<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

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 (IC 50 = 56 nM, K i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC 50 = 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.

A New Potent and Selective Monoamine Oxidase‐B Inhibitor with Extended Conjugation in a Chalcone Framework: 1‐[4‐(Morpholin‐4‐yl)phenyl]‐5‐phenylpenta‐2,4‐dien‐1‐one

“…The results were coincided to the studies that the rational design of two phenyl/heteroaryl rings connected via a short linker could lead to potent inhibitors targeting MAO-B and MAO-A. [31,32] Recently, Mathew et al reported that fluorinated morpholine-based chalcones (f1-f3) exhibited potent inhibitory activity and high SI towards recombinant human MAO-B (IC 50 = 0.21 to 0.087 μM; SI = 47.6 to 517.2). [24] The molecular selectivity could be also modulated on the basis of electron donating and withdrawing substitutions on the rings and depended on the length and the degree of conjugation of linker.…”

Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

“…In the exploration of novel, selective, and reversible MAO-B inhibitors, a general blueprint of drug design has been widely accepted recently, and it consists of a molecular framework of two hydrophobic rings of phenyl/heteroaryl, which are separated by an electron-rich and flexible short spacer unit ( Figure 1 ) [ 11 ]. Many of the molecules from this diverse class, such as pyrazolines, enamides, carboxamides, and α, β-unsaturated ketones, were identified as potent MAO-B inhibitors [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Novel Thiosemicarbazone Derivatives: In Vitro and In Silico Evaluation as Potential MAO-B Inhibitors

“…MAO-B, which degrades benzylamine and phenethylamine, is highly expressed in the central nervous system (CNS). Tryptamine, tyramine, and dopamine can be metabolized by both isoforms with individual metabolic activity for each substrate [6][7][8]. In light of all this information, the development of new MAO inhibitors (MAOIs) for the treatment of numerous neurological and psychiatric disorders represents a very important and useful approach [9,10].…”