Novel Diamides Inspired By Protein Kinase Inhibitors As Anti-Trypanosoma Cruzi Agents: In Vitro and In Vivo Evaluations

Abstract

Background: Chagas disease is a life-threatening illness caused by Trypanosoma cruzi. The involvement of serine-/arginine-rich protein kinase in the T. cruzi life cycle is significant. Aims: To synthesize, characterize and evaluate the trypanocidal activity of diamides inspired by kinase inhibitor, SRPIN340. Material & Methods: Synthesis using a three-step process and characterization by infrared, nuclear magnetic resonance and high-resolution mass spectrometry were conducted. The selectivity index was obtained by the ratio of CC₅₀/IC₅₀ in two in vitro models. The most active compound, 3j, was evaluated using in vitro cytokine assays and assessing in vivo trypanocidal activity. Results:3j activity in the macrophage J774 lineage showed an anti-inflammatory profile, and mice showed significantly reduced parasitemia and morbidity at low compound dosages. Conclusion: Novel diamide is active against T. cruziin vitro and in vivo.

Keywords:

• Chagas disease
• diamides
• in vitro activity
• in vivo activity
• SRPIN340
• Trypanosoma cruzi

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Author contributions

FKVS Torchelsen: execution, data analysis and curation, writing, reviewing and editing. TCF Pedrosa: execution, data analysis and writing. MP Rodrigues: execution, data analysis and curation and writing. AR Aguiar: data curation, formal analysis, reviewing and editing. FM Oliveira: Data curation, formal analysis, reviewing and editing. GW Amarante: data curation, formal analysis, reviewing and editing. P Sales-Junior: execution and data analysis. RT Branquinho: data analysis and curation. SPG Silva: execution and data analysis. AT Pedrosa: data analysis and curation. SMF Murta: data analysis and curation. FT Martins: data curation, formal analysis, reviewing and editing. RL Braun: execution, data analysis and writing. RR Teixeira: research conceptualization, data analysis and curation, writing, reviewing and editing. VCF Mosqueira: Research conceptualization, data analysis and curation, writing, reviewing and editing. M Lana: Research conceptualization and coordination, data analysis and curation, writing, reviewing and editing.

Financial & competing interests disclosure

The following organizations contributed financially to equipment and materials for this work: Fundação de Amparo à Pesquisa do Estado de Minas Gerais processes APQ-00940-18, APQ-02429-22 and APQ-02511-22; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) process APQ-02576-18 and Financiadora de Estudos e Projetos (FINEP) from Ministério da Ciência, Tecnologia e Inovações (MCTI). Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) financed part of the study with a student's fellowships. A bilateral CAPES-COFECUB research collaboration between Brazil and France (process: 88887.647088/2021-00) also partially funded this work. M Lana and VF Mosqueira are research fellows at CNPq. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval for all animal experimental investigations. Approved protocol number 8173140921.