2,4-Dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic Acid Derivatives: In Vitro Antidiabetic Activity, Molecular Modeling and In silico ADMET Screening

Author(s): Samridhi Thakral, Vikramjeet Singh*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 2 , 2019

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Abstract:

Background: Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase which is an effective approach in both preventing and treating diabetes.

Objective: The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl] benzoic acid derivatives and evaluate α-glucosidase and α-amylase inhibitory activity along with molecular docking and in silico ADMET property analysis.

Method: Chlorosulfonation of 2,4-dichloro benzoic acid followed by reaction with corresponding anilines/amines yielded 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For evaluating their antidiabetic potential α-glucosidase and α-amylase inhibitory assays were carried out. In silico molecular docking studies of these compounds were performed with respect to these enzymes and a computational study was also carried out to predict the drug-likeness and ADMET properties of the title compounds.

Results: Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be highly active having 3 fold inhibitory potential against α-amylase and 5 times inhibitory activity against α-glucosidase in comparison to standard drug acarbose.

Conclusion: Most of the synthesized compounds were highly potent or equipotent to standard drug acarbose for inhibitory potential against α-glucosidase and α-amylase enzyme and hence this may indicate their antidiabetic activity. The docking study revealed that these compounds interact with active site of enzyme through hydrogen bonding and different pi interactions.

Keywords: Sulphonamide, α-glucosidase inhibitor, α-amylase inhibitor, antidiabetic, docking, ADME properties.

[1]
Patel, H.S.; Mistry, H.J. Synthesis of novel sulphonamides and evaluation of their antibacterial efficacy. Phosphorus Sulfur Silicon , 2004, 179(6), 1085-1093.
[2]
Di Cesare Mannelli, L.; Micheli, L.; Carta, F.; Cozzi, A.; Ghelardini, C.; Supuran, C.T. Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 894-899.
[3]
Taha, M.; Baharudin, M.S.; Ismail, N.H.; Selvaraj, M.; Salar, U.; Alkadi, K.A.; Khan, K.M. Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β-glucuronidase inhibitors. Bioorg. Chem., 2017, 71, 86-96.
[4]
Riaz, S.; Khan, I.U.; Bajda, M.; Ashraf, M.; Shaukat, A.; Rehman, T.U.; Mutahir, S.; Hussain, S.; Mustafa, G.; Yar, M. Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and alzheimer’s disease: in vitro studies against yeast α-glucosidase, acetylcholinesterase and butyrylcholinesterase. Bioorg. Chem., 2015, 63, 64-71.
[5]
Navarrete-Vázquez, G.; Morales-Vilchis, M.G.; Estrada-Soto, S.; Ramírez-Espinosa, J.J.; Hidalgo-Figueroa, S.; Nava-Zuazo, C.; Tlahuext, H.; Leon-Rivera, I.; Medina-Franco, J.L.; López-Vallejo, F.; Webster, S.P. Synthesis of 2-2-[(α/β-naphthalen-1-ylsulfonyl) amino]-1, 3-thiazol-4-yl acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities. Eur. J. Med. Chem., 2014, 74, 179-186.
[6]
Ahmadi, A.; Khalili, M.; Sohrabi, L.; Delzendeh, N.; Nahri-Niknafs, B.; Ansari, F. Synthesis and evaluation of the hypoglycemic and hypolipidemic activity of sulfonamide-benzothiazole derivatives of benzylidene-2, 4-thiazolidnedione. Mini Rev. Med. Chem., 2017, 17(8), 721-726.
[7]
Seo, W.D.; Kim, J.H.; Kang, J.E.; Ryu, H.W.; Curtis-Long, M.J.; Lee, H.S.; Yang, M.S.; Park, K.H. Sulfonamide chalcone as a new class of α-glucosidase inhibitors. Bioorg. Med. Chem. Lett., 2005, 15(24), 5514-5516.
[8]
Husain, A.; Madhesia, D.; Rashid, M.; Ahmad, A.; Khan, S.A. Synthesis and in vivo diuretic activity of some new benzothiazole sulfonamides containing quinoxaline ring system. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1682-1689.
[9]
Altug, C.; Gunes, H.; Nocentini, A.; Monti, S.M.; Buonanno, M.; Supuran, C.T. Synthesis of isoxazole-containing sulfonamides with potent carbonic anhydrase II and VII inhibitory properties. Bioorg. Med. Chem., 2017, 25(4), 1456-1464.
[10]
Renzi, G.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: topical sulfonamide antiglaucoma agents incorporating secondary amine moieties. Bioorg. Med. Chem. Lett., 2000, 10, 673-676.
[11]
Mishra, C.B.; Kumari, S.; Angeli, A.; Monti, S.M.; Buonanno, M.; Tiwari, M.; Supuran, C.T. Discovery of benzenesulfonamides with potent human carbonic anhydrase inhibitory and effective anticonvulsant action: design, synthesis, and pharmacological assessment. J. Med. Chem., 2017, 60(6), 2456-2469.
[12]
Dudutiene, V.; Zubriene, A.; Smirnov, A.; Timm, D.D.; Smirnoviene, J.; Kazokaite, J.; Michailoviene, V.; Zaksauskas, A.; Manakova, E.; Grazulis, S.; Matulis, D. Functionalization of fluorinated benzenesulfonamides and their inhibitory properties toward carbonic anhydrases. ChemMedChem, 2015, 10(4), 662-687.
[13]
Ghorab, M.M.; Alsaid, M.S.; El-Gaby, M.S.; Safwat, N.A.; Elaasser, M.M.; Soliman, A.M. Biological evaluation of some new N-(2, 6-dimethoxypyrimidinyl) thioureido-benzenesulfonamide derivatives as potential antimicrobial and anticancer agents. Eur. J. Med. Chem., 2016, 124, 299-310.
[14]
Yaseen, S.; Ovais, S.; Bashir, R.; Rathore, P.; Samim, M.; Singh, S.; Nair, V.; Javed, K. Synthesis and biological evaluation of 4‐arylphthalazones bearing benzenesulfonamide as anti‐inflammatory and anticancer agents. Archiv der Pharmazie, , 2013, 346(6), 491-498.
[15]
Chohan, Z.H.; Shad, H.A.; Nasim, F.U.H. Synthesis, characterization and biological properties of sulfonamide‐derived compounds and their transition metal complexes. Appl. Organomet. Chem., 2009, 23(8), 319-328.
[16]
Gawin, R.; De Clercq, E.; Naesens, L.; Koszytkowska-Stawinska, M. Synthesis and antiviral evaluation of acyclic azanucleosides developed from sulfanilamide as a lead structure. Bioorg. Med. Chem., 2008, 16, 8379-8389.
[17]
Ugwu, D.I.; Okoro, U.C.; Ukoha, P.O.; Okafor, S.; Ibezim, A.; Kumar, N.M. Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide. Eur. J. Med. Chem., 2017, 135, 349-369.
[18]
Bhuva, N.H.; Talpara, P.K.; Singala, P.M.; Gothaliya, V.K.; Shah, V.H. Synthesis and biological evaluation of pyrimidinyl sulphonamide derivatives as promising class of antitubercular agents. J. Saudi Chem. Soc., 2017, 21(5), 517-527.
[19]
Zani, F.; Vicini, P. Antimicrobial activity of some 1, 2‐benzisothiazoles having a benzenesulfonamide moiety. Archiv. der Pharmazie, 1998, 331(6), 219-223.
[20]
Li, J.J.; Anderson, D.; Burton, E.G.; Cogburn, J.N.; Collins, J.T.; Garland, D.J.; Gregory, S.A.; Huang, H.C.; Isakson, P.C. 1,2-Diarylcyclopentenes as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents. J. Med. Chem., 1995, 38, 4570-4578.
[21]
Kim, D.K.; Lee, J.Y.; Lee, N.; Ryu, D.H.; Kim, J.S.; Lee, S.; Choi, J.Y.; Ryu, J.H.; Kim, N.H.; Im, G.J.; Choi, W.S.; Kim, T.K. Synthesis and phosphodiesterase inhibitory activity of new sildenafil analogues containing a carboxylic acid group in the 5′-sulfonamide moiety of a phenyl ring. Bioorg. Med. Chem., 2001, 9, 3013-3021.
[22]
Yelovitch, S.; Barr, H.M.; Camden, J.; Weisman, G.A.; Shai, E.; Varon, D.; Fischer, B. Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y1 receptor agonist. J. Med. Chem., 2012, 55(17), 7623-7635.
[23]
Xu, G.; Lv, B.; Roberge, J.Y.; Xu, B.; Du, J.; Dong, J.; Chen, Y.; Peng, K.; Zhang, L.; Tang, X.; Feng, Y. Design, synthesis, and biological evaluation of deuterated C-aryl glycoside as a potent and long-acting renal sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2014, 57(4), 1236-1251.
[24]
Meltzer-Mats, E.; Babai-Shani, G.; Pasternak, L.; Uritsky, N.; Getter, T.; Viskind, O.; Eckel, J.; Cerasi, E.; Senderowitz, H.; Sasson, S.; Gruzman, A. Synthesis and mechanism of hypoglycemic activity of benzothiazole derivatives. J. Med. Chem., 2013, 56(13), 5335-5350.
[25]
Silva, F.S.; Oliveira, P.J.; Duarte, M.F. Oleanolic, ursolic, and betulinic acids as food supplements or pharmaceutical agents for Type 2 diabetes: promise or illusion? J. Agric. Food Chem., 2016, 64(15), 2991-3008.
[26]
Puranik, N.V.; Puntambekar, H.M.; Srivastava, P. Antidiabetic potential and enzyme kinetics of benzothiazole derivatives and their non-bonded interactions with α-glucosidase and α-amylase. Med. Chem. Res., 2016, 25(4), 805-816.
[27]
Bian, X.; Fan, X.; Ke, C.; Luan, Y.; Zhao, G.; Zeng, A. Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides. Bioorg. Med. Chem., 2013, 21(17), 5442-5450.
[28]
Wang, G.; Li, X.; Wang, J.; Xie, Z.; Li, L.; Chen, M.; Chen, S.; Peng, Y. Synthesis, molecular docking and α-glucosidase inhibition of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides. Bioorg. Med. Chem. Lett., 2017, 27(5), 1115-1118.
[29]
Kim, K.Y.; Nguyen, T.H.; Kurihara, H.; Kim, S.M. α‐Glucosidase inhibitory activity of bromophenol purified from the red alga Polyopes lancifolia. J. Food Sci., 2010, 75(5), 145-150.
[30]
Nguyen, T.H.; Kim, S.M. α‐Glucosidase inhibitory activities of fatty acids purified from the internal organ of sea cucumber Stichopus japonicas. J. Food Sci., 2015, 80(4), 841-847.
[31]
Jhong, C.H.; Riyaphan, J.; Lin, S.H.; Chia, Y.C.; Weng, C.F. Screening alpha‐ glucosidase and alpha‐amylase inhibitors from natural compounds by molecular docking in silico. Biofactors, 2015, 41(4), 242-251.
[32]
Hsieh, J.F.; Lin, W.J.; Huang, K.F.; Liao, J.H.; Don, M.J.; Shen, C.C.; Shiao, Y.J.; Li, W.T. Antioxidant activity and inhibition of α-glucosidase by hydroxyl-functionalized 2-arylbenzo [b] furans. Eur. J. Med. Chem., 2015, 93, 443-451.
[33]
Wang, G.; Peng, Z.; Wang, J.; Li, J.; Li, X. Synthesis, biological evaluation and molecular docking study of N-arylbenzo [d] oxazol-2-amines as potential α-glucosidase inhibitors. Bioorg. Med. Chem., 2016, 24(21), 5374-5379.
[34]
Kam, A.; Li, K.M.; Razmovski‐Naumovski, V.; Nammi, S.; Shi, J.; Chan, K.; Li, G.Q. A comparative study on the inhibitory effects of different parts and chemical constituents of pomegranate on α‐amylase and α‐glucosidase. Phytother. Res., 2013, 27(11), 1614-1620.
[35]
Sun, H.; Wang, D.; Song, X.; Zhang, Y.; Ding, W.; Peng, X.; Zhang, X.; Li, Y.; Ma, Y.; Wang, R.; Yu, P. Natural prenylchalconaringenins and prenylnaringenins as antidiabetic agents: α-Glucosidase and α-Amylase inhibition and in vivo antihyperglycemic and antihyperlipidemic effects. J. Agric. Food Chem., 2017, 65(8), 1574-1581.
[36]
Wang, G.; Wang, J.; He, D.; Li, X.; Li, J.; Peng, Z. Synthesis, in vitro evaluation and molecular docking studies of novel coumarin‐isatin derivatives as α‐glucosidase inhibitors. Chem. Biol. Drug Des., 2017, 89(3), 456-463.
[37]
Singh, R.; Lather, V.; Pandita, D.; Judge, V.; Arumugam, K.N.; Singh, G.A. Synthesis, docking and antidiabetic activity of some newer benzamide derivatives as potential glucokinase activators. Lett. Drug Des. Discov., 2017, 14(5), 540-553.
[38]
Poreba, K.; Pawlik, K.; Rembacz, K.P.; Kurowska, E.; Matuszyk, J.; Długosz, A. Synthesis and antibacterial activity of new sulfonamide isoxazolo [5, 4-b] pyridine derivatives. Acta Pol. Pharm., 2014, 72(4), 727-735.
[39]
Rani, N.; Sharma, S.K.; Vasudeva, N. Assessment of antiobesity potential of Achyranthes aspera Linn. seed. Evid. Based Complement. Alternat. Med., 2012, 2012, 715912.
[40]
Rahim, F.; Malik, F.; Ullah, H.; Wadood, A.; Khan, F.; Javid, M.T.; Taha, M.; Rehman, W.; Rehman, A.U.; Khan, K.M. Isatin based Schiff bases as inhibitors of α-glucosidase: Synthesis, characterization, in vitro evaluation and molecular docking studies. Bioorg. Chem., 2015, 60, 42-48.
[41]
Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G.; Schmidt, T.; Kiefer, F.; Cassarino, T.G.; Bertoni, M.; Bordoli, L.; Schwede, T. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res., 2014, 42(W1), W252-W258.
[42]
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(20), 4205-4214.
[43]
Berendsen, H.J.C.; Grigera, J.R.; Straatsma, T.P. The missing term in effective pair potentials. J. Phys. Chem., 1987, 91(24), 6269-6271.
[44]
Jorgensen, W.L.; Tirado-Rives, J. The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J. Am. Chem. Soc., 1988, 110(6), 1657-1666.
[45]
Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.E.; Berendsen, H.J. GROMACS: fast, flexible, and free. J. Comput. Chem., 2005, 26(16), 1701-1718.
[46]
Dauter, Z.; Dauter, M.; Brzozowski, A.M.; Christensen, S.; Borchert, T.V.; Beier, L.; Wilson, K.S.; Davies, G.J. X-ray structure of Novamyl, the five-domain “maltogenic” α-amylase from Bacillus stearothermophilus: Maltose and acarbose complexes at 1.7 Å resolution. Biochemistry, 1999, 38(26), 8385-8392.
[47]
Trott, O.; Olson, J.A. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[48]
Dassault Systèmes, B.I.O.V.I.A. Discovery Studio Visualiser, v16.1.0.15350.San Diego; Dassault Systèmes, 2016.
[49]
El‐Gohary, N.S.; Shaaban, M.I. Antimicrobial and antiquorum‐sensing studies. Part 3: Synthesis and biological evaluation of new series of [1, 3, 4] thiadiazoles and fused [1, 3, 4] thiadiazoles. Archiv der Pharmazie, 2015, 348(4), 283-297.
[50]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[51]
Cardoso, M.F.; Rodrigues, P.C.; Oliveira, M.E.I.; Gama, I.L.; da Silva, I.M.; Santos, I.O.; Rocha, D.R.; Pinho, R.T.; Ferreira, V.F.; de Souza, M.C.B.; da Silva, F.D.C. Synthesis and evaluation of the cytotoxic activity of 1, 2-furanonaphthoquinones tethered to 1, 2, 3-1H-triazoles in myeloid and lymphoid leukemia cell lines. Eur. J. Med. Chem., 2014, 84, 708-717.
[52]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[53]
Murugavel, S.; Kannan, D.; Bakthadoss, M. Experimental and computational approaches of a novel methyl (2E)-2-[N-(2-formylphenyl)(4-methylbenzene) sulfonamido] methyl-3-(4-chlorophenyl) prop-2-enoate: A potential antimicrobial agent and an inhibition of penicillin-binding protein. J. Mol. Struct., 2016, 1115, 33-54.
[54]
Balam, S.K.; Krishnammagari, S.K.; Harinath, J.S.; Sthanikam, S.P.; Chereddy, S.S.; Pasupuleti, V.R.; Yellapu, N.K.; Peddiahgari, V.G.R.; Cirandur, S.R. Synthesis of N-(3-picolyl)-based 1, 3, 2λ5-benzoxazaphosphinamides as potential 11β-HSD1 enzyme inhibitors. Med. Chem. Res., 2015, 24(3), 1119-1135.
[55]
de Oliveira, K.N.; Souza, M.M.; Sathler, P.C.; Magalhaes, U.O.; Rodrigues, C.R.; Castro, H.C.; Palm, P.R.; Sarda, M.; Perotto, P.E.; Cezar, S.; de Brito, M.A. Sulphonamide and sulphonyl-hydrazone cyclic imide derivatives: Antinociceptive activity, molecular modeling and in Silico ADMET screening. Arch. Pharm. Res., 2012, 35(10), 1713-1722.


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Article Details

VOLUME: 15
ISSUE: 2
Year: 2019
Page: [186 - 195]
Pages: 10
DOI: 10.2174/1573406414666180924164327
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