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A comparative study of warheads for design of cysteine protease inhibitors.

Authors
  • Silva, Daniel G1
  • Ribeiro, Jean F R1
  • De Vita, Daniela1
  • Cianni, Lorenzo1
  • Franco, Caio Haddad2
  • Freitas-Junior, Lucio H2
  • Moraes, Carolina Borsoi2
  • Rocha, Josmar R1
  • Burtoloso, Antonio C B3
  • Kenny, Peter W4
  • Leitão, Andrei5
  • Montanari, Carlos A6
  • 1 Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil. , (Brazil)
  • 2 Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, São Paulo, Brazil. , (Brazil)
  • 3 Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil. , (Brazil)
  • 4 Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil. Electronic address: [email protected] , (Brazil)
  • 5 Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil. Electronic address: an[email protected] , (Brazil)
  • 6 Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil. Electronic address: [email protected] , (Brazil)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Nov 15, 2017
Volume
27
Issue
22
Pages
5031–5035
Identifiers
DOI: 10.1016/j.bmcl.2017.10.002
PMID: 29054358
Source
Medline
Keywords
License
Unknown

Abstract

The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.

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