Original article
Exploring new selective 3-benzylquinoxaline-based MAO-A inhibitors: Design, synthesis, biological evaluation and docking studies

https://doi.org/10.1016/j.ejmech.2015.02.020Get rights and content

Highlights

  • A series of quinoxalinyl hydrazones and hydrazides were synthesized.

  • The compounds were evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B.

  • Most of the compounds showed a potent and selective MAO-A inhibitory activity where 4e and 9g were the most potent derivatives.

  • Molecular modeling studies were performed to rationalize the recognition of all inhibitors with respect to hMAO-A.

Abstract

In this investigation, we searched for novel MAO-A inhibitors using a 3-benzylquinoxaline scaffold based on our earlier findings. Series of N′-(3-benzylquinoxalin-2-yl)acetohydrazide, 4a, N′-(3-benzylquinoxalin-2-yl)benzohydrazide derivatives 4bf, N′-[2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetyl]benzohydrazide derivatives 7ad, (9H-fluoren-9-yl)methyl 1-[2-(2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetyl)-hydrazinyl]-2-ylcarbamate derivatives 8ac, 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)-N′-benzylidene acetohydrazide derivatives 9ah, and ethyl 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetate derivatives 10ae were synthesized and evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B. Most of the compounds showed a selective MAO-A inhibitory activity in the nanomolar or low micromolar range. Compounds 4e and 9g were the most potent derivatives with high MAO-A selectivity and their molecular docking studies were performed in order to rationalize the obtained biological result.

Graphical abstract

Series of 3-benzylquinoxalinyl hydrazones and hydrazides were synthesized and were evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B. Most of the compounds showed a potent and selective MAO-A inhibitory activity especially 4e and 9g derivatives.

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Introduction

Depression has been reported to be the fourth global burden of disease, with nearly 12% of the global disability adjusted life years [1]. In addition to the psychological stress on patients and families, depression contributes to the development and progression of systemic and organ diseases [2], [3], [4], [5]. Anxiety disorders, which often precede and co-occur with depression, are found in 10–21% of children and adolescents [6]. In the Middle East (namely, Egypt and the Kingdom of Saudi Arabia (KSA)) changing in the socioeconomic status have been shown to be associated with increased chronic diseases including chronic mental diseases like depression [7], [8], [9].

The monoamine oxidase inhibitors (MAOIs) were the first drugs used to treat depression. They work by blocking the breakdown of a number of neurotransmitters involved in depression via an enzyme, MAO. MAO (EC 1.4.3.4; MAO) is a flavoprotein localized in the outer mitochondrial membrane and present in practically all mammalian tissues. The primary role of MAO lies in the metabolism of amines and in the regulation of neurotransmitter levels and intracellular amine stores [10]. Two isoforms of MAO (MAO-A and MAO-B) have been found [11]. These two forms of MAO are characterized by their different affinities to inhibitors and their different specificities to substrates [12]. MAO-A preferably metabolizes serotonin, adrenaline, and noradrenaline [13], whereas β-phenylethylamine and benzylamine are predominantly metabolized by MAO-B [14]. Tyramine, dopamine, and some other important amines are common substrates for both isoenzymes [15]. Nowadays, the therapeutic interest of MAOIs falls into two major categories. MAO-A inhibitors have been used mostly in the treatment of mental disorders, in particular depression and anxiety [16], [17], [18], while MAO-B inhibitors could be used in the treatment of Parkinson's disease and Alzheimer's disease [19], [20].

In our efforts to add to the development of novel selective MAO-A inhibitors, we have recently focused on utilizing the 3-benzylquinoxaline scaffold where compound such 3-benzyl-2-(2-morpholin-4-yl-ethyl)amino-quinoxaline I showed potent and high selectivity MAO-A inhibition activity [21], [22]. We have also showed that a structurally related pyridazinylacetic acid derivatives synthesized in our laboratory were able to inhibit MAO-A with high selectivity index (SI) values [23]. The main goal of the present study was to synthesize a new family of hybrid quinoxaline derivatives IIIV based on the 3-benzylquinoxalin-2(1H)-one unit (Chart 1, Chart 2). The rational design of the new compounds was based on the following considerations: (i) the possession of the hydrazido functionality (e.g. Iproniazid), (ii) the presence of the benzamido functionality (e.g. Moclobemide), and (iii) the keeping benzylquinoxalinyl group which seems to play a role in orientation and complex formation at the active site of the enzyme.

Section snippets

Chemistry

In our synthesis, the quinoxaline scaffold was easily prepared according to the reported method in the literature (Scheme 1) [24]. The reaction of compound 1 with phosphoryl chloride afforded the rapid formation of the corresponding 2-benzyl-3-chloroquinoxaline 2 after neutralization with saturated sodium bicarbonate (Scheme 1). Further reaction of 2 with hydrazine hydrate in ethanol as a solvent afforded the 2-benzyl-3-hydrazinoquinoxaline 3 (Scheme 1) [24].

The syntheses of N

Conclusion

A new class of quinoxaline highly potent and selective MAO-A inhibitors was identified. All the compounds exhibited good inhibition in nanomolar range especially 4e and 9g showed high potency (1.7 and 1.6 nM) combined with high selectivity comparable to the standard drugs clorgyline and moclobemide. This work introduces novel benzylquinoxaline-based analogs for synthesis of MAO-A inhibitors displaying good activity and selectivity profiles. Molecular modeling studies were done to better

Chemistry

Melting points were determined with a Mel-Temp apparatus and are uncorrected. Magnetic resonance spectra (1H NMR and 13C NMR spectra) were recorded using a JEOL 500 MHz spectrometer with the chemical shift values reported in δ units (part per million). Infrared data were obtained using a Perkin–Elmer 1600 series Fourier transform instrument as KBr pellets. The compounds were named using Chem. Draw Ultra version 12, Cambridge soft Corporation. Elemental analyses were performed on Perkin–Elmer

Acknowledgment

The authors would like to acknowledge the Chemical Computing Group for using MOE software.

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