Synthesis of 2-aminoacetonitriles derivatives as molecular fragments of reversible covalent inhibitors of cruzain enzyme

• Grant number: 19/14836-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2019
• End date: March 31, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Fernanda Pavani Silva
• 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

Abstract

Cruzain, the main cysteine protease of Trypanosoma cruzi, is an essential enzyme for the life cycle of the parasite and has been used in the NEQUIMED/IQSC/USP group for the identification of new trypanocidal agents. The substances synthesized in in the group in the era of the thematic project FAPESP #2013/18009-4, are active against cruzain in concentrations of low-nanomolar down to sub-nanomolar. However, not all inhibitors that are decorated with nitriles-based electrophilic groups have shown the expected activity on T. cruzi. For example, the cruzain inhibitor Neq0570 containing as the electrophilic group 1-aminocyclopropane-1-carbonitrile whereby the cruzain has high affinity (pKiCz = 6.6) has a pEC50T. cruzi value of 5.1. This means that 1.5 log units were lost in translation from the biochemical to the biological assay. On the other hand, Neq0410 bearing the 2-amino-2-methylpropanenitrile group in the same position has a pKiCz of 4.6 and a pEC50 T. cruzi less than 5 and therefore considered inactive. The hypothesis thus established motivates us to better investigate the substitution at position 2 of the 2-aminocetonitrile group in order to establish a structure-activity relationship (SAR) depending on the decoration in P1. A series of derivatives of P1-substituted 2-aminocetonitriles will be synthesized as the electrophilic group which will then be employed in the synthesis of cruzain inhibitors.