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Synthesis, Molecular Modeling and Biological Evaluation of 5-arylidene- N,N-diethylthiobarbiturates as Potential α-glucosidase Inhibitors

Author(s):

Momin Khan*, Sehrish Khan, Amir Ul Mulk, Anis Ur Rahman, Abdul Wadood, Sulaiman Shams, Muhammad Ashraf, Jameel Rahman, Abdul Hameed, Zahid Hussain, Abbas Khan, Khair Zaman, Khalid Mohammed Khan and Shahnaz Perveen   Pages 1 - 11 ( 11 )

Abstract:


Background: Barbituric acid derivatives are a versatile group of compounds which are identified as potential pharmacophores for the treatment of anxiety, epilepsy and other psychiatric disorders. They are also used as anesthetics and have sound effects on the motor and sensory functions. Barbiturates are malonylurea derivatives with a variety of substituents at C-5 position showing resemblance with nitrogen and sulfur containing compounds like thiouracil which exhibited potent anticancer and antiviral activities. Recently, barbituric acid derivatives have also received great interest for applications in nanoscience.

Objective: Synthesis of 5-arylidene-N,N-diethylthiobarbiturates, biological evaluation as potential α-glucosidase inhibitors and molecular modeling.

Methods: In the present study, N,N-Diethylthiobarbituric acid derivatives were synthesized by refluxing of N,N-diethylthiobarbituric acid and different aromatic aldehydes in distilled water. In a typical reaction; a mixture of N,N-diethylthiobarbituric acid 0.20 g (1 mmol) and 5-bromo-2- hydroxybenzaldehyde 0.199 g (1 mmol) mixed in 10 mL distilled water and reflux for 30 minutes. After completion of the reaction, the corresponding product 1 was filtered and dried and yield calculated. It was crystallized from ethanol. The structures of synthesized compounds 1-25 were carried out by using 1H, 13C NMR, EI spectroscopy and CHN analysis used for the determination of their structures. The α-glucosidase inhibition assay was performed as given by Chapdelaine et al., with slight modifications and optimization.

Results: Our newly synthesized compounds showed a varying degree of α-glucosidase inhibition and at least four of them were found as potent inhibitors. Compounds 6, 5, 17, 11 exhibited IC50 values (Mean±SEM) of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 μM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 μM).

Conclusion: Our present study has shown that Compounds 6, 5, 17, 11 exhibited IC50 values of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 μM, respectively. The studies were supported by in silico data analysis.

Keywords:

N, N-Diethylthiobarbiturates, Aromatic aldehydes, α-Glucosidase, Docking studies, Homology modeling.

Affiliation:

Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Department of Biochemistry, Abdul Wali Khan University, Mardan-23200, Department of Biochemistry, Abdul Wali Khan University, Mardan-23200, Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur - 63100, Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur - 63100, H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Department of Chemistry, Abdul Wali Khan University, Mardan-23200, H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280



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