2. Academic Validation
  3. Design, synthesis and biological evaluation of novel thiosemicarbazones as cruzipain inhibitors

Design, synthesis and biological evaluation of novel thiosemicarbazones as cruzipain inhibitors

  • Eur J Med Chem. 2023 Apr 7;254:115345. doi: 10.1016/j.ejmech.2023.115345.
Gabriel Jasinski 1,  Emir Salas-Sarduy 2,  Daniel Vega 3,  Lucas Fabian 4,  M Florencia Martini 1,  Albertina G Moglioni 5
Affiliations

Affiliations

  • 1 Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Medicinal, Buenos Aires, C1113AAD, Argentina; CONICET-Universidad de Buenos Aires, Instituto de la Química y el Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, 1113, Argentina.
  • 2 Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo Ugalde" (IIBIO), CONICET, San Martín, Buenos Aires, 1650, Argentina; Escuela de Bio y Nanotecnología (EByN), Universidad Nacional de San Martín (UNSAM), San Martín, Buenos Aires, 1650, Argentina.
  • 3 Departamento de Física de la Materia Condensada, GIyA, CAC, CNEA, Buenos Aires, B1650KNA, Argentina; Escuela de Ciencia y Tecnología, UNSAM, San Martín, Buenos Aires, B1650KNA, Argentina.
  • 4 CONICET-Universidad de Buenos Aires, Instituto de la Química y el Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, 1113, Argentina.
  • 5 Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Medicinal, Buenos Aires, C1113AAD, Argentina; CONICET-Universidad de Buenos Aires, Instituto de la Química y el Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, 1113, Argentina. Electronic address: bmoglio2015@gmail.com.
PMID: 37054562 DOI: 10.1016/j.ejmech.2023.115345
Abstract

Based on the activity of 23 TSCs on CZ taken from the literature, we have developed a QSAR model for predicting the activity of TSCs. New TSCs were designed and then tested against CZP, resulting in inhibitors with IC50 values in the nanomolar range. The modelling of the corresponding TSC-CZ complexes by molecular docking and QM/QM ONIOM refinement indicates a binding mode compatible with what was expected for active TSCs, according to a geometry-based theoretical model previously developed by our research group. Kinetic experiments on CZP suggest that the new TSCs act by a mechanism that involves the formation of a reversible covalent adduct with slow association and dissociation kinetics. These results demonstrate the strong inhibitory effect of the new TSCs and the benefit of the combined use of QSAR and molecular modelling techniques in the design of new and potent CZ/CZP inhibitors.

Keywords

Chagas disease; Cruzipain inhibitors; Drug design; QSAR; Thiosemicarbazones.

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