Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors

Abstract Compounds of hybrid structure pyridazine-coumarin were discovered as potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B). These compounds were synthesized in good yield following a multistep approach based on Knoevenagel reaction and using as key intermediate pyridazinone 16 , which was obtained from maleic anhydride and furan. Compounds 9b and 9d are the most active compounds of these series, with IC 50 values in the sub-micromolar range, and lack of cytotoxic effects. Theoretical calculation of ADME properties also suggested a good pharmacokinetic profile for both compounds. Docking simulations provided insights into enzyme inhibitor interactions and allowed us to rationalize the observed structure-activity relationships (SARs).