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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A comparative study of warheads for design of cysteine protease inhibitors

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Silva, Daniel G. [1] ; Ribeiro, Jean F. R. [1] ; De Vita, Daniela [1] ; Cianni, Lorenzo [1] ; Franco, Caio Haddad [2] ; Freitas-Junior, Lucio H. [2, 3, 4] ; Moraes, Carolina Borsoi [2, 3, 4] ; Rocha, Josmar R. [1] ; Burtoloso, Antonio C. B. [5] ; Kenny, Peter W. [1] ; Leitao, Andrei [1] ; Montanari, Carlos A. [1]
Total Authors: 12
[1] Univ Sao Paulo, Grp Quim Med IQSC USP, Inst Quim Sao Carlos, Sao Carlos, SP - Brazil
[2] CNPEM, Lab Nacl Biociencias LNBio, Campinas, SP - Brazil
[3] Inst Butantan, Sao Paulo, SP - Brazil
[4] Univ Sao Paulo, Dept Microbiol, Inst Ciencias Biomed, Sao Paulo, SP - Brazil
[5] Univ Sao Paulo, Inst Quim Sao Carlos, Sao Carlos, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry Letters; v. 27, n. 22, p. 5031-5035, NOV 15 2017.
Web of Science Citations: 6

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 alpha 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. (C) 2017 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 15/14304-7 - Design, Synthesis and Trypanocidal Activity of Covalent Reversible Inhibitors of the Enzyme Cruzain. Molecular Hybridization
Grantee:Daniela de Vita
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support type: Research Projects - Thematic Grants
FAPESP's process: 16/10362-5 - Synthesis of cruzain inhibitors for dipeptidyl nitriles warhead exchange
Grantee:Daniel Gedder Silva
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 13/01128-0 - Molecular design and synthesis of reversible cruzain inhibitors
Grantee:Daniel Gedder Silva
Support type: Scholarships in Brazil - Doctorate