title: Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease.
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.
authors.affiliation: Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada , E-18071 Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.forename: Carmen
authors.initials: C
authors.lastname: Rotger
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ramírez-Macías
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.forename: Lucas
authors.initials: L
authors.lastname: Carreras
authors.forename: Kristína
authors.initials: K
authors.lastname: Urbanová
authors.forename: Manel
authors.initials: M
authors.lastname: Vega
authors.forename: Guillermo
authors.initials: G
authors.lastname: Chaves-Lemaur
authors.forename: Angel
authors.initials: A
authors.lastname: Sampedro
authors.forename: María Jose
authors.initials: MJ
authors.lastname: Rosales
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
authors.forename: Antonio
authors.initials: A
authors.lastname: Costa
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D002522:Chlorocebus aethiops; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D003959:Diamines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D007165:Immunosuppression Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014709:Vero Cells
chemical_list: C587730:3-(butylamino)-4-((3-(dimethylamino)propyl)(methyl)amino)cyclobut-3-en-1,2-dione; D003503:Cyclobutanes; D003959:Diamines; D014344:Trypanocidal Agents