Synthesis and biological evaluation of new long-chain squaramides as anti-chagasic agents in the BALB/c mouse model. Issue 5 (1st March 2019)

• Record Type: Journal Article
• Authors: Martín-Escolano, Rubén; Marín, Clotilde; Vega, Manuel; Martin-Montes, Álvaro; Medina-Carmona, Encarnación; López, Carlos; Rotger, Carmen; Costa, Antonio; Sánchez-Moreno, Manuel
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 5(2019)
• Page Start: 865
• Page End: 879
• Publication Date: 2019-03-01
• Subjects: CD Chagas Disease -- BZN Benznidazole -- NFX Nifurtimox -- MILT Miltefosine -- Fe- SOD iron superoxide dismutase -- ppm parts per million -- DMSO dimethyl sulfoxide -- DTU discrete typing unit -- IC inhibitory concentration -- BTs bloodstream trypomastigotes -- pi post-infection -- CP cyclophosphamide monohydrate -- IS immunosuppression -- PCR polymerase chain reaction -- ELISA enzyme-linked immunosorbent assay -- 1H NMR proton nuclear magnetic resonance -- Rho rhodamine 123 -- AO acridine orange -- SI selectivity index -- IgG immunoglobulin G -- PEP phosphoenolpyruvate -- PK pyruvate kinase -- PPDK pyruvate phosphate dikinase -- TCA tricarboxylic acid; Chagas Disease -- Chemotherapy -- Murine model -- Squaramides -- Trypanosoma cruzi; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.01.033
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Improved in vitro efficiency and lower toxicity than Benznidazole. Activity against different T. cruzi strains, included those Benznidazole-resistant. Compound7 obtained promising results in acute and chronic phase treatments. Compound7 trypanocidal effect is due to a mitochondrial membrane depolarisation. Compound7 should be implemented in future clinical experiments. Abstract: Chagas Disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi and affects more than 10 million people. It is a paradigmatic example of a chronic disease without an effective treatment in Latin America where the current therapies, based on Benznidazole and Nifurtimox, are characterised by limited efficacy, toxic side-effects and frequent failures in the treatment. We present a series of new long-chain squaramides, identified based on their 1 H and 13 C NMR spectra, and their trypanocidal activity and cytotoxicity were tested in vitro through the determination of IC50 values. Compounds4 and7 were more active and less toxic than the reference drug Benznidazole, and these results were the basis of promoting in vivo assays, where parasitaemia levels, assignment of cure, reactivation of parasitaemia and others parameters were determined in mice treated in both the acute and chronic phases. Finally, the mechanisms of action were elucidated at metabolic and mitochondrial levels and superoxide dismutase inhibition. The experiments allowed us to select compound7 as a promising candidate for treating Chagas Disease, where the activity, stability and low cost make long-chain squaramides appropriate molecules for the development of an affordable anti-chagasic agent versus current treatments.