Structure-Metabolism Relationships of Benzimidazole Derivatives with anti-Trypanosoma cruzi Activity for Chagas Disease

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Espinoza-Chavez, Rocio Marisol ; Rezende Junior, Celso de Oliveira ; de Souza, Mariana Laureano ; Chelucci, Rafael Consolin ; Michelan-Duarte, Simone ; Krogh, Renata ; Ferreira, Leonardo Luiz Gomes ; Valli, Marilia ; de Oliveira, Aldo Sena ; Andricopulo, Adriano D. ; Dias, Luiz Carlos

• Document type: Journal article
• Source: CHEMMEDCHEM; v. 19, n. 20, p. 21-pg., 2024-08-27.

Abstract

This study introduces further insights from the hit-to-lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure-metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42 e and 49 b) exhibiting enhanced metabolic stability, anti-Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non-cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds. (AU)

• FAPESP's process: 18/14268-9 - Converting natural product leads into structure- and ligand-based drug discovery campaigns against Leishmaniasis and Chagas' Disease
• Grantee: Adriano Defini Andricopulo
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/25658-9 - Design and Development of Drug Candidates for Chagas Disease
• Grantee: Leonardo Luiz Gomes Ferreira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/11967-3 - Sustainable use of Brazilian biodiversity: using Linked Data for natural product discovery
• Grantee: Vanderlan da Silva Bolzani
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/50926-0 - INCT 2014: biodiversity and natural products
• Grantee: Vanderlan da Silva Bolzani
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 19/05967-3 - Understanding the biological function of Natural Products' scaffolds from Databases for the design of active compounds for the treatment of infectious diseases
• Grantee: Marilia Valli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• 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: 22/08333-8 - Accelerating natural product discovery
• Grantee: Vanderlan da Silva Bolzani
• Support Opportunities: Regular Research Grants
• 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