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Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors

Grant number: 15/04947-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2015
Effective date (End): April 30, 2016
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Carlos Alberto Montanari
Grantee:Josmar Rodrigues da Rocha
Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.TEM


All the synthesised NEQUIMED compounds, supported by FAPESP Processes 2011/01893-3, 2011/20572-3 e 2008/04127-7, were active against cruzain in the range of low- to sub-micromolar concentrations. The most potent compound, Nequimed409 (Neq409), inhibited the enzyme with IC50 of 1.89 ± 0.11 µM (pIC50 = 5.7). These compounds showed trypanocidal activity against the trypomastigote/amastigote infective form Tulahuen lacZ strain at concentrations less than 50 µM. The prototype compound Neq409, potent against cruzain is also a trypanocidal agent (concentration-dependent response) with IC50 of 2.7 ± 0.3 µM (pIC50 = 5.6). Neq409 is more potent than the drug benznidazole (BZ), which was used as control (pIC50 = 4.6) and has minimal cytotoxicity in mice spleen (> 500 µM, comparable to BZ which is > 500 µM). The most promising dipeptidyl nitriles exhibit characteristics of leads that can be optimized for drug candidates: T. cruzi pIC50 > 5 (pIC50 (Neq409) = 5.6) with SI > 10 (SI ratio = IC50(cyto)/IC50(T. cruzi) = 185, BZ = 20.6); PFI < 8 (PFINeq409 = 3.7); # Ar rings < 5 and MW 500 < Da.

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