A New Nitroimidazole-Based Drug Attenuates Skeletal Myositis and Overcomes Benznidazole Resistance in Experimental Chagas Disease

  • ACS Pharmacol Transl Sci. 2026 Jun 2;9(6):1567-1583. doi: 10.1021/acsptsci.6c00179.
Graziela Domingues De Almeida Lima  1 ,  Elda Gonçalves-Santos  2 ,  Monique Dias Benedetti  1 ,  Thiago Donizeth Silva  1 ,  Aristides Pinheiro  2 ,  Silvânia Mól Pelinsari  3 ,  Luis Felipe Cunha Dos Reis  4 ,  Reggiani Vilela Gonçalves  3  5  6 ,  Ivo Santana Caldas  1  4 ,  Lucas Lopardi Franco  7 ,  Rômulo Dias Novaes  1  2  4  5
Affiliations
  • 1. Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Alfenas, Alfenas, State of Minas Gerais 37130-001, Brazil.
  • 2. Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Universidade Federal de Alfenas, Alfenas, State of Minas Gerais 37130-001, Brazil.
  • 3. Departamento de Biologia Geral, Programa de Pós-Graduação em Biologia Celular e Estrutural, Universidade Federal de Viçosa, Viçosa, State of Minas Gerais 36570-900, Brazil.
  • 4. Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, State of Minas Gerais 37130-001, Brazil.
  • 5. Departamento de Biologia Animal, Programa de Pós-Graduação em Biologia Animal, Universidade Federal de Viçosa, Viçosa, State of Minas Gerais 36570-900, Brazil.
  • 6. North Carolina State University (NCSU), Kannapolis, North Carolina 28081, United States.
  • 7. Instituto de Ciências Farmacêuticas, Laboratório de Pesquisa em Química Farmacêutica (LQFar), Universidade Federal de Alfenas, Alfenas, State of Minas Gerais 37130-001, Brazil.
PMID: 42312169 DOI: 10.1021/acsptsci.6c00179
Abstract

Skeletal myositis is a disabling complication of Chagas disease for which the first-choice antiparasitic chemotherapy has limited efficacy. Therefore, we synthesized and investigated the potential of the novel nitroimidazole-based drug 1-(2-(2-methoxy-6-nitro-4-propylphenoxy)-ethyl)-2-methyl-5-nitro-1H-imidazole (ME) administered alone or combined with benznidazole (BZ) to control myocytes parasitism and skeletal myositis in Chagas disease. ME antiparasitic efficacy was investigated in vitro and in vivo in C2C12 skeletal myocytes and mice challenged with Trypanosoma cruzi Y strain. Physicochemical modeling indicated that ME presented characteristics compatible with orally bioactive drugs. Similar to BZ, our results indicated that ME showed a marked antiparasitic effect in vitro, attenuating T. cruzi viability, Infection rate, and Parasite load in C2C12 myocytes in a dose-dependent manner. In vivo, T. cruzi Infection induced intense parasitemia, muscle parasitism, oxidative stress, and inflammation, features associated with pathological microstructural remodeling of the skeletal muscle. ME administered alone and mainly in combination with BZ significantly reduced parasitemia, Parasite load, production of Reactive Oxygen Species (ROS) and nitrogen species (RNS), oxidation of lipids and cellular proteins, inflammation (e.g., inflammatory infiltrate, NAG and MPO activity, IFN-γ, TNF, IL-6, and IL-10 levels), and microstructural damage in skeletal muscle of T. cruzi-infected Animals. Our findings provide evidence that ME has direct antiparasitic effects in vitro and in vivo, showing potential efficacy for use as monotherapy and mainly in combination with BZ. This combination may be relevant to improve the etiological treatment of Chagas disease, simultaneously attenuating parasitism, oxidative stress, and skeletal myositis more efficiently than monotherapy with these drugs.

Keywords
antiparasitic chemotherapy; chagas disease; oxidative stress; parasitology; skeletal muscle.
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