New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production
Metadatos
Mostrar el registro completo del ítemAutor
Moya Garzón, María Dolores; Franco Montalbán, Francisco; Gómez Vidal, José Antonio; Pey Rodríguez, Ángel Luis; Díaz Gavilán, MónicaEditorial
Elsevier
Materia
Hyperoxaluria Salicylic acid Glycolate oxidase Lactate dehydrogenase Oxalate Glyoxylate
Fecha
2022-04-25Referencia bibliográfica
Maria Dolores Moya-Garzon... [et al.]. New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production, European Journal of Medicinal Chemistry, Volume 237, 2022, 114396, ISSN 0223-5234, [https://doi.org/10.1016/j.ejmech.2022.114396]
Patrocinador
xalosis and Hyperoxaluria Foundation (OHF) [Research Grant OHF2012]; Spanish Ministry of Economy [Predoctoral Fellowship to C.M.H. BES-2012- 052719]; ERDF/Spanish Ministry of Science, Innovation and Universities [Research Projects RTI2018-098560-B-C21 and RTI2018- 096246-B-I00]; University of Granada [Predoctoral Fellowship to M. D.M.G, Postdoctoral Grant to M. D.M.G]; Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía [Grant P18-RT-2413 to A.L.P]Resumen
The synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing
a salicylic acid moiety is described. The target compounds are obtained in an easily scalable two-step synthetic
procedure. These compounds showed low micromolar IC50 values against the two key enzymes in the metabolism
of glyoxylate. Mechanistically they behave as noncompetitive inhibitors against both enzymes and this fact is
supported by docking studies. The biological evaluation also includes in vitro and in vivo assays in hyperoxaluric
mice. The compounds are active against the three types of primary hyperoxalurias. Also, possible causes of
adverse effects, such as cyclooxygenase inhibition or renal toxicity, have been studied and discarded. Altogether,
this makes this chemotype with drug-like structure a good candidate for the treatment of primary hyperoxalurias.