Synthesis, Biological Evaluation, QSAR, Molecular Docking and ADMET Studies of N-aryl/N,N-dimethyl Substituted Sulphonamide Derivatives

Author(s): Samridhi Thakral, Vikramjeet Singh*

Journal Name: Anti-Infective Agents
Anti-Infective Agents in Medicinal Chemistry

Volume 18 , Issue 2 , 2020

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Abstract:

Background: Rapid evolution of drug resistance and side effects of currently used drugs develop more efficacious and newer antimicrobial agents. Further, for the management of Type II Diabetes, α-gulcosidase and α-amylase inhibitors play a very important role by inhibiting the postprandial hyperglycemia.

Objectives: The objective of this study was to synthesize N-aryl/N,N-dimethyl sulphonamides, investigate their antihyperglycemic and antimicrobial potential, develop QSAR model for identifying molecular descriptors and predict their binding modes and in silico ADMET properties.

Methods: Synthesized derivatives were subjected to in vitro studies for their antidiabetic activity against α-glucosidase and α-amylase enzymes and antimicrobial activity. Molecular docking studies were carried out to find out molecular binding interactions of the ligand molecules with their respective targets. QSAR studies were carried out to identify structural determinants responsible for antimicrobial activity.

Results: Antidiabetic study demonstrated the potent activity of two compounds 2 and 6 as α- glucosidase and α-amylase inhibitors, as well as compound 1 and 2, exhibited potent antimicrobial activity against all the tested microbes. All the compounds have more antifungal potential against Candida albicans. QSAR studies confirmed the role of molecular connectivity indices (valence first order and second order) in controlling the antimicrobial activity. Molecular docking studies supported the observed in vitro biological activities of the synthesized compounds.

Conclusion: The compounds with 2,3-dimethyl substitution were found to be antidiabetic agents and molecules having bromo and 2,3-dimethyl substituents on phenyl ring have established themselves as potent antimicrobial agents. The role of valence first and 2nd order molecular connectivity indices as molecular properties were identified for antimicrobial activity and various electrostatic, hydrogen bonding and hydrophobic interactions were found to be prominent in the binding of molecules at the target site.

Keywords: Sulphonamides, antidiabetic, antimicrobial, QSAR, molecular docking, ADMET studies.

[1]
Ammar, Y.A.Sh.; Sh El-Sharief, A.M.; Belal, A.; Abbas, S.Y.; Mohamed, Y.A.; Mehany, A.B.M.; Ragab, A. Design, synthesis, antiproliferative activity, molecular docking and cell cycle analysis of some novel (morpholinosulfonyl) isatins with potential EGFR inhibitory activity. Eur. J. Med. Chem., 2018, 156, 918-932.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.061] [PMID: 30096580]
[2]
Ghorab, M.M.; Alsaid, M.S.; El-Gaby, M.S.A.; Elaasser, M.M.; Nissan, Y.M. Antimicrobial and anticancer activity of some novel fluorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking. Chem. Cent. J., 2017, 11(1), 32.
[http://dx.doi.org/10.1186/s13065-017-0258-4] [PMID: 29086809]
[3]
Janakiramudu, D.B.; Rao, D.S.; Srikanth, C.; Madhusudhana, S.; Murthy, P.S.; Nagalakshmidevamma, M.; Chalapathi, P.V.; Raju, C.N. Sulfonamides and carbamates of 3-fluoro-4-morpholinoaniline (linezolid intermediate): synthesis, antimicrobial activity and molecular docking study. Res. Chem. Intermed., 2018, 44, 469-489.
[http://dx.doi.org/10.1007/s11164-017-3114-1]
[4]
Nasr, T.; Bondock, S.; Eid, S. Design, synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole. J. Enzyme Inhib. Med. Chem., 2016, 31(2), 236-246.
[http://dx.doi.org/10.3109/14756366.2015.1016514] [PMID: 25815670]
[5]
Naidu, K.M.; Nagesh, H.N.; Singh, M.; Sriram, D.; Yogeeswari, P.; Gowri Chandra Sekhar, K.V. Novel amide and sulphonamide derivatives of 6-(piperazin-1-yl)phenanthridine as potent Mycobacterium tuberculosis H37Rv inhibitors. Eur. J. Med. Chem., 2015, 92, 415-426.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.013] [PMID: 25590862]
[6]
Dofe, V.S.; Sarkate, A.P.; Lokwani, D.K.; Kathwate, S.H.; Gill, C.H. Synthesis, antimicrobial evaluation, and molecular docking studies of novel chromone based 1,2,3-triazoles. Res. Chem. Intermed., 2017, 43, 15-28.
[http://dx.doi.org/10.1007/s11164-016-2602-z]
[7]
Ur Rehman, N.; Khan, A.; Al-Harrasi, A.; Hussain, H.; Wadood, A.; Riaz, M.; Al-Abri, Z. New α-Glucosidase inhibitors from the resins of Boswellia species with structure-glucosidase activity and molecular docking studies. Bioorg. Chem., 2018, 79, 27-33.
[http://dx.doi.org/10.1016/j.bioorg.2018.04.020] [PMID: 29715636]
[8]
Yousuf, S.; Khan, K.M.; Salar, U.; Chigurupati, S.; Muhammad, M.T.; Wadood, A.; Aldubayan, M.; Vijayan, V.; Riaz, M.; Perveen, S. 2′-Aryl and 4′-arylidene substituted pyrazolones: As potential α-amylase inhibitors. Eur. J. Med. Chem., 2018, 159, 47-58.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.052] [PMID: 30268823]
[9]
Larik, F.A.; Saeed, A.; Faisal, M.; Channar, P.A.; Azam, S.S.; Ismail, H.; Dilshad, E.; Mirza, B. Synthesis, molecular docking and comparative efficacy of various alkyl/aryl thioureas as antibacterial, antifungal and α-amylase inhibitors. Comput. Biol. Chem., 2018, 77, 193-198.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.10.007] [PMID: 30340081]
[10]
Thakral, S.; Singh, V. 2,4-Dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives: in vitro antidiabetic activity, molecular modeling and in silico ADMET screening. Med. Chem., 2019, 15(2), 186-195.
[http://dx.doi.org/10.2174/1573406414666180924164327] [PMID: 30251608]
[11]
Singh, R.; Lather, V.; Pandita, D.; Judge, V.; Arumugam, K.N.; Grewal, A.S. Synthesis, docking and antidiabetic activity of some newer benzamide derivatives as potential glucokinase activators. Lett. Drug Des. Discov., 2017, 14, 540-553.
[http://dx.doi.org/10.2174/1570180813666160819125342]
[12]
Poręba, 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., 2015, 72(4), 727-735.
[PMID: 26647630]
[13]
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), H145-H150.
[http://dx.doi.org/10.1111/j.1750-3841.2010.01629.x] [PMID: 20629879]
[14]
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), H841-H847.
[http://dx.doi.org/10.1111/1750-3841.12810] [PMID: 25735900]
[15]
Rani, N.; Sharma, S.K.; Vasudeva, N. Assessment of antiobesity potential of Achyranthes aspera Linn. seed. Evid. Based Complement. Alternat. Med., 2012, 2012715912
[http://dx.doi.org/10.1155/2012/715912] [PMID: 22919417]
[16]
Laboratory assessment of antibacterial activity; Spooner, D.F.; Sykes, G.; Chapter, I.V. Methods in MicrobiologyAcademic Press, 1972, 7, 211-276.
[17]
Judge, V.; Narasimhan, B.; Ahuja, M. Topological models for the prediction of antimycobacterial activity of 4-(5-substituted-1, 3, 4-oxadiazol-2-yl) pyridines. Med. Chem. Res., 2012, 21(7), 1363-1375.
[http://dx.doi.org/10.1007/s00044-011-9645-x]
[18]
Judge, V.; Narasimhan, B.; Ahuja, M.; Sriram, D.; Yogeeswari, P.; De Clercq, E.; Pannecouque, C.; Balzarini, J. Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides. Med. Chem. Res., 2012, 21(8), 1935-1952.
[http://dx.doi.org/10.1007/s00044-011-9705-2]
[19]
Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G.; Schmidt, T.; Kiefer, F.; Gallo Cassarino, T.; Bertoni, M.; Bordoli, L.; Schwede, T. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information Nucleic Acids Res., 2014. 48(Web Server issue), W252, 8
[http://dx.doi.org/10.1093/nar/gku340]
[20]
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 1.7A resolution. Biochemistry, 1999, 38(26), 8385-8392.
[http://dx.doi.org/10.1021/bi990256l] [PMID: 10387084]
[21]
Ghorab, M.M.; Soliman, A.M.; Alsaid, M.S.; Askar, A.A. Synthesis, antimicrobial activity and docking study of some novel 4-(4,4-dimethyl-2,6-dioxocyclohexylidene)methylamino derivatives carrying biologically active sulfonamide moiety. Arab. J. Chem., 2017.
[22]
Zhao, S.; Wei, P.; Wu, M.; Zhang, X.; Zhao, L.; Jiang, X.; Hao, C.; Su, X.; Zhao, D.; Cheng, M. Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51. Bioorg. Med. Chem., 2018, 26(12), 3242-3253.
[http://dx.doi.org/10.1016/j.bmc.2018.04.054] [PMID: 29748145]
[23]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[24]
Thakral, S.; Saini, D.; Kumar, A.; Jain, N.; Jain, S. A synthetic approach and molecular docking study of hybrids of quinazolin-4-ones and thiazolidin-4-ones as anticancer agents. Med. Chem. Res., 2017, 26(8), 1595-1604.
[http://dx.doi.org/10.1007/s00044-017-1857-2]
[25]
Dassault Systèmes, B.I.O.V.I.A. Discovery Studio Visualiser, v16.1.0.15350; Dassault Systèmes: San Diego, 2016.
[26]
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. Arch. Pharm. (Weinheim), 2015, 348(4), 283-297.
[http://dx.doi.org/10.1002/ardp.201400381] [PMID: 25773477]
[27]
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.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[28]
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, Fde.C.; Silva, F.P., Jr 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.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.079] [PMID: 25064348]
[29]
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.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[30]
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.
[http://dx.doi.org/10.1016/j.molstruc.2016.02.084]
[31]
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, 1119-1135.
[http://dx.doi.org/10.1007/s00044-014-1194-7]
[32]
de Oliveira, K.N.; Souza, M.M.; Sathler, P.C.; Magalhães, U.O.; Rodrigues, C.R.; Castro, H.C.; Palm, P.R.; Sarda, M.; Perotto, P.E.; Cezar, S.; de Brito, M.A.; Ferreira, A.S.; Cabral, L.M.; Machado, C.; Nunes, R.J. Sulphonamide and sulphonyl-hydrazone cyclic imide derivatives: antinociceptive activity, molecular modeling and in silico ADMET screening. Arch. Pharm. Res., 2012, 35(10), 1713-1722.
[http://dx.doi.org/10.1007/s12272-012-1002-1] [PMID: 23139121]
[33]
Keche, A.P.; Hatnapure, G.D.; Tale, R.H.; Rodge, A.H.; Kamble, V.M. Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties. Bioorg. Med. Chem. Lett., 2012, 22(21), 6611-6615.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.118] [PMID: 23026000]
[34]
Noreen, M.; Rasool, N.; Gull, Y.; Nasim, F.; Zahoor, A.F.; Yaqoob, A.; Kousar, S.; Zubair, M.; Bukhari, I.T.; Rana, U.A. A facile synthesis of new 5-aryl-thiophenes bearing sulfonamide moiety via Pd(0)-catalyzed Suzuki–Miyaura cross coupling reactions and 5-bromothiophene-2-acetamide: As potent urease inhibitor, antibacterial agent and hemolytically active compounds. J. Saudi Chem. Soc., 2017, 21, S403-S414.
[http://dx.doi.org/10.1016/j.jscs.2014.04.007]
[35]
Golbraikh, A.; Tropsha, A. Beware of q2! J. Mol. Graph. Model., 2002, 20(4), 269-276.
[http://dx.doi.org/10.1016/S1093-3263(01)00123-1] [PMID: 11858635]


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Article Details

VOLUME: 18
ISSUE: 2
Year: 2020
Page: [190 - 199]
Pages: 10
DOI: 10.2174/2211352517666190902130014

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