fernando Bezerra Romualdo ; Cruz, Fabio Cardoso ; de Oliveira, Aldo Sena ; Andricopulo, Adriano Defini ; Dias, Luiz Carlos

• Document type: Journal article
• Source: Future Medicinal Chemistry; v. 16, n. 3, p. 18-pg., 2024-01-09.

Abstract

Background: Chagas disease is caused by the parasite Trypanosoma cruzi, and the lack of effective and safe treatments makes identifying new classes of compounds with anti-T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N-imidazoylpiperazine was performed. Results: Compound 2, a piperazine derivative active against T. cruzi, was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds. [GRAPHICS] (AU)

• FAPESP's process: 15/50655-9 - FAPESP/MMV/DNDi/UNICAMP/USP Consortium to discover new drugs for the treatment of tropical parasitic diseases
• Grantee: Luiz Carlos Dias
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/09080-2 - Evaluation of candidate drugs for the treatment of Leishmaniasis in Brazil
• Grantee: Silvia Reni Bortolin Uliana
• Support Opportunities: Regular Research Grants