Thiosemicarbazone derivatives: Evaluation as cruzipain inhibitors and molecular modeling study of complexes with cruzain.
Jasinski, G., Salas-Sarduy, E., Vega, D., Fabian, L., Martini, M. F. and Moglioni, A. G.
Catedra de Quimica Medicinal, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, CABA, C1113AAD, Argentina; Instituto de la Quimica y el Metabolismo del Farmaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, CABA, 1113, Argentina.
Instituto de Investigaciones Biotecnologicas "Dr. Rodolfo Ugalde" (IIBIO), CONICET-Universidad de San Martin (UNSAM), San Martin, Buenos Aires 1650, Argentina.
Departamento de Fisica de la Materia Condensada, GIyA, CAC, CNEA, Buenos Aires B1650KNA, Argentina; Escuela de Ciencia y Tecnologia, UNSAM, San Martin, Buenos Aires B1650KNA, Argentina.
Instituto de la Quimica y el Metabolismo del Farmaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, CABA, 1113, Argentina.
The development of cruzipain inhibitors represents one of the most attractive challenges in the search for drugs for the treatment of Chagas disease. A recombinant form of this enzyme, cruzain, has been crystallized with numerous inhibitors, excluding thiosemicarbazones. These compounds have been established as potent inhibitors of cruzain, although there is very little data in the literature of thiosemicarbazones tested on cruzipain. In this work, we present the results of the evaluation of eleven thiosemicarbazones on cruzipain, isolated from T. cruzi epimastigotes, six of them previously evaluated on cruzain. For these latter, we studied through computational methods, the mode of interaction with the active site of cruzain and the contribution of geometric parameters to the possible mechanism of action involved in the observed inhibition. Finally, from some geometric parameters analyzed on modeled TSC-cruzain complexes, a semi-quantitative relationship was established that could explain the inhibitory activity of thiosemicarbazones on cruzipain, the enzyme actually present in the parasite.
Bioorganic and Medicinal Chemistry 61: 116708 (2022)