Novel 6-hydroxybenzothiazol-2-carboxamides as potent and selective monoamine oxidase B inhibitors endowed with neuroprotective activity

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 (IC 50 = 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 alpha-synuclein (alpha-syn) aggregation. We identified the phenethylamide 30 as a multipotent inhibitor of MAO -B (IC 50 = 41 nM) and alpha-syn and tau aggregation. It showed no cytotoxic effects on SH-SY5Y neuroblastoma cells, while also providing neuroprotection against toxicities induced by alpha-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.