In Vitro Effects of Aminopyridyl Ligands Complexed to Copper(II) on the Physiology and Interaction Process of Trypanosoma cruzi

Author:

Silva-Oliveira Rafaela1,Sangenito Leandro S.12,Reddy Andrew3ORCID,Velasco-Torrijos Trinidad45ORCID,Santos André L. S.16ORCID,Branquinha Marta H.1ORCID

Affiliation:

1. Laboratório de Estudos Avancados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil

2. Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Nilópolis 26530-060, Brazil

3. Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand

4. Department of Chemistry, Maynooth University, W23VP22 Maynooth, Co. Kildare, Ireland

5. The Kathleen Lonsdale Institute for Human Health Research, Maynooth University, W23VP22 Maynooth, Co. Kildare, Ireland

6. Programa de Pós-Graduação em Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil

Abstract

Chagas disease is derived from the infection by the protozoan Trypanosoma cruzi. In many countries, benznidazole is the only drug approved for clinical use despite several side effects and the emergence of resistant parasite strains. In this context, our group has previously pointed out that two novel aminopyridine derivatives complexed with Cu2+, namely, cis-aquadichloro(N-[4-(hydroxyphenyl)methyl]-2-pyridinemethamino)copper (3a) and its glycosylated ligand cis-dichloro (N-{[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pheny]lmethyl}-2-pyridinemethamino)copper (3b), are effective against T. cruzi trypomastigote forms. With this result in mind, the present work aimed to investigate the effects of both compounds on trypomastigotes physiology and on the interaction process with host cells. Apart from loss of plasma membrane integrity, an increased generation of reactive oxygen species (ROS) and decreased mitochondrial metabolism were observed. Pretreatment of trypomastigotes with these metallodrugs inhibited the association index with LLC-MK2 cells in a typical dose-dependent manner. Both compounds showed low toxicity on mammalian cells (CC50 > 100 µM), and the IC50 values calculated for intracellular amastigotes were determined as 14.4 µM for 3a and 27.1 µM for 3b. This set of results demonstrates the potential of these aminopyridines complexed with Cu2+ as promising candidates for further antitrypanosomal drug development.

Funder

Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

Publisher

MDPI AG

Subject

Infectious Diseases,Public Health, Environmental and Occupational Health,General Immunology and Microbiology

Reference37 articles.

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4. World Health Organization (2023, March 22). Chagas Disease (American Trypanosomiasis). Available online: https://www.who.int/health-topics/chagas-disease.

5. World Health Organization (2023, March 22). Ending the Neglect to Attain the Sustainable Development Goals: A Road Map for Neglected Tropical Diseases 2021–2030: Overview. Available online: https://www.who.int/publications/i/item/9789240010352.

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