Synthesis, Characterization, Antimicrobial, Anti-tubercular, Antioxidant Activities and Docking Simulations of Derivatives of 2-(pyridin-3-yl)-1Hbenzo[ d]imidazole and 1,3,4-Oxadiazole Analogy

Author(s): Shipra Bhati, Vijay Kumar*, Simranjeet Singh, Joginder Singh*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 8 , 2020


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Abstract:

Background: Antimicrobial Resistance (AMR) and Tuberculosis (TB) are global concern. According to the WHO fact sheet on tuberculosis, in 2017, 10 million people fell ill with TB, and 1.6 million including 230,000 children died from the disease. There is a critical need of design and development of novel chemotherapeutic agents to combat the emergence and increasing prevalence of resistant pathogens. In the present study, a new series of 1,3,4-oxadiazoles incorporating benzimidazole and pyridine scaffolds in a single molecular framework has been reported.

Methods: The structures of the synthesized derivatives (4a to 4e) were assigned by IR, NMR and mass spectral techniques. The hybrid compounds were evaluated for their antimicrobial, antitubercular and antioxidant activities. In addition, docking simulations were performed to study ligand-protein interactions and to determine the probable binding conformations.

Results: Molecule 4a has shown anti-tubular activities with MIC 1.6 μg/ml. As compared to ascorbic acid activities (IC50 = 62.91 μg/ml), molecule 4e exhibited better antioxidant activities (IC50 = 24.85 μg/ml). Also, molecule 4e has shown significant antimicrobial activities.

Conclusion: The synthesized derivatives from 4a to 4e have exhibited various medicinal activities and could be emerged as lead compounds and further explored as potential therapeutic agents.

Keywords: Antimicrobial, anti-tubercular, antioxidant, bioavailability, docking simulations, IR, NMR.

[1]
Global Antimicrobial Resistance Surveillance System (Glass) report: Early implementation 2016-2017. geneva: available at: world health organization; 2017. license: cc by-nc-sa 3.0 igo, [accessed: 12/7/2018].
[2]
Xu, Z.; Zhao, S.; Lv, Z.; Feng, L.; Wang, Y.; Zhang, F.; Bai, L.; Deng, J.; Deng, J. Benzofuran derivatives and their anti-tubercular, anti-bacterial activities. Eur. J. Med. Chem., 2019, 162, 266-276.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.025] [PMID: 30448416]
[3]
Martelli, G.; Giacomini, D. Antibacterial and antioxidant activities for natural and synthetic dual-active compounds. Eur. J. Med. Chem., 2018, 158, 91-105.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.009] [PMID: 30205261]
[4]
Holmes, A.H.; Moore, L.S.P.; Sundsfjord, A.; Steinbakk, M.; Regmi, S.; Karkey, A.; Guerin, P.J.; Piddock, L.J.V. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet, 2016, 387(10014), 176-187.
[http://dx.doi.org/10.1016/S0140-6736(15)00473-0] [PMID: 26603922]
[5]
Liu, H.B.; Gao, W.W.; Tangadanchu, V.K.R.; Zhou, C.H.; Geng, R.X. Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation. Eur. J. Med. Chem., 2018, 143, 66-84.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.027] [PMID: 29172083]
[6]
Gao, C.; Chang, L.; Xu, Z.; Yan, X.F.; Ding, C.; Zhao, F.; Wu, X.; Feng, L.S. Recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents. Eur. J. Med. Chem., 2019, 163, 404-412.
[http://dx.doi.org/10.1016/j.ejmech.2018.12.001] [PMID: 30530192]
[7]
Fan, Y.L.; Jin, X.H.; Huang, Z.P.; Yu, H.F.; Zeng, Z.G.; Gao, T.; Feng, L.S. Recent advances of imidazole-containing derivatives as anti-tubercular agents. Eur. J. Med. Chem., 2018, 150, 347-365.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.016] [PMID: 29544148]
[8]
Zhang, S.; Xu, Z.; Gao, C.; Ren, Q.C.; Chang, L.; Lv, Z.S.; Feng, L.S. Triazole derivatives and their anti-tubercular activity. Eur. J. Med. Chem., 2017, 138, 501-513.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.051] [PMID: 28692915]
[9]
Tuberculosis Fact Sheet- World Health Organization available at: https://www.who.int news › fact sheets › detail. [accessed:27/12/2018]
[10]
Badger, G.M. The Chemistry of Heterocyclic Compounds; Academic Press: New York, London, 1961.
[11]
Guan, A.Y.; Liu, C.L.; Sun, X.F.; Xie, Y.; Wang, M.A. Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods. Bioorg. Med. Chem., 2016, 24(3), 342-353.
[http://dx.doi.org/10.1016/j.bmc.2015.09.031] [PMID: 26481150]
[12]
Grombein, C.M.; Hu, Q.; Heim, R.; Rau, S.; Zimmer, C.; Hartmann, R.W. 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors. Eur. J. Med. Chem., 2015, 89, 597-605.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.027] [PMID: 25462268]
[13]
Abdel-Megeed, M.F.; Badr, B.E.; Azaam, M.M.; El-Hiti, G.A. Synthesis, antimicrobial and anticancer activities of a novel series of diphenyl 1-(pyridin-3-yl)ethylphosphonates. Bioorg. Med. Chem., 2012, 20(7), 2252-2258.
[http://dx.doi.org/10.1016/j.bmc.2012.02.015] [PMID: 22370339]
[14]
Wen, J.; Luo, Y.L.; Zhang, H.Z.; Zhao, H.H.; Zhou, C.H.; Cai, G.X. A green and convenient approach toward benzimidazole derivatives and their antimicrobial activity. Chin. Chem. Lett., 2016, 27, 391-394.
[http://dx.doi.org/10.1016/j.cclet.2015.12.014]
[15]
Cheong, J.E.; Zaffagni, M.; Chung, I.; Xu, Y.; Wang, Y.; Jernigan, F.E.; Zetter, B.R.; Sun, L. Synthesis and anticancer activity of novel water soluble benzimidazole carbamates. Eur. J. Med. Chem., 2018, 144, 372-385.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.037] [PMID: 29288939]
[16]
Jeyakkumar, P.; Zhang, L.; Avula, S.R.; Zhou, C.H. Design, synthesis and biological evaluation of berberine-benzimidazole hybrids as new type of potentially DNA-targeting antimicrobial agents. Eur. J. Med. Chem., 2016, 122, 205-215.
[http://dx.doi.org/10.1016/j.ejmech.2016.06.031] [PMID: 27371924]
[17]
Yoon, Y.K.; Ali, M.A.; Wei, A.C.; Choon, T.S.; Ismail, R. Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters. Eur. J. Med. Chem., 2015, 93, 614-624.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.025] [PMID: 24996257]
[18]
Gaba, M.; Gaba, P.; Uppal, D.; Dhingra, N.; Bahia, M.S.; Silakari, O.; Mohan, C. Benzimidazole derivatives: Search for GI-friendly anti-inflammatory analgesic agents. Acta Pharm. Sin. B, 2015, 5(4), 337-342.
[http://dx.doi.org/10.1016/j.apsb.2015.05.003] [PMID: 26579464]
[19]
Shingalapur, R.V.; Hosamani, K.M.; Keri, R.S.; Hugar, M.H. Derivatives of benzimidazole pharmacophore: Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur. J. Med. Chem., 2010, 45(5), 1753-1759.
[http://dx.doi.org/10.1016/j.ejmech.2010.01.007] [PMID: 20122763]
[20]
Ranganatha, V.L.; Vijay Avin, B.R.; Thirusangu, P.; Prashanth, T.; Prabhakar, B.T.; Khanum, S.A. Synthesis, angiopreventive activity, and in vivo tumor inhibition of novel benzophenone-benzimidazole analogs. Life Sci., 2013, 93(23), 904-911.
[http://dx.doi.org/10.1016/j.lfs.2013.10.001] [PMID: 24135459]
[21]
Arora, R.K.; Kaur, N.; Bansal, Y.; Bansal, G. Novel coumarin-benzimidazole derivatives as antioxidants and safer anti-inflammatory agents. Acta Pharm. Sin. B, 2014, 4(5), 368-375.
[http://dx.doi.org/10.1016/j.apsb.2014.07.001] [PMID: 26579406]
[22]
Rao, A.; Chimirri, A.; De Clercq, E.; Monforte, A.M.; Monforte, P.; Pannecouque, C.; Zappalà, M. Synthesis and anti-hIV activity of 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole structurally-related 1,2-substituted benzimidazoles. Farmaco, 2002, 57(10), 819-823.
[http://dx.doi.org/10.1016/S0014-827X(02)01300-9] [PMID: 12420877]
[23]
Garuti, L.; Roberti, M.; Gentilomi, G. Synthesis and antiviral assays of some benzimidazole nucleosides and acyclonucleosides. Farmaco, 2001, 56(11), 815-819.
[http://dx.doi.org/10.1016/S0014-827X(01)01164-8] [PMID: 11765032]
[24]
Mayence, A.; Vanden Eynde, J.J.; Kaiser, M.; Brun, R.; Yarlett, N.; Huang, T.L. Bis(oxyphenylene)benzimidazoles: Aa novel class of anti-Plasmodium falciparum agents. Bioorg. Med. Chem., 2011, 19(24), 7493-7500.
[http://dx.doi.org/10.1016/j.bmc.2011.10.039] [PMID: 22061825]
[25]
Zhu, W.; Da, Y.; Wu, D.; Zheng, H.; Zhu, L.; Wang, L.; Yan, Y.; Chen, Z. Design, synthesis and biological evaluation of new 5-nitro benzimidazole derivatives as AT1 antagonists with anti-hypertension activities. Bioorg. Med. Chem., 2014, 22(7), 2294-2302.
[http://dx.doi.org/10.1016/j.bmc.2014.02.008] [PMID: 24613628]
[26]
Zhou, L.; Jia, C.; Wan, Z.; Li, Z.; Bai, J.; Zhang, L.; Zhang, J.; Yao, X. Triphenylamine-based organic dyes containing benzimidazole derivatives for dye-sensitized solar cells. Dyes Pigments, 2012, 95, 743-750.
[http://dx.doi.org/10.1016/j.dyepig.2012.05.007]
[27]
Özdemir, Y.; Üregen, N.; Devrim, Y. Polybenzimidazole based nanocomposite membranes with enhanced proton conductivity for high temperature PEM fuel cells. Int. J. Hydr. Ener., 2017, 42, 2648-2657.
[http://dx.doi.org/10.1016/j.ijhydene.2016.04.132]
[28]
Tang, L.; Cai, M.; Huang, Z.; Zhong, K.; Hou, S.; Bian, Y.; Nandhakumar, R. Rapid and highly selective relay recognition of Cu(II) and sulfide ions by a simple benzimidazole-based fluorescent sensor in water. Sens. Actuators B Chem., 2013, 185, 188-194.
[http://dx.doi.org/10.1016/j.snb.2013.04.109]
[29]
Lima, L.M.; Barreiro, E.J. Bioisosterism: a useful strategy for molecular modification and drug design. Curr. Med. Chem., 2005, 12(1), 23-49.
[http://dx.doi.org/10.2174/0929867053363540] [PMID: 115638729]
[30]
Shyma, P.C.; Kalluraya, B.; Peethambar, S.K.; Telkar, S.; Arulmoli, T. Synthesis, characterization and molecular docking studies of some new 1,3,4-oxadiazolines bearing 6-methylpyridine moiety for antimicrobial property. Eur. J. Med. Chem., 2013, 68, 394-404.
[http://dx.doi.org/10.1016/j.ejmech.2013.07.019] [PMID: 23994867]
[31]
Malladi, S.; Isloor, A.M.; Peethambar, S.K.; Fun, H.K. Synthesis and biological evaluation of newer analogues of 2,5-disubstituted 1,3,4-oxadiazole containing pyrazole moiety as antimicrobial agents. Arab. J. Chem., 2014, 7, 1185-1191.
[http://dx.doi.org/10.1016/j.arabjc.2013.12.020]
[32]
Macaev, F.; Rusu, G.; Pogrebnoi, S.; Gudima, A.; Stingaci, E.; Vlad, L.; Shvets, N.; Kandemirli, F.; Dimoglo, A.; Reynolds, R. Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure-anti-mycobacterial activities. Bioorg. Med. Chem., 2005, 13(16), 4842-4850.
[http://dx.doi.org/10.1016/j.bmc.2005.05.011] [PMID: 15993090]
[33]
Akhter, M.; Husain, A.; Azad, B.; Ajmal, M. Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: synthesis and their anti-inflammatory and analgesic activities. Eur. J. Med. Chem., 2009, 44(6), 2372-2378.
[http://dx.doi.org/10.1016/j.ejmech.2008.09.005] [PMID: 18977556]
[34]
Zhang, S.; Luo, Y.; He, L.Q.; Liu, Z.J.; Jiang, A.Q.; Yang, Y.H.; Zhu, H.L. Synthesis, biological evaluation, and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity. Bioorg. Med. Chem., 2013, 21(13), 3723-3729.
[http://dx.doi.org/10.1016/j.bmc.2013.04.043] [PMID: 23673215]
[35]
Pidugu, V.R.; Yarla, N.S.; Pedada, S.R.; Kalle, A.M.; Satya, A.K. Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity. Bioorg. Med. Chem., 2016, 24(21), 5611-5617.
[http://dx.doi.org/10.1016/j.bmc.2016.09.022] [PMID: 27665180]
[36]
Guda, D.R.; Park, S.J.; Lee, M.W.; Kim, T.J.; Lee, M.E. Syntheses and anti-allergic activity of 2-((bis(trimethylsilyl)methylthio/methylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazoles. Eur. J. Med. Chem., 2013, 62, 84-88.
[http://dx.doi.org/10.1016/j.ejmech.2012.12.035] [PMID: 23353735]
[37]
Ma, L.; Xiao, Y.; Li, C.; Xie, Z.L.; Li, D.D.; Wang, Y.T.; Ma, H.T.; Zhu, H.L.; Wang, M.H.; Ye, Y.H. Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan. Bioorg. Med. Chem., 2013, 21(21), 6763-6770.
[http://dx.doi.org/10.1016/j.bmc.2013.08.002] [PMID: 23993673]
[38]
Zheng, X.; Li, Z.; Wang, Y.; Chen, W.; Huang, Q.; Liu, C.; Song, G. Syntheses and insecticidal activities of novel 2,5-disubstituted 1,3,4-oxadiazoles. J. Fluor. Chem., 2003, 123, 163-169.
[http://dx.doi.org/10.1016/S0022-1139(03)00168-4]
[39]
Harish, K.P.; Mohana, K.N.; Mallesha, L.; Prasanna Kumar, B.N. Synthesis of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives and evaluation of their in vivo anticonvulsant activity. Eur. J. Med. Chem., 2013, 65, 276-283.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.054] [PMID: 23727537]
[40]
molinspiration cheminformatics, nova ulica, sk-900 26slovensky grob, slovak republic. available at: http://www.Molinspiration.Com/cgi-bin/properties[accessed:14/12/2018].
[41]
Jain, S.K.; Vyas, S.P.; Dixit, V.K. A new approach towards the development of transdermal terbutaline releasing system. J. Control. Release, 1992, 22, 117-124.
[http://dx.doi.org/10.1016/0168-3659(92)90196-X]
[42]
Kumar, V.; Singh, S.; Singh, A.; Dixit, A.K.; Srivastava, B.; Sidhu, G.K.; Singh, R.; Meena, A.K.; Singh, R.P.; Subhose, V.; Prakash, O. Phytochemical, antioxidant, antimicrobial, and protein binding qualities of hydro-ethanolic Extract of Tinospora cordifolia. J. Biolog. Active Prod. Nat., 2018, 8, 192-200.
[http://dx.doi.org/10.1080/22311866.2018.1485513]
[43]
Kumar, V.; Singh, S.; Singh, R.; Upadhyay, N.; Singh, J.; Pant, P.; Singh, R.; Shrivastava, B.; Singh, A.; Subhose, V. Spectral, structural and energetic study of acephate, glyphosate, monocrotophos and phorate: An experimental and computational approach. J. Taibah Uni. Sci., 2018, 12, 69-78.
[http://dx.doi.org/10.1080/16583655.2018.1451109]
[44]
Kumar, V.; Singh, S.; Singh, R.; Upadhyay, N.; Singh, J. Design, synthesis, and characterization of 2,2-bis(2,4-dinitrophenyl)-2-(phosphonatomethylamino)acetate as a herbicidal and biological active agent. J. Chem. Biol., 2017, 10(4), 179-190.
[http://dx.doi.org/10.1007/s12154-017-0174-z] [PMID: 29075355]
[45]
Kumar, V.; Kaur, S.; Singh, S.; Upadhyay, N. unexpectedformation of n-phenyl-thiophosphorohydrazidic acid o,s-dimethyl ester from acephate: chemical biotechnical and computational study 3 biotech, 2016, 6, 1-11.
[46]
Franzblau, S.G.; Witzig, R.S.; McLaughlin, J.C.; Torres, P.; Madico, G.; Hernandez, A.; Degnan, M.T.; Cook, M.B.; Quenzer, V.K.; Ferguson, R.M.; Gilman, R.H. Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. J. Clin. Microbiol., 1998, 36(2), 362-366.
[PMID: 9466742]
[47]
Lourenco, M.C.S.; deSouza, M.V.N.; Pinheiro, A.C. Fer reira, M.L.; Goncalves, R.B. Thais Cristina M Nogneira, Monica, A. P. Evaluation of anti-tubercular activity of nicotinic and isoniazid analogues. ARKIVOC, 2007, 15, 181-191.
[48]
Kumar, V.; Chawla, M.; Cavallo, L.; Wani, A.B.; Manhas, A.; Kaur, S.; Poater, A.; Chadar, H.; Upadhyay, N. Complexation of trichlorosalicylic acid with alkaline and first row transition metals as a switch for their antibacterial activity. Inorg. Chim. Acta, 2018, 469, 379-386.
[http://dx.doi.org/10.1016/j.ica.2017.08.064]
[49]
Kumar, V.; Upadhyay, N.; Manhas, A. Designing syntheses characterization computational study and biological activities of silver-phenothiazine metal complex. J. Mol. Struct., 2015, 1099, 135-141.
[http://dx.doi.org/10.1016/j.molstruc.2015.06.055]
[50]
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a lamarckian genetic algorithm and and empirical binding free energy function. J. Comput. Chem., 1998, 19, 1639-1662. [http://dx.doi.org/].
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B]
[51]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[52]
Yuan, S.; Chan, H.C.S.; Filipek, S.; Vogel, H. PyMOL and Inkscape bridge the data and the data visualization. Structure, 2016, 24(12), 2041-2042.
[http://dx.doi.org/10.1016/j.str.2016.11.012] [PMID: 27926832]
[53]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341. [http://dx.doi.org/10.1016/j.ddtec.2004.11.007]. [PMID: 24981612].
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]


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VOLUME: 17
ISSUE: 8
Year: 2020
Page: [1047 - 1059]
Pages: 13
DOI: 10.2174/1570180816666191122105313
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