Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification.

Autor: Braga SF; Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., Martins LC; Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., da Silva EB; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., Sales Júnior PA; Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil., Murta SM; Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil., Romanha AJ; Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil., Soh WT; Structural Biology Group by Department of Molecular Biology, University of Salzburg, Salzburg, Austria., Brandstetter H; Structural Biology Group by Department of Molecular Biology, University of Salzburg, Salzburg, Austria., Ferreira RS; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., de Oliveira RB; Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address: renatabo.ufmg@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Mar 15; Vol. 25 (6), pp. 1889-1900. Date of Electronic Publication: 2017 Feb 09.
DOI: 10.1016/j.bmc.2017.02.009
Abstrakt: 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 IC 50 values 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; IC 50 =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 (IC 50 =67.7µM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC 50 =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.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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