title: Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents.
abstract: The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K(i) = 0.8 μM). With the goal of achieving a better understanding of the structure-activity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, K(i) = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas' disease.
authors.affiliation: Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo , Avenida João Dagnone 1100, Jardim Santa Angelina, São Carlos, SP 13563-120, Brazil.
authors.forename: Rafaela S
authors.initials: RS
authors.lastname: Ferreira
authors.forename: Marco A
authors.initials: MA
authors.lastname: Dessoy
authors.forename: Ivani
authors.initials: I
authors.lastname: Pauli
authors.forename: Mariana L
authors.initials: ML
authors.lastname: Souza
authors.forename: Renata
authors.initials: R
authors.lastname: Krogh
authors.forename: Ana I L
authors.initials: AI
authors.lastname: Sales
authors.forename: Glaucius
authors.initials: G
authors.lastname: Oliva
authors.forename: Luiz C
authors.initials: LC
authors.lastname: Dias
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
chemical_list: D007202:Indicators and Reagents; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi