Synthesis, biological evaluation, and computational studies of novel fused six-membered O-containing heterocycles as potential acetylcholinesterase inhibitors

https://doi.org/10.1016/j.compbiolchem.2019.04.004Get rights and content

Highlights

  • Synthesis of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring in a one-pot is described.

  • Molecular dynamics studies are presented for most potent AChEI.

  • ADMETox prediction was provided for all compounds.

  • Inhibitory activity of all compounds against AChE enzyme was assessed.

  • Kinetic study of AChE inhibition was provided.

Abstract

An efficient, borax-catalyzed protocol for the synthesis of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring in a one-pot is described. By this achievement, some novel 4-aryl substituted 4H-pyrans fused to the α-pyrone ring as potential acetylcholinesterase inhibitors (AChEIs) with good to excellent yields are obtained from a one-pot three-component reaction between various aryl aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one and malononitrile. The method is a facile, inexpensive, practical and highly efficient one to obtain target compounds. The chemical structures of all compounds were characterized by FT-IR, FT-13CNMR and FT-1HNMR, MS spectroscopy and also elemental analyses data. Furthermore, the purity of all novel compounds was checked by HPLC. In addition, both molecular modelling studies and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMETox) prediction nominated all compounds as good acetylcholinesterase inhibitors to the potential treatment of Alzheimer, Parkinson and Autism diseases that among them compound 4f showed the best activity against acetylcholinesterase enzyme.

Graphical abstract

Herein, an efficient and practical approach for the synthesis and molecular modeling of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring is reported. The molecular modeling studies nominated all compounds to the inhibition of AChE enzyme, and also ADMETox prediction confirm that they are good candidates for anti-Alzheimer, anti-Parkinson, and anti-Autism drugs.

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Introduction

4H-pyrans-fused α-pyrones are very important six-membered O-containing fused heterocycles that nowadays their synthesis and expansion of domain have attracted the interest of chemists and pharmacists (Mishra and Choudhury, 2016; Rad-Moghadam et al., 2014). The reason is often related to their significant applications, especially their biological properties such as anti-Alzheimer (Ramesh et al., 2018), anti-leishmanial (Fan et al., 2010), anti-microbial (Makawana et al., 2011), anti-tumor and anti-oxidant activities (Rajguru et al., 2013). Also these compounds have been applied as SOAT2 inhibitors (Ohtawa et al., 2018), and potent modulator of insect transient receptors (Kandasamy et al., 2017). Furthermore, there are many strong pieces of evidence which reveal these compounds have cytotoxic effects on the neuroblastoma cells, and also necrotic effects on the human IPC melanoma cells (Leutbecher et al., 2007). In addition, some compounds of this family showed TMV (Tobacco Mosaic Virus) inhibitory activity (Yang et al., 2012). As well as, to more mention the importance of α-pyrones and 4H-pyranes it is just enough to consider the fact that many reviews have been written (Pratap and Ram, 2017; Eskandari and Rafieian-Kopaei, 2016), and many papers published on these compounds (Kumar et al., 2019; Pourshojaei et al., 2018a, b; Asadipour et al., 2017). For instance, in a recently reported study, this type of compounds has been introduced as anti-Alzheimer’s disease and has been showed potent cholinesterase inhibitory activity (Fig. 1) (Khoobi et al., 2013). To the best of our knowledge, the compounds that can inhibit cholinesterase enzyme are considered as anti-Alzheimer, anti-Parkinson, and anti-Autism diseases (Colovic et al., 2013). Considering the fact that Donepezil (an FDA approved drug used for treatment of above diseases) has overriding side effects such as “torsades de point” which is characterized as marked QT prolongation in electrocardiogram, and may result in cardiac syncope (Kitt et al., 2015), and also so far none of FDA approved drugs could absolutely or effectively treat above diseases, therefore the creation and expansion of their domain is inevitable. To find, develop, and explore of potent and permissive anti-Alzheimer drugs without any harmful side effects many attempts have been made so far. For instance, Kushwaha and co-workers (Kushwaha et al., 2018), Dgachi and co-workers (Dgachi et al., 2019), Najafi and co-workers (Najafi et al., 2019), and also Srivastava and co-workers (Srivastava et al., 2019) designed and synthesized a broad range of AChEIs as anti-Alzheimer agents. Besides, the need for these studies is still unavoidable and the efforts to extend AChEIs are continuing.

On the other hand, at the present time, there are prestigious computational methods such as molecular docking that can predict in an accurate way biological activity of organic compounds and the results are often consistent with experimental analyses (Yuan and Xu, 2018; Natchimuthu et al., 2016). Therefore the uses of computational methods and molecular modeling to design and predict the activity of newly prepared compounds have been increasingly interested and expanded (Singh et al., 2019; Chhajed et al., 2016).

Nowadays, there are many practical routes to the synthesis of 4H-pyran derivatives. For instance, the condensation reaction between carbonyl compounds and β-keto esters (firstly reported by Hantzsch) (Hantzsch, 1885), cyclization of 1,5-dicarbonyl compounds, and syntheses based on pyrylium salts (Drygina and Garnovskii, 1983) can be countered as most well-known approaches. Besides above, they also can be obtained with more diversity via a practical three-component reaction between carbonyl compounds, a CH-acidic compound and a 1,3-dinucleophile in which one of the nucleophiles is oxygen (Eskandari et al., 2014; Khodabakhshi et al., 2014; Sun et al., 2015).

Besides, catalytic technology is one of the most important aspects of chemical reactions and has attracted the interest of chemists and industrialists because of its benefits and advantages that the details have extensively explained in the literature (Cusumano, 1995; Karami et al., 2013; Eskandari et al., 2015a, b). Sodium tetraborate decahydrate also known as borax is a mineral, and an important boron compound in which its derivatives have recently been shown wood protection properties (Carr et al., 2011) and itself have been applied as green and highly efficient catalyst in chemical syntheses (Molla et al., 2013, 2018).

Considering above, in continuous of our previous studies on the highly efficient synthesis of novel heterocycles (Eskandari et al., 2015a, b; Eskandari and Karami, 2018), organic compounds (Asadipour et al., 2018; Pourshojaei et al., 2018a, b), and potentially interesting biological active compounds (Mehrabi et al., 2017; Eskandari and Karami, 2016; Eskandari et al., 2018) herein, we wish to report a highly efficient approach to the one-pot synthesis of novel 4H-pyran derivatives fused to α-pyrone ring 4 from three component reaction between malononitrile 1, aryl aldehydes 2 and 4-hydroxy-6-methyl-2H-pyran-2-one 3 in the presence of borax as a powerful and green catalyst (Scheme 1). Next, evaluate in silico all compounds activities against acetylcholinesterase (AChE) enzyme and study their ADMETox properties to make the results more reliable and introduce them as remarkable candidates to inhibition of AChE.

Section snippets

Material and methods

All chemicals were purchased from Merck and Sigma-Aldrich chemical companies. An electrothermal IA9100 melting point apparatus fixed at 1 °C / min was applied for recording melting points. An FT-IR Tensor 27 infrared spectrophotometer (Bruker) was used for recording FT-IR spectra using KBr as a matrix. Provided 1H NMR and 13C NMR spectra were taken by an FT-NMR Bruker Avance Ultra Shield Spectrometer (300 and 75 MHz in frequencies for 1H and 13C respectively) using DMSO as solvent. A Heraeus

Chemistry

One of the important aspects of chemical syntheses is the running of reactions under optimum conditions to achieve products with the highest yields in the shortest reaction times (Zhou et al., 2018; Peng et al., 2018). Therefore, first of all, we turned our attention towards finding optimum conditions for the reaction before expanding the reaction scope. For this purpose, the synthesis of 4g opted as a model reaction. In the first step, the reaction was loaded in a synthesizer in the absence

Conclusions

In summary, in this work, an efficient and novel catalytic approach to the synthesis of unprecedented 4-aryl-substituted-4H-pyran derivatives fused to the α-pyrone ring was described by the use of borax as a highly efficient and environmentally-benign catalyst. In addition, AChE inhibitory activity, kinetic assay, docking study and ADMETox prediction of the compounds were performed and the results revealed that they are able to and can be proper candidates to inhibit AChE enzyme. Therefore, by

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgment

The authors would like to say thanks to Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences for partial support of this work.

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