Synthesis and Biological Evaluation of N,N′-Squaramides with High in Vivo Efficacy and Low Toxicity: Toward a Low-Cost Drug against Chagas Disease
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- 作者：Francisco Olmo ; Carmen Rotger ; Inmaculada Ramírez-Macías ; Luis Martínez ; Clotilde Marín ; Lucas Carreras ; Kristína Urbanová ; Manel Vega ; Guillermo Chaves-Lemaur ; Angel Sampedro ; María Jose Rosales ; Manuel Sánchez-Moreno ; Antonio Costa
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：February 13, 2014
- 年：2014
- 卷：57
- 期：3
- 页码：987-999
- 全文大小：601K
- ISSN：1520-4804
文摘
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鈥?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鈥檚 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.