Synthesis, Stereochemical Identification, and Selective Inhibitory Activity against Human Monoamine Oxidase-B of 2-Methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones

A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. The new compounds were significantly selective hMAO-B inhibitors. For this reason it was important to have the pure enantiomers of the most active compounds inorder to evaluate the influence of stereochemistry on the inhibitory activity. All compounds showed higher activity against the human MAO-B isoform with IC50 values ranging between 26.81 ( 2.74 ?M and 14.20 ( 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8. The molecular modeling study of the most active and selective hMAO inhibitor 8 was qualitatively in agreement with the selectivity for isoform B as well as the different enantioselective inhibition of the enantiomers for the same enzyme. Moreover, both MM and QM studies indicated that both E and Z configurations are thermodynamically possible for the inhibitor 8. The docking results show that the Z configuration has the best recognition for hMAO-B. This information should be taken into account in the rational design of new more potent and selective inhibitors.