Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products.
Iván KanizsaiRamóna MadácsiLászló HacklerMárió GyurisLászló G PuskásOrsolya HuziánLászló G PuskásPublished in: Molecules (Basel, Switzerland) (2018)
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.
Keyphrases
- high throughput
- molecular docking
- wastewater treatment
- single cell
- genome wide identification
- liquid chromatography
- cerebrospinal fluid
- oxidative stress
- amino acid
- tissue engineering
- hydrogen peroxide
- molecular dynamics
- current status
- blood brain barrier
- copy number
- heavy metals
- single molecule
- stem cells
- high speed
- structure activity relationship
- cell therapy
- human health
- molecular dynamics simulations
- dna methylation
- transcription factor
- bone marrow
- high performance liquid chromatography
- case control
- mesenchymal stem cells
- high resolution