New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production Moya Garzón, María Dolores Franco Montalbán, Francisco Gómez Vidal, José Antonio Pey Rodríguez, Ángel Luis Díaz Gavilán, Mónica Hyperoxaluria Salicylic acid Glycolate oxidase Lactate dehydrogenase Oxalate Glyoxylate Funding: This work was supported by the Oxalosis and Hyperoxaluria Foundation (OHF) [Research Grant OHF2012], the Spanish Ministry of Economy [Predoctoral Fellowship to C.M.H. BES-2012- 052719], the ERDF/Spanish Ministry of Science, Innovation and Universities [Research Projects RTI2018-098560-B-C21 and RTI2018- 096246-B-I00 to M.D.G. and A.L.P, respectively], the University of Granada [Predoctoral Fellowship to M. D.M.G, Postdoctoral Grant to M. D.M.G], and the Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía [Grant P18-RT-2413 to A.L.P]. 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. 2022-05-27T06:23:10Z 2022-05-27T06:23:10Z 2022-04-25 info:eu-repo/semantics/article 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] http://hdl.handle.net/10481/75001 10.1016/j.ejmech.2022.114396 eng http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess Atribución-NoComercial-SinDerivadas 3.0 España Elsevier