Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease.


Olmo, F; Rotger, C; Ramírez-Macías, I; Martínez, L; Marín, C; Carreras, L; Urbanová, K; Vega, M; Chaves-Lemaur, G; Sampedro, A; Rosales, MJ; Sánchez-Moreno, M; Costa, A; (2014) Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease. Journal of medicinal chemistry, 57 (3). pp. 987-99. ISSN 0022-2623 DOI: https://doi.org/10.1021/jm4017015

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Abstract

Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Neglected Tropical Diseases Network
PubMed ID: 24410674
Web of Science ID: 331493000031
URI: http://researchonline.lshtm.ac.uk/id/eprint/2921351

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