Synthesis of Urease Inhibitory 2, 4-bis (4-cyanobenzyl)glycoluril using Sandmeyer Reaction and Density Functional Theory Investigation

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Author(s): Mirza Arfan Yawer*, Shehar Bano, Muhammad Saleem*, Affiefa Yawer, Riaz Hussain, Muhammad Imran, Ahmad Irfan, Abdur Rauf, Tareq Abu-Izneid

Journal Name: Current Organic Synthesis


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Abstract:

Aims: The aim of present research was to synthesize glycoluril derivative 2,4-Bis(4-cyanobenzyl)glycoluril through convergent scheme.

Background: For this purpose Sandmeyer reaction procedure was employed for the synthesis of said compound. The structure of the pure compound was confirmed by using different spectroscopic techniques such as 1H-NMR, 13C-NMR and (HR-MS) Mass spectrometry.

Objective: Convergent synthesis of 2,4-BIS (4-CYANOBENZYL)GLYCOLURIL USING SANDMEYER REACTION and urease inhibition study.

Methods: The structure of the pure compound was confirmed by using different spectroscopic techniques such as 1H-NMR, 13C-NMR and (HR-MS) Mass spectrometry. The electronic properties of newly synthesized compound and thiourea were determined by using density functional theory.

Results: Furthermore compound was evaluated against urease enzyme and was found to be potent inhibitors with IC50 value of 11.5 ± 1.50 µM when compared with standard inhibitor thiourea (IC50 = 21.0 ± 1.90 µM). Compound may serve as lead compound for the synthesis of new cyano based bambusuril in future with enhanced biological properties.

Conclusion: We have synthesized a new glycoluril derivative 2,4-Bis(4-cyanobenzyl)glycoluril by the sandmeyer reaction. It has obtained in the form of light yellowish powder in good yield (96%). Glycoluril based macrocycles have been used in various fields. Starting from the 2,4-Bis(4-nitrobenzyl)glycoluril (already reported compound) which has undergone reduction (CH3OH,Pt/C) , diazotization (NaNO2/HCl), cyanation (CuCl/KCN) respectively in order to synthesize the desired new glycoluril derivative. The obtained product will be used as a building block for the synthesis of the cyano based bambusuril marcocycle in future. The yield of the obtained product has been monitored by using different amount of cyanating reagent but the best results shown by the use of 4 mmol of CuCl/KCN. KCN with CuCl assisted the conversion of diazo group into cyano group with enhanced yield when used in excess amount. It act as a catalyst. Solubility characteristic of 2,4-Bis(4-cyanobenzyl)glycoluril has determined also in different organic solvents. 1H NMR technique proved to be very helpful for the structure determination of our desired product. Benzylic protons give signals at 7.5 ppm and 7.8 ppm respectively. The downfield peaks confirm about the presence of CN group near the benzylic protons. Methine protons show signal at 5.2 ppm which ensures about the basic skeleton of glycoluril. Ureidyl protons also confirm the synthesis of the heterocyclic 2,4-Bis(4-cyanobenzyl)glycoluril compound. The negative and positive electrostatic potential sites, molecular descriptors, and charge density distribution of frontier molecular orbitals are revealing that 4a with promising sites for electrophilic and nucleophilic attacks would result to enhance the urease inhbition which is in good agreement with the experimental data.

Keywords: Glycoluril derivative, sandmeyer reaction, 1H NMR, (HR-MS) mass spectrometry, urease enzyme, thiourea, IC50, density functional theory (DFT), bambusuril.

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(E-pub Ahead of Print)
DOI: 10.2174/1570179418666210113162909
Price: $95

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