title: Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification.
abstract: Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC50values ranging from 15 to 125µM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC50=15µM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC50=67.7µM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC50=3.1µM) with remarkable selectivity index (SI=128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Saulo Fehelberg Pinto
authors.initials: SF
authors.lastname: Braga
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Luan Carvalho
authors.initials: LC
authors.lastname: Martins
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Elany Barbosa
authors.initials: EB
authors.lastname: da Silva
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil.
authors.forename: Policarpo Ademar
authors.initials: PA
authors.lastname: Sales Júnior
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil.
authors.forename: Silvane Maria Fonseca
authors.initials: SM
authors.lastname: Murta
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil.
authors.forename: Alvaro José
authors.initials: AJ
authors.lastname: Romanha
authors.affiliation: Structural Biology Group by Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Wai Tuck
authors.initials: WT
authors.lastname: Soh
authors.affiliation: Structural Biology Group by Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Brandstetter
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address: renatabo.ufmg@gmail.com.
authors.forename: Renata Barbosa
authors.initials: RB
authors.lastname: de Oliveira
mesh_terms: D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013057:Spectrum Analysis / Q000379:methods; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain
keywords: 4-Aminopyrimides; 4-Aminoquinolines; Chagas disease; Cruzain; Molecular simplification; Rhodesain