000118161 001__ 118161
000118161 005__ 20230519145556.0
000118161 0247_ $$2doi$$a10.1016/j.bioorg.2021.105472
000118161 0248_ $$2sideral$$a126719
000118161 037__ $$aART-2021-126719
000118161 041__ $$aeng
000118161 100__ $$0(orcid)0000-0002-8839-6796$$aMahía A.
000118161 245__ $$aDesign, synthesis and structure-activity evaluation of novel 2-pyridone-based inhibitors of a-synuclein aggregation with potentially improved BBB permeability
000118161 260__ $$c2021
000118161 5060_ $$aAccess copy available to the general public$$fUnrestricted
000118161 5203_ $$aThe treatment of Parkinson''s disease (PD), the second most common neurodegenerative human disorder, continues to be symptomatic. Development of drugs able to stop or at least slowdown PD progression would benefit several million people worldwide. SynuClean-D is a low molecular weight 2-pyridone-based promising drug candidate that inhibits the aggregation of a-synuclein in human cultured cells and prevents degeneration of dopaminergic neurons in a Caenorhabditis elegans model of PD. Improving SynuClean-D pharmacokinetic/pharmacodynamic properties, performing structure/activity studies and testing its efficacy in mammalian models of PD requires the use of gr-amounts of the compound. However, not enough compound is on sale, and no synthetic route has been reported until now, which hampers the molecule progress towards clinical trials. To circumvent those problems, we describe here an efficient and economical route that enables the synthesis of SynuClean-D with good yields as well as the synthesis of SynuClean-D derivatives. Structure-activity comparison of the new compounds with SynuClean-D reveals the functional groups of the molecule that can be disposed of without activity loss and those that are crucial to interfere with a-synuclein aggregation. Several of the derivatives obtained retain the parent''s compound excellent in vitro anti-aggregative activity, without compromising its low toxicity. Computational predictions and preliminary testing indicate that the blood brain barrier (BBB) permeability of SynuClean-D is low. Importantly, several of the newly designed and obtained active derivatives are predicted to display good BBB permeability. The synthetic route developed here will facilitate their synthesis for BBB permeability determination and for efficacy testing in mammalian models of PD. © 2021 The Authors
000118161 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000118161 592__ $$a0.728$$b2021
000118161 590__ $$a5.307$$b2021
000118161 593__ $$aBiochemistry$$c2021$$dQ2
000118161 591__ $$aCHEMISTRY, ORGANIC$$b8 / 57 = 0.14$$c2021$$dQ1$$eT1
000118161 593__ $$aMolecular Biology$$c2021$$dQ2
000118161 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b99 / 297 = 0.333$$c2021$$dQ2$$eT2
000118161 593__ $$aDrug Discovery$$c2021$$dQ2
000118161 594__ $$a7.1$$b2021
000118161 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000118161 700__ $$aPeña-Díaz S.
000118161 700__ $$aNavarro S.
000118161 700__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos J.J.
000118161 700__ $$aPallarés I.
000118161 700__ $$aPujols J.
000118161 700__ $$0(orcid)0000-0001-9033-8459$$aDíaz-de-Villegas M.D.
000118161 700__ $$0(orcid)0000-0002-4972-7476$$aGálvez J.A.$$uUniversidad de Zaragoza
000118161 700__ $$aVentura S.
000118161 700__ $$0(orcid)0000-0002-2879-9200$$aSancho J.$$uUniversidad de Zaragoza
000118161 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDpto. Química Orgánica$$cÁrea Química Orgánica
000118161 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000118161 773__ $$g117 (2021), [12 pp]$$pBioorg. chem.$$tBioorganic Chemistry$$x0045-2068
000118161 8564_ $$s3607258$$uhttps://zaguan.unizar.es/record/118161/files/texto_completo.pdf$$yVersión publicada
000118161 8564_ $$s2428760$$uhttps://zaguan.unizar.es/record/118161/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000118161 909CO $$ooai:zaguan.unizar.es:118161$$particulos$$pdriver
000118161 951__ $$a2023-05-18-15:55:39
000118161 980__ $$aARTICLE