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

Authors Hagenow J, Hagenow S, Grau K, Khanfar M, Hefke L, Proschak E, Stark H

Received 30 October 2019

Accepted for publication 19 December 2019

Published 28 January 2020 Volume 2020:14 Pages 371—393


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Tin Wui Wong

Jens Hagenow,1 Stefanie Hagenow,1 Kathrin Grau,1 Mohammad Khanfar,1– 3 Lena Hefke,4 Ewgenij Proschak,4 Holger Stark1

1Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Duesseldorf 40225, Germany; 2Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan; 3College of Pharmacy, Alfaisal University, Riyadh 11533, Saudi Arabia; 4Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Frankfurt 60438, Germany

Correspondence: Holger Stark
Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, Duesseldorf 40225, Germany
Tel +49 211 81-10478
Fax +49 211 81-13359

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, Ki = 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

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