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

Abstract

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

N-(2,4-Dinitrophenyl)benzo[d][1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC₅₀ = 56 nM, K_i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC₅₀ = 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.

Keywords:

• salicylic acid derivatives
• molecular modeling
• Parkinson’s disease
• enzyme inhibitor
• pharmacophore
• structure-activity relationships

Acknowledgments

This work was kindly supported by COST action CM1103, CA15135 and CA18133 as well as DFG INST 208/664e1 FUGG (Germany). Mohammad Khanfar and Holger Stark have been supported by the George Forster Research Fellowship granted by the Alexander von Humboldt-Foundation.

Disclosure

The authors report no conflicts of interest in this work.