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Synthesis of cruzain inhibitors for dipeptidyl nitriles warhead exchange

Grant number: 16/10362-5
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 01, 2016
Effective date (End): June 30, 2017
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal researcher:Carlos Alberto Montanari
Grantee:Daniel Gedder Silva
Supervisor abroad: Michael H. Gelb
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Research place: University of Washington, United States  
Associated to the scholarship:13/01128-0 - Molecular design and synthesis of reversible cruzain inhibitors, BP.DR


The proponent is a FAPESP fellow (process 2013/01128-0), which is linked to the thematic project 2013/18009-4 under my supervision and presents this project of work to request a BEPE type scholarship to the University of Washington in Seattle, USA, under the supervision of Prof. Michael Gelb. Our best cruzain inhibitors (sub-micromolar) kill T. cruzi in varying concentrations and several of them have potency over low micromolar. However, the dipeptidyl nitriles are not killing the T. cruzi as expected: best drug candidate for Neq0594 inhibiting cruzain with a Ki = 2.019 ± 0.5899 and pKi = 5.7 kills T. cruzi amastigote CL-Brener with EC50 = 0.0265 ± 0.0246 µM, pEC50 = 7.4, noEffect: p = 1.3*10-10 for a good dose-response curve, with a cytotoxicity CC50 = 710 that yields a SI = 26792. Therefore, this proposal is essentially based on the substitution of nitrile for other warheads in maintaining the scaffold already identified in our work and thereby synthesize new compounds for preclinical assays. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SILVA, DANIEL G.; RIBEIRO, JEAN F. R.; DE VITA, DANIELA; CIANNI, LORENZO; FRANCO, CAIO HADDAD; FREITAS-JUNIOR, LUCIO H.; MORAES, CAROLINA BORSOI; ROCHA, JOSMAR R.; BURTOLOSO, ANTONIO C. B.; KENNY, PETER W.; LEITAO, ANDREI; MONTANARI, CARLOS A. A comparative study of warheads for design of cysteine protease inhibitors. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 22, p. 5031-5035, NOV 15 2017. Web of Science Citations: 6.
SILVA, DANIEL G.; GILLESPIE, J. ROBERT; RANADE, RANAE M.; HERBST, ZACKARY M.; NGUYEN, UYEN T. T.; BUCKNER, FREDERICK S.; MONTANARI, CARLOS A.; GELB, MICHAEL H. New Class of Antitrypanosomal Agents Based on Imidazopyridines. ACS Medicinal Chemistry Letters, v. 8, n. 7, p. 766-770, JUL 2017. Web of Science Citations: 6.
SILVA, DANIEL GEDDER; ROCHA, JOSMAR RODRIGUES; SARTORI, GERALDO RODRIGUES; MONTANARI, CARLOS ALBERTO. Highly predictive hologram QSAR models of nitrile-containing cruzain inhibitors. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, v. 35, n. 15, p. 3232-3249, 2017. Web of Science Citations: 0.

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