Flavonoid-Quinoxaline Hybrid Compounds as Cathepsin Inhibitors Against Fascioliasis.

Autor: Ferraro F; Laboratorio de I+D de Moléculas Bioactivas, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Ruta 3 km 363, Paysandú, 60000, Uruguay., Merlino A; Laboratorio de Química Teórica y Computacional, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo, 11400, Uruguay., Gil J; Laboratorio de Reproducción Animal, Producción y Reproducción de Rumiantes, Departamento de Ciencias Biológicas, CENUR Litoral Norte-Facultad de Veterinaria, Universidad de la República, Ruta 3 km 363, Paysandú, 60000, Uruguay., Pérez-Silanes S; ISTUN Institute of Tropical Health, Department of Pharmaceutical Sciences, Universidad de Navarra, IdiSNA (Navarra Institute for Health Research), Campus Universitario, 31009, Pamplona, Spain., Corvo I; Laboratorio de I+D de Moléculas Bioactivas, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Ruta 3 km 363, Paysandú, 60000, Uruguay., Cabrera M; Laboratorio de I+D de Moléculas Bioactivas, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Ruta 3 km 363, Paysandú, 60000, Uruguay.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Sep 16; Vol. 19 (18), pp. e202400305. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1002/cmdc.202400305
Abstrakt: Fasciola hepatica is a parasitic trematode that infects livestock animals and humans, causing significant health and economic burdens worldwide. The extensive use of anthelmintic drugs has led to the emergence of resistant parasite strains, posing a threat to treatment success. The complex life cycle of the liver fluke, coupled with limited funding and research interest, have hindered progress in drug discovery. Our group has been working in drug development against this parasite using cathepsin proteases as molecular targets, finding promising compound candidates with in vitro and in vivo efficacy. Here, we evaluated hybrid molecules that combine two chemotypes, chalcones and quinoxaline 1,4-di- N-oxides, previously found to inhibit F. hepatica cathepsin Ls and tested their in vitro activity with the isolated targets and the parasites in culture. These molecules proved to be good cathepsin inhibitors and to kill the juvenile parasites at micromolar concentrations. Also, we performed molecular docking studies to analyze the compounds-cathepsins interface, finding that the best inhibitors interact at the active site cleft and contact the catalytic dyad and residues belonging to the substrate binding pockets. We conclude that the hybrid compounds constitute promising scaffolds for the further development of new fasciolicidal compounds.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: