Design, Synthesis and Antidiabetic Activity of Novel Sulfamoyl Benzamide Derivatives as Glucokinase Activators

  • Ajmer Singh Grewal Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
  • Kapil Sharma Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa, 125055, Haryana, India
  • Sukhbir Singh Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
  • Vikramjeet Singh Department of Pharmaceutical Sciences, GJUS&T, Hisar, 125001, Haryana, India
  • Deepti Pandita Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida, 201303, Uttar Pradesh, India
  • Viney Lather Amity Institute of Pharmacy, Amity University, Noida, 201303, Uttar Pradesh, India
Keywords: Antidiabetic activity, Benzamides, Diabetes mellitus, Glucokinase, GK activators, Molecular Docking

Abstract

The present work has been planned to design, synthesize and evaluate the antidiabetic potential of a series of sulfamoyl benzamide derivatives as potential glucokinase (GK) activators. A new series of sulfamoyl benzamide derivatives was synthesized starting from 3-nitrobenzoic acid and characterized. In silico docking studies were performed to determine the binding interactions for the best fit conformations in the allosteric site of GK enzyme. Based on the results of in silico studies, the selected molecules were tested for their antidiabetic activity in animal studies (alloxan induced diabetic animal model). Compound 7 exhibited highest antidiabetic activity in animal studies. The results of in vivo antidiabetic activity studies were found to be in parallel to that of docking studies. These newly synthesized sulfamoyl benzamide derivatives thus can be treated as the initial hits for the development of novel, safe, effective and orally bioavailable GK activators as therapeutic agents for the treatment of type 2 diabetes.

References

[1] Akinola, O., Gabriel, M., Suleiman, A., and Olorunsogbon, F. (2012). Treatment of alloxaninduced diabetic rats with metformin or glitazones is associated with amelioration of hyperglycaemia and neuroprotection. The Open Diabetes Journal, 5, 8–12. https://doi.org/10.2174/1876524601205010008
[2] Bastaki, S. (2005). Diabetes mellitus and its treatment. International Journal of Diabetes Metabolism, 13, 111–134.
[3] Brownlee, M. (2001). Biochemistry and molecular cell biology of diabetic complications. Nature, 414, 813–820. https://doi.org/10.1038/414813
[4] Cade, W. T. (2008). Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Physical Therapy, 88, 1322–1335. https://doi.org/10.2522/ptj.20080008
[5] Charaya N., Pandita D., Grewal A. S., and Lather V.(2018). Design, synthesis and biological evaluation of novel thiazol-2-yl benzamide derivatives as glucokinase activators. Computational Biology and Chemistry, 73, 221–229. https://doi.org/10.1016/j.compbiolchem.2018.02.018
[6] Cheruvallath, Z. S., Gwaltney, S. L., Sabat, M., Tang, M., Feng, J., Wang, H., et al. (2013). Design, synthesis and SAR of novel glucokinase activators. Bioorganic and Medicinal Chemistry Letters, 23(7), 2166–2171. https://doi.org/10.1016/j.bmcl.2013.01.093
[7] Coghlan, M. and Leighton, B. (2008). Glucokinase activators in diabetes management. Expert Opinion on Investigational Drugs, 17(2), 145–167. https://doi.org/10.1517/13543784.17.2.145
[8] Filipski, K. J., Guzman-Perez, A., Bian, J., Perreault, C., Aspnes, G. E., Didiuk, M. T., et al. (2013). Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif. Bioorganic and Medicinal Chemistry Letters, 23(16), 4571–4578. https://doi.org/10.1016/j.bmcl.2013.06.036
[9] Grewal, A. S., Sekhon, B. S., and Lather, V. (2014). Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. Mini Reviews in Medicinal Chemistry, 14(7), 585–602. https://doi.org/10.2174/1389557514666140722082713
[10] Grewal, A. S., Bhardwaj, S., Pandita, D., Lather, V. and Sekhon, B. S. (2016). Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini Reviews in Medicinal Chemistry, 16(2), 120–162. https://doi.org/10.2174/1389557515666150909143737
[11] Grewal, A. S., Lather, V., Pandita, D. and Bhayana, G. (2017). Synthesis, docking and biological evaluation of phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPARδ agonists. Letters in Drug Design and Discovery, 14(11), 1239–1251. https://doi.org/10.2174/1570180814666170327164443
[12] Grewal, A. S., Viney Lather, V., Pandita, D. and Dalal, R. (2017). Synthesis, docking and anti-inflammatory activity of triazole amine derivatives as potential phosphodiesterase-4 inhibitors. Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry, 16(1), 58–67. https://doi.org/10.2174/1871523016666170616115752
[13] Hinklin, R. J., Boyd, S. A., Chicarelli, M. J., Condroski, K. R., DeWolf, W. E., Lee, P. A., et al. (2013). Identification of a new class of glucokinase activators through structure-based design. Journal of Medicinal Chemistry, 56(19), 7669–7678. https://doi.org/10.1021/jm401116k
[14] Iino, T., Sasaki, Y., Bamba, M., Mitsuya, M., Ohno, A., Kamata, K., et al. (2009). Discovery and structureactivity relationships of a novel class of quinazoline glucokinase activators. Bioorganic and Medicinal Chemistry Letters, 19(19), 5531–5538. https://doi.org/10.1016/j.bmcl.2009.08.064
[15] Iino, T., Hashimoto, N., Hasegawa, T., Chiba, M., Eiki, J. and Nishimura, T. (2010). Metabolic activation of N-thiazol-2-yl benzamide as glucokinase activators: impacts of glutathione trapping on covalent binding. Bioorganic and Medicinal Chemistry Letters, 20(5), 1619–1622. https://doi.org/10.1016/j.bmcl.2010.01.041
[16] Ishikawa, M., Nonoshita, K., Ogino, Y., Nagae, Y., Tsukahara, D., Hosaka, H., et al. (2009). Discovery of novel 2-(pyridine-2-yl)-1H-benzimidazole derivatives as potent glucokinase activators. Bioorganic and Medicinal Chemistry Letters, 19(15), 4450–4454. https://doi.org/10.1016/j.bmcl.2009.05.038
[17] Kohei, K. (2010). Pathophysiology of type 2 diabetes and its treatment policy. Japan Medical Association Journal, 53, 41–46.
[18] Li, F., Zhu. Q., Zhang, Y., Feng, Y., Leng, Y. and Zhang, A. (2010). Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazole-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators. Bioorganic and Medicinal Chemistry, 18(11), 3875–3884. https://doi.org/10.1016/j.bmc.2010.04.038
[19] Li, Y. Q., Zhang, Y. L., Hu, S. Q., Wang, Y. L., Song, H. R., Feng, Z.Q. et al. (2011). Design, synthesis and biological evaluation of novel glucokinase activators. Chinese Chemical Letters, 22(1), 73–76. https://doi.org/10.1016/j.cclet.2010.07.023
[20] Li, Y., Tian, K., Qin, A., Zhang, L., Huo, L., Lei, L. et al. (2014) Discovery of novel urea derivatives as dual-target hypoglycemic agents that activate glucokinase and PPARγ. European Journal of Medicinal Chemistry, 76, 182–192. https://doi.org/10.1016/j.ejmech.2014.02.024
[21] Mao, W., Ning, M., Liu, Z., Zhu, Q., Leng, Y. and Zhang, A. (2012). Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators. Bioorg. Medicinal Chemistry, 20(9), 2982–2991. https://doi.org/10.1016/j.bmc.2012.03.008
[22] Matschinsky, F. M. and Porte, D. (2010) Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics. F1000 Medicine Reports, 2, 43. https://doi.org/10.3410/M2-43
[23] Matschinsky, F. M., Zelent, B., Doliba, N., Li, C., Vanderkooi, J. M., Naji, A. et al. (2011). Glucokinase activators for diabetes therapy. Diabetes Care, 34, S236–S243. https://doi.org/10.2337/dc11-s236
[24] Miteva, M. A., Guyon, F. and Tufféry, P. (2010). Frog2: Efficient 3D conformation ensemble generator for small compounds. Nucleic Acids Research, 38, W622–627. https://doi.org/10.1093/nar/gkq325
[25] Mitsuya, M., Kamata, K., Bamba, M., Watanabe, H., Sasaki, Y., Sasaki, K. et al. (2009). Discovery of novel 3,6-disubstituted 2-pyridinecarboxamide derivatives as GK activators. Bioorganic and Medicinal Chemistry Letters, 19(10), 2718–2721. https://doi.org/10.1016/j.bmcl.2009.03.137
[26] Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. et al. (2009). Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. Journal of Computational Chemistry, 16, 2785–2791. https://doi.org/10.1002/jcc.21256
[27] Olokoba, A. B., Obateru, O. A. and Olokoba, L. B. (2012). Type 2 diabetes mellitus: a review of current trends. Oman Medical Journal, 27, 269–273. https://doi.org/10.5001/omj.2012.68
[28] Pal, M. (2009). Recent advances in glucokinase activators for the treatment of type 2 diabetes. Drug Discovery Today, 14, 784–792. https://doi.org/10.1016/j.drudis.2009.05.013
[29] Pal, M. (2009a). Medicinal chemistry approaches for glucokinase activation to treat type 2 diabetes. Current Medicinal Chemistry, 16(29), 3858–3874. https://doi.org/10.2174/092986709789177993
[30] Park, K., Lee, B. M., Kim, Y. H., Han, T., Yi, W., Lee, D.H. et al. (2013). Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus. Bioorganic and Medicinal Chemistry Letters, 23(2), 537–542. https://doi.org/10.1016/j.bmcl.2012.11.018
[31] Park, K., Lee, M., Hyun, H., Lee, H., Choi, H., Kim, H. et al. (2014). Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1Hpyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus. Bioorganic and Medicinal Chemistry, 22(7), 2280–2293. https://doi.org/10.1016/j.bmc.2014.02.009
[32] Perseghin, G. (2010). Exploring the in vivo mechanisms of action of glucokinase activators in type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism, 95(11), 4871–4873. https://doi.org/10.1210/jc.2010-2049
[33] Pfefferkorn, J. A., Guzman-Perez, A., Litchfield, J., Aiello, R., Treadway, J. L., Pettersen, J., et al. (2012). Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol- 1-yl)propanamido) nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. Journal of Medicinal Chemistry, 55(3), 1318–1333. https://doi.org/10.1021/jm2014887
[34] Pfefferkorn, J. A., Tu, M., Filipski, K. J., Guzman- Perez, A., Bian, J., Aspnes, G. E. et al. (2012a). The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of type 2 diabetes mellitus. Bioorganic and Medicinal Chemistry Letters, 22(23), 7100–7105. https://doi.org/10.1016/j.bmcl.2012.09.082
[35] Pike, K. G., Allen, J. V., Caulkett, P. W., Clarke, D. S., Donald, C. S., Fenwick, M. L. et al. (2011). Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life. Bioorganic and Medicinal Chemistry Letters, 21(11), 3467–3470. https://doi.org/10.1016/j.bmcl.2011.03.093
[36] Sidduri, A., Grimsby, J. S., Corbett, W. L., Sarabu, R., Grippo, J. F., Lou, J. et al. (2010). 2,3-Disubstituted acrylamides as potent glucokinase activators. Bioorganic and Medicinal Chemistry Letters, 20(19), 5673-5676. https://doi.org/10.1016/j.bmcl.2010.08.029
[37] Singh, R., Lather, V., Pandita, D., Vikramjeet, J., Karthikeyan, A. N. and Singh, A. S. (2016). Synthesis, docking and antidiabetic activity of some newer benzamide derivatives as potential glucokinase activators. Letters in Drug Design and Discovery, 14(5), 540–553. https://doi.org/10.2174/1570180813666160819125342
[38] Takahashi, K., Hashimoto, N., Nakama, C., Kamata, K., Sasaki, K., Yoshimoto, R. et al. (2009). The design and optimization of a series of 2-(pyridin-2-yl)-1Hbenzimidazole compounds as allosteric glucokinase activators. Bioorganic and Medicinal Chemistry, 17(19), 7042–7051. https://doi.org/10.1016/j.bmc.2009.05.037
[39] Trott, O., and Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. Journal of Computational Chemistry, 31, 455–461.
[40] Tsumura, Y., Tsushima, Y., Tamura, A., Hasebe, M., Kanou, M., Kato, H. et al. (2017). TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models. PLoS One, 12(2), e0172252. https://doi.org/10.1371/journal.pone.0172252
[41] Wang, Z., Shi, X., Zhang, H., Yu, L., Cheng, Y., Zhang, H. et al. (2017). Discovery of cycloalkylfused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: design, synthesis, and biological evaluation. European Journal of Medicinal Chemistry, 139, 128–152. https://doi.org/10.1016/j.ejmech.2017.07.051
[42] Ye, N., Xu, X., Li, F., Ning, M., Liu, Z., Cao, Y. et al. (2012). Investigation on the oxidation of aryl oxiranylmethanols and the synthesis of 2-aryl-Nthiazolyl-oxirane-2-carboxamides as glucokinase activators. Tetrahedron Letters, 53(35), 4738–4742. https://doi.org/10.1016/j.tetlet.2012.06.111
[43] Zhang, L., Chen, X., Liu, J., Zhu, Q., Leng, Y., Luo, X. et al. (2012). Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase. European Journal of Medicinal Chemistry, 58, 624–639. https://doi.org/10.1016/j.ejmech.2012.06.020
[44] Zhang, L., Tian, K., Li, Y., Lei, L., Qin, A., Zhang, L. et al. (2012a). Novel phenyl-urea derivatives as dualtarget ligands that can activate both GK and PPARγ. Acta Pharmaceutica Sinica B, 2(6), 588–597. https://doi.org/10.1016/j.apsb.2012.10.002
Published
2018-11-02
How to Cite
Ajmer Singh Grewal, Kapil Sharma, Sukhbir Singh, Vikramjeet Singh, Deepti Pandita, & Viney Lather. (2018). Design, Synthesis and Antidiabetic Activity of Novel Sulfamoyl Benzamide Derivatives as Glucokinase Activators. Journal of Pharmaceutical Technology, Research and Management, 6(2), 115-124. Retrieved from https://jptrm.chitkara.edu.in/index.php/jptrm/article/view/101
Section
Articles