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Molecules 2018, 23(8), 1934; https://doi.org/10.3390/molecules23081934

Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products

1
Avidin Ltd., Alsó kikötő sor. 11D, H-6726 Szeged, Hungary
2
Avicor Ltd., Alsó kikötő sor. 11D, H-6726 Szeged, Hungary
*
Authors to whom correspondence should be addressed.
Received: 11 July 2018 / Revised: 31 July 2018 / Accepted: 31 July 2018 / Published: 2 August 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

The 8-hydroxyquinoline pharmacophore scaffold has been shown to possess a range of activities as metal chelation, enzyme inhibition, cytotoxicity, and cytoprotection. Based on our previous findings we set out to optimize the scaffold for cytoprotective activity for its potential application in central nervous system related diseases. A 48-membered Betti-library was constructed by the utilization of formic acid mediated industrial-compatible coupling with sets of aromatic primary amines such as anilines, oxazoles, pyridines, and pyrimidines, with (hetero)aromatic aldehydes and 8-hydroxiquinoline derivatives. After column chromatography and re-crystallization, the corresponding analogues were obtained in yields of 13–90%. The synthesized analogs were optimized with the utilization of a cytoprotection assay with chemically induced oxidative stress, and the most active compounds were further tested in orthogonal assays, a real time cell viability method, a fluorescence-activated cell sorting (FACS)-based assay measuring mitochondrial membrane potential changes, and gene expression analysis. The best candidates showed potent, nanomolar activity in all test systems and support the need for future studies in animal models of central nervous system (CNS) disorders. View Full-Text
Keywords: 8-hydroxyquinoline; 8-HQ; Mannich-reaction; Betti-reaction; multicomponent reaction; cytoprotection; phenotypic screening; neurodegeneration; multitarget directed ligand; mitochondrial membrane potential; HIF1A 8-hydroxyquinoline; 8-HQ; Mannich-reaction; Betti-reaction; multicomponent reaction; cytoprotection; phenotypic screening; neurodegeneration; multitarget directed ligand; mitochondrial membrane potential; HIF1A
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Kanizsai, I.; Madácsi, R.; Hackler Jr., L.; Gyuris, M.; Szebeni, G.J.; Huzián, O.; Puskás, L.G. Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products. Molecules 2018, 23, 1934.

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