Aldoxime- and hydroxy-functionalized chalcones as highly potent and selective monoamine oxidase-B inhibitors

A panel of 30 chalcone derivatives, including 19 aldoxime-chalcone ethers (ACE), and 11 hydroxyl- chalcones (HC), previously synthesized using a Pd-catalyzed C-O cross-coupling method were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and xe002;-secretase (BACE-1). HC6 was the most potent inhibitor of MAO-B with an IC 50 value of 0.0046 mu M and a selectivity index (SI) of 1,113. HC3 also potently inhibited MAO-B (IC 50 = 0.0067 mu M) and had the highest SI (1,455). ACE7 and ACE15 were also potent MAO-B inhibitors (IC 50 = 0.012 and 0.018 mu M, respectively), with SIs of 260 and 1,161, respectively. HC3 and HC6 were reversible competitive inhibitors of MAO-B, with K i values of 0.0036 and 0.0013 mu M, respectively. A structure-activity relationship revealed that methyl and fluorine substituents contributed to increasing both inhibition and selectivity. ACE7 was the most effective inhibitor of MAO-A (IC 50 = 1.49 mu M), followed by ACE3 (IC 50 = 3.75 mu M). No compounds effectively inhibited AChE, BChE, or BACE-1. A docking simulation showed that the ligand efficiency and docking scores of HC3 and HC6 toward MAO-B were consistent with the experimental IC 50 values. These results suggest that HC3 and HC6 can be considered promising candidates for the treatment of neurological disorders. (c) 2021 Elsevier B.V. All rights reserved.