Abstract
Eight glycosyl benzoxazole derivatives are synthesized by nucleophilic addition reactions of glycosyl isothiocyanate with o-aminophenol in tetrahydrofuran. The reaction conditions are optimized, and good yields (86%–94%) were obtained. The structures of all new products are confirmed by infrared, 1H nuclear magnetic resonance, and high-resolution mass spectrometry (electrospray ionization). In addition, the in vitro cholinesterase inhibitory activities of these new compounds are tested by Ellman’s method.
Introduction
As a natural monosaccharide, glucosamine is an indispensable substance in human cartilage and other tissues. 1 It is abundant in marine organisms and has a wide range of sources and broad application prospects. 2 Glucosamine has a wide spectrum of biological activities, and the synthesis of its derivatives has become a recent research hotspot for improving its biological activities. 3 Many studies have shown that glucosamine derivatives have strong biological properties, including antioxidant, anticancer, antibacterial, and anticholinesterase.4–8
Benzoxazole is a type of heterocyclic compound containing nitrogen and oxygen atoms. It has anti-inflammatory, anticancer, antibacterial, and plant virus killing activities,8–12 and is widely used in medicine, pesticides, and biological fields. Examples of main clinical drugs containing the benzoxazole skeleton include suvorexant for insomnia and flunoxaprofen for anti-inflammatory and analgesic activity.13,14
In recent years, many studies have used molecular hybrid-based approaches to search for new compounds with potential biological activities.15–17 Based on such approaches, we have designed and synthesized a series of novel glycosyl benzoxazole derivatives in an attempt to find new potent cholinesterase inhibitors. The inhibitory activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were tested by the Ellman method, and glycosylated heterocyclic compounds with improved AChE and BuChE inhibitory activity were obtained.
Results and discussion
Chemistry
To develop a simple synthetic pathway toward glycosyl benzoxazole compounds, 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl isothiocyanate 2 proved to be an important intermediate. In our studies, an acetyl group was used as the protecting group to realize the selective chemical modification of the hydroxyl on the glucosamine. First, glycosyl isothiocyanate 2 was synthesized according to the literature.18,19 Using tetrahydrofuran (THF) as the solvent, glycosyl isothiocyanate 2 was reacted with different o-aminophenols overnight, and then p-toluenesulfonyl chloride (p-TsCl) and pyridine were added resulting in desulfuration and cyclization to give glycosyl benzoxazole derivatives 5a–h (Scheme 1).
Synthetic pathway toward the glycosyl benzoxazole derivatives
In the second stage, glycosyl thiourea
Optimization of the cyclization reagent and catalyst.
Optimization of the conditions for the synthesis of
Biological activity
The AChE and BuChE inhibition activities of the newly synthesized compounds
In vitro cholinesterase inhibition activities of compounds
The inhibition activities of the compounds at a concentration of 100 µg mL−1; the results are the mean ± standard deviations (SDs).
As shown in Table 3, the inhibitory activity of all the prepared compounds on AChE and BuChE was higher than that of precursor compound glucosamine hydrochloride
Conclusion
Eight glycosyl benzoxazole derivatives were designed and synthesized by a green, efficient, and convenient method. The optimum reaction conditions were determined, that is, compound
Experimental
Chemistry
All chemicals were purchased from commercial sources and were used without further purification unless otherwise stated. Melting points were determined on a Yanaco melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Bruker Tensor 27 spectrometer as KBr discs. 1H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 500 MHz spectrometer at ambient temperature using dimethyl sulfoxide–d6 (DMSO-d6) as the solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in ppm. High-resolution mass spectrometry (HRMS) (electrospray ionization (ESI)) analysis was performed on an Agilent 6230 mass spectrometer. Flash column chromatography was performed on silica gel (200–300 mesh).
General procedure for the synthesis of N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-N′-o-hydroxyphenylthioureas 4a –h
The o-aminophenol compound
General procedure for the synthesis of glycosyl benzoxazoles 5a –h
Pyridine (2.1 mmol) was added directly to the suspension of compound
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX19-2277, KYCX19-2281), the Open-End Funds of Jiangsu Key Laboratory of Marine Biotechnology (HS2014007), Project 521 funded by Lianyungang (LYG52105-2018023), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Public Science and Technology Research Funds Projects of Ocean (201505023).
