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, Iltaf Khan, Abdul Hameed, Zahid Hussain, Abbas Khan, Khair Zaman, Khalid M. Khan, Shahnaz Perveen.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


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, barbituric acid, α-Glucosidase, docking studies, homology modeling.

[1]
Temiz-Arpaci, O.; Yildiz, I.; Ozkan, S.; Kaynak, F.; Aki-Sener, E.; Yalçin, I. Synthesis and biological activity of some new benzoxazoles. Eur. J. Med. Chem., 2008, 43, 1423-1431.
[2]
Fillaut, J.L.; De Los Rios, I.; Masi, D.; Romerosa, A.; Zanobini, F.; Peruzzini, M. Synthesis and structural characterization of (carbene) ruthenium complexes binding nucleobases. Eur. J. Inorg. Chem., 2002, 2002, 935-942.
[3]
Ivaska, A.; Vaneesorn, Y.; Davidson, I.E.; Smyth, W.F. Voltammetric on-line analysis for some sulphur-containing drugs. Anal. Chim. Acta, 1980, 121, 51-59.
[4]
Abu-Eittah, R.; Osman, A. Studies on the formation of mixed-ligand complexes of cobalt (II) with ammonia and some barbiturates. J. Inorg. Nucl. Chem., 1979, 41, 1079-1085.
[5]
Murphy, R.; Svehla, G. An analytical study of metal-thiobarbituric acid complexes. Anal. Chim. Acta, 1978, 99, 115-124.
[6]
Smyth, W.; Svehla, G.; Zuman, P. Polarography of some sulphur-containing compounds: Part XVI. Polarographic and spectral investigation of acid-base equilibria in aqueous solutions of 2-thiobarbituric acids with substituents on sulphur. Anal. Chim. Acta, 1970, 52, 129-138.
[7]
Izatt, R.M.; Christensen, J.J.; Rytting, J.H. Sites and thermodynamic quantities associated with proton and metal ion interaction with ribonucleic acid, deoxyribonucleic acid, and their constituent bases, nucleosides, and and nucleotides. Chem. Rev., 1971, 71, 439-481.
[8]
Smyth, W.F.; Jenkins, T.; Siekiera, J.; Baydar, A. Acid-base equilibria of some 6-membered n-heterocyclic compounds. Anal. Chim. Acta, 1975, 80, 233-244.
[9]
Tóth, A.; Billes, F. Ultraviolet spectroscopic study of the acid base equilibrium of pyrimidine derivatives. I. Uracil derivatives. Acta Chir. Acad. Sci. Hung., 1968, 56, 229-250.
[10]
Martin, H.; Driscoll, J. Gas chromatographic identification and determination of barbiturates. Anal. Chem., 1966, 38, 345-346.
[11]
Gudzinowicz, B.; Clark, S. The gas chromatographic analysis of low concentrations of barbiturates using an electron affinity detector. J. Chromatogr. Sci., 1965, 3, 147-151.
[12]
Poethke, W.; Behrendt, H. Polarography of 1,8-dihydroxy-anthraquinone. Pharm. Zentralhalle Dtschl., 1964, 104, 4-13.
[13]
Jain, N.C.; Fontan, C.R.; Kirk, P.L. Rapid extraction method for barbiturates from blood for gas-liquid chromatographic analysis. Microchem. J., 1964, 8, 28-34.
[14]
Kazyak, L.; Knoblock, E.C. Application of gas chromatography to analytical toxicology. Anal. Chem., 1963, 35, 1448-1452.
[15]
Svendsen, A.B.; Brochmann-Hanssen, E. Gas chromatography of barbiturates II. Application to the study of their metabolism and excretion in humans. J. Pharm. Sci., 1962, 51, 494-495.
[16]
Brochmann-Hanssen, E.; Svendsen, A.B. Separation and identification of barbiturates and some related compounds by means of gas-liquid chromatography. J. Pharm. Sci., 1962, 51, 318-321.
[17]
Bassani, D.M. From supramolecular photochemistry to self-assembled photoactive architectures: the emergence of photochemical nanosciences. Int. J. Chem., 2006, 60, 175-178.
[18]
Brewer, A.D.; Minatelli, J.A.; Plowman, J.; Paull, K.D.; Narayanan, V. 5-(N-phenylcarboxamido)-2-thiobarbituric acid (NSC 336628), a novel potential antitumor agent. Biochem. Pharmacol., 1985, 34, 2047-2050.
[19]
Haley, T.J.; Gidley, J. Pharmacological comparison of R(+), S(−) and racemic thiopentone in mice. Eur. J. Pharmacol., 1976, 36, 211-214.
[20]
Agarwal, A.; Lata, S.; Saxena, K.; Srivastava, V.; Kumar, A. Synthesis and anticonvulsant activity of some potential thiazolidinonyl 2-oxo/thiobarbituric acids. Eur. J. Med. Chem., 2006, 41, 1223-1229.
[21]
Osman, A.; Kandeel, M.; Said, M.; Ahmed, E. Synthesis and anticonvulsant activity of some spiro compounds derived frombarbituric and thiobarbituric acids: Part i. Indian J. Chem. B., 1996, 35, 1073-1078.
[22]
Cheng, Q.; Wang, Q.; Tan, T.; Wang, M.; Chen, N. Synthesis and in vitro antibacterial activities of 5-(2,3,4,5-tetrahy-dro-1H-chromeno [2,3-d] pyrimidin-5-yl)pyrimidione derivatives. Chin. J. Chem., 2012, 30, 386-390.
[23]
Yan, Q.; Cao, R.; Yi, W.; Chen, Z.; Wen, H.; Ma, L.; Song, H. Inhibitory effects of 5-benzylidene barbiturate derivatives on mushroom tyrosinase and their antibacterial activities. Eur. J. Med. Chem., 2009, 44, 4235-4243.
[24]
Zhang, D.; Zhang, J.; Li, M.; Li, W.; Aimaiti, G.; Tuersun, G.; Ye, J.; Chu, Q. A novel miniaturized electrophoretic method for determining formaldehyde and acetaldehyde in food using 2-thiobarbituric acid derivatization. Food Chem., 2011, 129, 206-212.
[25]
Matsushita, T.; Inoue, S-I.; Tanaka, R. Method for determining the total lipid content of fish meat using a 2-thiobarbituric acid reaction. J. Am. Oil Chem. Soc., 2010, 87, 963-972.
[26]
De Melo, E.B.; da Silveira Gomes, A.; Carvalho, I. α- and β-Glucosidase inhibitors: Chemical structure and biological activity. Tetrahedron, 2006, 62, 10277-10302.
[27]
Asano, N. Glycosidase inhibitors: update and perspectives on practical use. Glycobiology, 2003, 13, 93R-104R.
[28]
Lee, H.Y.; Lee, D.S.; Kim, D.H.; Cho, S.K.; Lee, D.S. Antiviral activity of methylelaiophylin, an α-glucosidase inhibitor. J. Microbiol. Biotechnol., 2011, 21, 263-266.
[29]
Jacob, G.S. Glycosylation inhibitors in biology and medicine. Curr. Opin. Struct. Biol., 1995, 5, 605-611.
[30]
Dennis, J.W.; Laferte, S.; Waghorne, C.; Breitman, M.L.; Kerbel, R.S. Beta 1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science, 1987, 236, 582-585.
[31]
Khan, K.M.; Khan, M.; Ali, M.; Taha, M.; Hameed, A.; Ali, S.; Perveen, S.; Choudhary, M.I. Synthesis and DPPH radical scavenging activity of 5-arylidene-N,N-dimethylbarbiturates. Med. Chem., 2011, 7, 231-236.
[32]
Chapdelaine, P.; Tremblay, R.R.; Dube, J. p-Nitrophenol-alpha-D-glucopyranoside as substrate for measurement of maltase activity in human semen. Clin. Chem., 1978, 24, 208-211.
[33]
Guerreiro, L.R.; Carreiro, E.P.; Fernandes, L.; Cardote, T.A.; Moreira, R.; Caldeira, A.T.; Guedes, R.C.; Burke, A. Five-membered iminocyclitol α-glucosidase inhibitors: Synthetic, biological screening and in silico studies. Bioorg. Med. Chem., 2013, 21, 1911-1917.
[34]
Yamamoto, K.; Miyake, H.; Kusunoki, M.; Osaki, S. Crystal structures of isomaltase from Saccharomyces cerevisiae and in complex with its competitive inhibitor maltose. FEBS J., 2010, 277, 4205-4214.
[35]
Khan, M.; Yousaf, M.; Wadood, A.; Junaid, M.; Ashraf, M.; Alam, U.; Ali, M.; Arshad, M.; Hussain, Z.; Khan, K.M. Discovery of novel oxindole derivatives as potent α-glucosidase inhibitors. Bioorg. Med. Chem., 2014, 22, 3441-3448.
[36]
Halgren, T.A. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem., 1996, 17, 490-519.
[37]
Wang, J.; Cieplak, P.; Kollman, P.A. How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J. Comput. Chem., 2000, 21, 1049-1074.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 2
Year: 2019
Page: [175 - 185]
Pages: 11
DOI: 10.2174/1573406414666180912114814
Price: $65

Article Metrics

PDF: 27
HTML: 2

Special-new-year-discount