Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson's disease: Synthesis, in vitro and in vivo studies
MetadataShow full item record
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 Parkinsońs 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 exponentially 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. © 2020 Elsevier Inc.
Showing items related by title, author, creator and subject.
3-Arylcoumarins as highly potent and selective monoamine oxidase B inhibitors: Which chemical features matter? (2020) Mellado M.; Mella J.; González C.; Viña D.; Uriarte E.; Matos M.J. (Academic Press Inc., 2020)
Synthesis, biological evaluation, and molecular simulation of chalcones and aurones as selective MAO-B inhibitors (2020) Morales-Camilo N.; Salas C.O.; Sanhueza C.; Espinosa-Bustos C.; Sepúlveda-Boza S.; Reyes-Parada M.; Gonzalez-Nilo F.; Caroli-Rezende M.; Fierro A. (Blackwell Publishing Ltd, 2015)
Coumarin-Rasagiline Hybrids as Potent and Selective hMAO-B Inhibitors, Antioxidants, and Neuroprotective Agents (2020) Matos M.J.; Herrera Ibatá D.M.; Uriarte E.; Viña D. (John Wiley and Sons Ltd, 2020)