Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson¿s disease: Synthesis, in vitro and in vivo studies

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Rodríguez-Enríquez, F (Author) Other; Viña, D (Author) Other; Uriarte, E (Author) Other; Fontenla, JA (Author) Other; Matos, MJ (Author) FCUP

Journal

Title: Bioorganic Chemistry

Vol. 101

ISSN: 0045-2068

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 1 Citation

Scopus - 1 Citation

Other information

Authenticus ID: P-00V-3S3

DOI: 10.1016/j.bioorg.2020.103986

Abstract (EN): Monoamine oxidase B (MAO-B) inhibitors are still receiving great attention as promising therapeutic agents for central nervous system disorders. This study explores, for the first time, the potential of 3-thiophenylcoumarins as in vitro and in vivo agents against Parkinsons disease. Twelve compounds were synthesized via Perkin-Oglialoro reaction, and in vitro evaluation of six hydroxylated molecules was performed. MAO-A and MAO-B inhibition, DPPH scavenging and inhibition of ROS formation, neurotoxicity on motor cortex neurons and neuroprotection against H2O2, were studied. In vivo effect on locomotor activity using the open field test was also evaluated for the best candidate [3-(4 '-bromothiophen-2 '-yl)-7-hydroxycoumarin, 5], a potent, selective and reversible MAO-B inhibitor (IC50 = 140 nM). This compound proved to have a slightly better in vivo profile than selegiline, one of the currently treatments for Parkinson's disease, in reserpinized mice pretreated with levodopa and benserazide. Results suggested that, comparing positions 7 and 8, substitution at position 7 of the coumarin scaffold is better for the enzymatic inhibition. However, the presence of a catechol at positions 7 and 8 ex-ponentially increases the antioxidant potential and the neuroprotective properties. Finally, all the molecules present good theoretical physicochemical properties that make them excellent candidates for the optimization of a lead compound.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9