Synthesis, Molecular Modeling, and Selective Inhibitory Activity against Human Monoamine Oxidases of 3-Carboxamido-7-Substituted Coumarins.

A large series of 3-carboxamido-7-substituted coumarins have been synthesized and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory activity. Taking into account all the relevant structural information on MAOs reported in the literature, we made some changes in the coumarin nucleus and examined with particular attention the effect on activity and selectivity of substituting at position 3 with N-aryl or N-alkyl carboxamide and at position 7 with a benzyloxy or a 4?-F-benzyloxy group. Some of the assayed compounds proved to be potent, selective inhibitors of hMAO-B with IC50 values in the micromolar range. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution, hMAO-A and hMAO-B crystallographic structures. With the aim of carrying out a detailed analysis of the hMAOs binding modes of the most active compounds 18 and 21, we graphically inspected the most stable configurations of all complexes of these compounds with both isoforms. Both ligands showed productive recognition of both hMAO-Aand hMAO-B. The coumarin moiety was always located in the known hMAOs binding clefts, leaving the lactone function close to the FAD cofactor.