2-Mercapto Benzothiazole Derivatives: As Potential Leads for the Diabetic Management

Author(s): Saeed Ullah, Salma Mirza, Uzma Salar, Shafqat Hussain, Kulsoom Javaid, Khalid M. Khan*, Ruqaiya Khalil, Atia-tul-Wahab, Zaheer Ul-Haq, Shahnaz Perveen, Muhammad I. Choudhary

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Background: Results of our previous studies on antiglycation activity, and the noncytotoxicity of 2-mercapto benzothiazoles, encouraged us to further widen our investigation towards the identification of leads against diabetes mellitus.

Methods: 33 derivatives of 2-mercapto benzothiazoles 1-33 were evaluated for in vitro α- glucosidase inhibitory activity. Mode of inhibition was deduced by kinetic studies. To predict the interactions of 2-mercapto benzothiazole derivatives 1-33 with the binding pocket of α-glucosidase enzyme, molecular docking studies were performed on the selected inhibitors.

Results: Compounds 2-4, 6-7, 9-26, 28 and 30 showed many folds potent α-glucosidase inhibitory activity in the range of IC50 = 31.21-208.63 μM, as compared to the standard drug acarbose (IC50 = 875.75 ± 2.08 μM). It was important to note that except derivative 28, all other derivatives were also found previously to have antiglycating potential in the range of IC50 = 187.12-707.21 μM.

Conclusion: A number of compounds were identified as dual nature as antiglycating agent and α- glucosidase inhibitors. These compounds may serve as potential lead candidates for the management of diabetes mellitus.

Keywords: 2-Mercapto benzothiazole, in vitro α-glucosidase inhibitory activity, hyperglycemia, in silico studies. Type-II diabetes mellitus, insulin.

Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care, 2004, 27, 1047.
Dall, T.; Nikolov, P.; Hogan, P.F. Economic costs of diabetes in the US in 2002. Diabetes Care, 2003, 26, 917.
Bonora, E.; Muggeo, M. Postprandial blood glucose as a risk factor for cardiovascular disease in type II diabetes: the epidemiological evidence. Diabetologia, 2001, 44, 2107.
Young, B.A.; Lin, E.; Von Korff, M.; Simon, G.; Ciechanowski, P.; Ludman, E.J.; Everson-Stewart, S.; Kinder, L.; Oliver, M.; Boyko, E.J. Diabetes complications severity index and risk of mortality, hospitalization, and healthcare utilization. Am. J. Manag. Care, 2008, 14, 15.
Krentz, A.J.; Bailey, C.J. Oral antidiabetic agents. Drugs, 2005, 65, 385.
Krentz, A.J.; Patel, M.B.; Bailey, C.J. New drugs for type 2 diabetes mellitus. Drugs, 2008, 68, 2131.
Bailey, C.J. Drugs on the horizon for diabesity. Curr. Diab. Rep., 2005, 5, 353.
Koro, C.E.; Lee, B.H.; Bowlin, S.J. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin. Ther., 2009, 31, 2608.
Levetan, C. Oral antidiabetic agents in type 2 diabetes. Curr. Med. Res. Opin., 2007, 23, 945.
Sarabu, R.; Tilley, J. Recent advances in therapeutic approaches totype 2 diabetes. Annu. Rep. Med. Chem., 2005, 40, 167.
Tilley, J.; Grimsby, J.; Erickson, S.; Berthel, S. Diabetes drugs: present and emerging; Burger's Med. Chem. Drug Discov, 2010.
Chiba, S. Molecular mechanism in α-glucosidase and glucoamylase. Biosci. Biotech. Biochem., 1997, 61, 1233.
Javaid, K.; Saad, S.M.; Rasheed, S.; Moin, S.T.; Syed, N.; Fatima, I.; Salar, U.; Khan, K.M.; Perveen, S.; Choudhary, M.I. 2-Arylquinazolin-4 (3H)-ones: A new class of α-glucosidase inhibitors. Bioorg. Med. Chem., 2015, 23, 7417.
Kashtoh, H.; Hussain, S.; Khan, A.; Saad, S.M.; Khan, J.A.; Khan, K.M.; Perveen, S.; Choudhary, M.I. Oxadiazoles and thiadiazoles: Novel α-glucosidase inhibitors. Bioorg. Med. Chem., 2014, 22, 5454.
Salar, U.; Taha, M.; Khan, K.M.; Ismail, N.H.; Imran, S.; Perveen, S.; Gul, S.; Wadood, A. Syntheses of new 3-thiazolylcoumarin derivatives, in vitro α-glucosidase inhibitory activity, and molecular modeling studies. Eur. J. Med. Chem., 2016, 122, 196.
Khan, K.M.; Qurban, S.; Salar, U.; Taha, M.; Hussain, S.; Perveen, S.; Hameed, A.; Ismail, N.H.; Riaz, M.; Wadood, A. Synthesis, in vitro α-glucosidase inhibitory activity and molecular docking studies of new thiazole derivatives. Bioorg. Chem., 2016, 68, 245.
Arshad, T.; Khan, K.M.; Rasool, N.; Salar, U.; Hussain, S.; Tahir, T.; Ashraf, M.; Wadood, A.; Riaz, M.; Perveen, S.; Taha, M.; Ismail, N.H. Syntheses, in vitro evaluation and molecular docking studies of 5-bromo-2-aryl benzimidazoles as α-glucosidase inhibitors. Med. Chem. Res., 2016, 25, 2058.
Jaychandran, E.; Sreenivasa, G.; Sathe, B. Synthesis of some fluoro substituted sulphonamide benzothiazole comprising thiazole for anti-microbial screening. IJPBS, 2010, 2, 1.
Ban, M.; Taguchi, H.; Katsushima, T.; Takahashi, M.; Shinoda, K.; Watanabe, A.; Tominaga, T. Novel antiallergic and antiinflammatory agents. Part I: Synthesis and pharmacology of glycolic amide derivatives. Bioorg. Med. Chem., 1998, 6, 1069.
Mittal, S.; Samota, M.; Kaur, J.; Seth, G. Synthesis, Spectral, and Antifungal Evaluation of Phosphorylated and Thiophosphorylated Benzothiazole Derivatives. Phosphorus Sulfur Silicon Relat. Elem., 2007, 182, 2105.
Siddiqui, N.; Rana, A.; Khan, S.A.; Bhat, M.A.; Haque, S.E. Synthesis of benzothiazole semicarbazones as novel anticonvulsants-the role of hydrophobic domain. Bioorg. Med. Chem. Lett., 2007, 17, 4178.
Hout, S.; Azas, N.; Darque, A.; Robin, M.; Di Giorgio, C.; Gasquet, M.; Galy, J.; Timon-David, P. Activity of benzothiazoles and chemical derivatives on Plasmodium falciparum. Parasitology, 2004, 129, 525.
Hunasnalkar, S.G.; Gazi, S.; Patil, S.; Surwase, U.S. Synthesis and biological activities of some benzothiazole derivatives. Asian J. Res. Chem, 2010, 3, 421.
Bhusari, K.; Khedekar, P.; Umathe, S.; Bahekar, R.; Rao, A. Synthesis of 8-bromo-9-substituted-1, 3-benzothiazolo-[5, 1-b]-1, 3, 4-triazoles and their anthelmintic activity. Indian J. Heterocycl. Chem., 2000, 9, 275.
Telvekar, V.N.; Bairwa, V.K.; Satardekar, K.; Bellubi, A. Novel 2-(2-(4-aryloxybenzylidene) hydrazinyl) benzothiazole derivatives as anti-tubercular agents. Bioorg. Med. Chem. Lett., 2012, 22, 649.
Havrylyuk, D.; Mosula, L.; Zimenkovsky, B.; Vasylenko, O.; Gzella, A.; Lesyk, R. Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety. Eur. J. Med. Chem., 2010, 45, 5012.
Karalı, N.; Güzel, Ö.; Özsoy, N.; Özbey, S.; Salman, A. Synthesis of new spiroindolinones incorporating a benzothiazole moiety as antioxidant agents. Eur. J. Med. Chem., 2010, 45, 1068.
Bryson, H.M.; Fulton, B.; Benfield, P. Riluzole. Drugs, 1996, 52, 549.
Moreno-Díaz, H.; Villalobos-Molina, R.; Ortiz-Andrade, R.; Díaz-Coutiño, D.; Medina-Franco, J.L.; Webster, S.P.; Binnie, M.; Estrada-Soto, S.; Ibarra-Barajas, M.; León-Rivera, I. Antidiabetic activity of N-(6-substituted-1, 3-benzothiazol-2-yl) benzenesulfonamides. Bioorg. Med. Chem. Lett., 2008, 18, 2871.
Meltzer-Mats, E.; Babai-Shani, G.; Pasternak, L.; Uritsky, N.; Getter, T.; Viskind, O.; Eckel, J.; Cerasi, E.; Senderowitz, H.; Sasson, S. Synthesis and mechanism of hypoglycemic activity of benzothiazole derivatives. J. Med. Chem., 2013, 56, 5335.
Mariappan, G.; Prabhat, P.; Sutharson, L.; Banerjee, J.; Patangia, U.; Nath, S. Synthesis and antidiabetic evaluation of benzothiazole derivatives. J. Korean Chem. Soc., 2012, 56, 251.
Nitta, A.; Fujii, H.; Sakami, S.; Nishimura, Y.; Ohyama, T.; Satoh, M.; Nakaki, J.; Satoh, S.; Inada, C.; Kozono, H. (3R)-3-Amino-4-(2, 4, 5-trifluorophenyl)-N-4-[6-(2-methoxyethoxy) benzothiazol-2-yl] tetrahydropyran-4-yl butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett., 2008, 18, 5435.
Abbasi, S.; Mirza, S.; Rasheed, S.; Hussain, S.; AJ., Khan J.; Khan, K. M.; Perveen, S.; Choudhary, M.I. Benzothiazole derivatives: Novel inhibitors of methylglyoxal mediated glycation of proteins in vitro. Med. Chem., 2014, 10, 824.
Choudhary, M.I.; Shah, S.A.A.; Khan, S-N.; Khan, M.T.H. α-Glucosidase and tyrosinase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones. Steroids, 2010, 75, 956.
Hooft, R.W.; Sander, C.; Vriend, G. Objectively judging the quality of a protein structure from a Ramachandran plot. CABIOS, 1997, 13, 425.
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.
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera-A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25, 1605.
Schwede, T.; Kopp, J.; Guex, N.; Peitsch, M.C. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res., 2003, 31, 3381.
Salentin, S.; Schreiber, S.; Haupt, V.J.; Adasme, M.F.; Schroeder, M. PLIP: Fully automated protein-ligand interaction profiler. Nucleic Acids Res., 2015, 43, W443.
Bharatham, K.; Bharatham, N.; Park, K.H.; Lee, K.W. Binding mode analyses and pharmacophore model development for sulfonamide chalcone derivatives, a new class of α-glucosidase inhibitors. J. Mol. Graph. Model., 2008, 26, 1202.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 07 September, 2020
Page: [826 - 840]
Pages: 15
DOI: 10.2174/1573406415666190612153150
Price: $65

Article Metrics

PDF: 31
PRC: 2