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

Grant number: 16/01375-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2016
Effective date (End): February 28, 2017
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Antonio Carlos Bender Burtoloso
Grantee:Larissa Regina Diniz
Home 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


Cruzain, the main cysteine protease of Trypanosoma cruzi, is an essential enzyme for the life cycle of the parasite and has been used as a viable target for searching for enzyme inhibitors as drug candidates. The peptide mimetic compound K11777 inhibits cruzain at nanomolar concentrations, and acts by an irreversible inhibition mechanism. Analogs or derivatives of K11777 usually contain electrophilic functional groups known as "warheads" that can bind covalently to the active site of cruzain via nucleophilic attack promoted by catalytic cysteine. Previous studies realized in the NEQUIMED found several dipeptidyl nitriles similars to the prototypical inhibitors of cathepsin K (which has been used in the pharmaceutical industry as a target) with activity against cruzain in the range of low- to sub-micromolar concentrations, being more potent than Neq409, which inhibited the enzyme with IC50 of 1.89 ± 0.11 µM (pIC50 = 5.7). 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 the BZ which is > 500 µM). The dipeptidyl nitriles exhibit characteristics of leads that can be optimized for drug candidates: T. cruzi IC50 > 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. The aim of this proposal is search new potencially candidates cruzain inhibitors. (AU)