Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs.

BACKGROUND

Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors.

METHODS

The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results.

RESULTS

-(2,4-Dinitrophenyl)benzo[][1,3]dioxole-5-carboxamide (, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC = 56 nM, K = 6.3 nM), while -(2,4-dinitrophenyl)benzamide (, ST-2023) showed higher preference for MAO A (IC = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites.

CONCLUSION

The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.