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

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.