Novel 6-hydroxybenzothiazol-2-carboxamides as potent and selective monoamine oxidase B inhibitors endowed with neuroprotective activity
Omar M. Al-Saad, Moustafa T. Gabr, Sarah S. Darwish, Mariagrazia Rullo, Leonardo Pisani, Daniela Valeria Miniero, Grazia Maria Liuzzi, Andreas M. Kany, Anna K. H. Hirsch, Alireza Abadi, Matthias Engel, Marco Catto, Mohammad Abdel‐Halim
Abstract
In neurodegenerative diseases, using a single molecule that can exert multiple effects to modify the disease may have superior activity over the classical “one molecule-one target” approach. Herein, we describe the discovery of 6-hydroxybenzothiazol-2-carboxamides as highly potent and selective MAO-B inhibitors. Variation of the amide substituent led to several potent compounds having diverse side chains with cyclohexylamide 40 displaying the highest potency towards MAO-B (IC50 = 11 nM). To discover new compounds with extended efficacy against neurotoxic mechanisms in neurodegenerative diseases, MAO-B inhibitors were screened against PHF6, R3 tau, cellular tau and α-synuclein (α-syn) aggregation. We identified the phenethylamide 30 as a multipotent inhibitor of MAO-B (IC50 = 41 nM) and α-syn and tau aggregation. It showed no cytotoxic effects on SH-SY5Y neuroblastoma cells, while also providing neuroprotection against toxicities induced by α-syn and tau. The evaluation of key physicochemical and in vitro-ADME properties revealed a great potential as drug-like small molecules with multitarget neuroprotective activity.