Synthesis and in vitro Evaluation of Dihydrobenzimidazole Thiopyranooxazinone Derivatives as a Potent Biological Agents

Deepak P. Kardile; Mrunal K. Shirsat

doi:10.14233/ajomc.2020.AJOMC-P251

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Abstract

In the present study, dihydrobenzimidazole thiopyranooxazinone derivatives were efficiently synthesized, which were further characterized and authenticated by means of TLC and different spectral analysis such as IR and ¹H NMR. The synthesized compounds DPK2d2 to DPK2d8 were screened for their in vitro antimicrobial, antitubercular and anticancer activities. The results showed that the titled compounds DPK3d1, DPK3d2 and DPK3d4 exhibited potent antimicrobial activity, shows a broad-spectrum activity against Bacillus subtilis, Escherichia coli (antibacterial) and Aspergillus niger (antifungal) as compared to ciprofloxacin and fluconazole, respectively. Compounds DPK3d1, DPK3d3 and DPK3d5 exhibited potent antitubercular activities against Mycobacterium tuberculosis as compared to pyrazinamide, ciprofloxacin and streptomycin. Compounds DPK3d3, DPK3d4 and DPK3d5 showed highly potent cytotoxic activity against human lung cancer cell line (A549) as compared to adriamycin. In silico molecular docking studies shown that all the ligands highest binding affinity range -6.7 to -8.7 for selected 1CB4 PDB of superoxide dismutase, which recognized that ligands having antioxidant activity.

Keywords

Dihydrobenzimidazole Thiopyranooxazinone Antimicrobial activity Antitubercular activity Anticancer activity Molecular docking

How to Cite

P. Kardile, D., & K. Shirsat, M. (2020). Synthesis and in vitro Evaluation of Dihydrobenzimidazole Thiopyranooxazinone Derivatives as a Potent Biological Agents. Asian Journal of Organic & Medicinal Chemistry, 5(2), 164–170. https://doi.org/10.14233/ajomc.2020.AJOMC-P251

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References

S.S. Morse, Factors in the Emergence of Infectious Diseases, Emerg. Infect. Dis., 1, 7 (1995); https://doi.org/10.3201/eid0101.950102
A. Matsos and I.N. Johnston, Chemotherapy-Induced Cognitive Impair-ments: A Systematic Review of the Animal Literature, Neurosci. Biobehav. Rev., 102, 382 (2019); https://doi.org/10.1016/j.neubiorev.2019.05.001
S. Saeed, N. Rashid, P.G. Jones and M.A. Hussain, Synthesis, Charact-erization and Biological Evaluation of Some Thiourea Derivatives Bearing Benzothiazole Moiety as Potential Antimicrobial and Anti-cancer Agents, Eur. J. Med. Chem., 45, 1323 (2010); https://doi.org/10.1016/j.ejmech.2009.12.016
S.K. Mohanty, A. Khuntia, N. Yellasubbaiah, C. Ayyanna, B.N. Sudha and M.S. Harika, Design, Synthesis of Novel Azo Derivatives of Benzimidazole as Potent Antibacterial and Anti-Tubercular Agents, Beni-Suef Univ. J. Basic Appl. Sci., 7, 646 (2018); https://doi.org/10.1016/j.bjbas.2018.07.009
S.E. Knudson, K. Kumar, D. Awasthi, I. Ojima and R.A. Slayden, in vitro-in vivo Activity Relationship of Substituted Benzimidazole Cell Division Inhibitors with Activity Against Mycobacterium tuberculosis, Tuberculosis, 94, 271 (2014); https://doi.org/10.1016/j.tube.2014.03.007
Y.K. Yoon, M.A. Ali, A.C. Wei, T.S. Choon and R. Ismail, Synthesis and Evaluation of Antimycobacterial Activity of New Benzimidazole Aminoesters, Eur. J. Med. Chem., 93, 624 (2015); https://doi.org/10.1016/j.ejmech.2013.06.025
C.R. Sears and P.J. Mazzone, Clin. Chest Med., 41, 115 (2020); https://doi.org/10.1016/j.ccm.2019.10.004
K.L. Shelton, M.A. DeBord, P.O. Wagers, M.R. Southerland, T.M. Williams, N.K. Robishaw, L.P. Shriver, C.A. Tessier, M.J. Panzner, W.J. Youngs, T.M. Williams, N.K. Robishaw, L.P. Shriver, C.A. Tessier, M.J. Panzner and W.J. Youngs, Synthesis, Anti-Proliferative Activity, SAR Study and Preliminary in vivo Toxicity Study of Substituted N,N'-bis(arylmethyl)-Benzimidazolium Salts Against a Panel of Non-small Cell Lung Cancer Cell Lines, Bioorg. Med. Chem., 25, 421 (2017); https://doi.org/10.1016/j.bmc.2016.11.009
Y.K., Yoon, M.A. Ali, A.C. Wei and A.N. Shirazi, K. Parang and T.S. Choon, Benzimidazoles as New Scaffold of Sirtuin Inhibitors: Green Synthesis, in vitro Studies, Molecular Docking Analysis and Evaluation of their Anticancer Properties, Eur. J. Med. Chem., 83, 448 (2014); https://doi.org/10.1016/j.ejmech.2014.06.060
Y.H.R. Jois, M.A.G. Berg, J.S. Merola and H.W. Gibson, X-Ray Crystal Structure and Reactions of 2-Cyano-1,3-dibenzoyl-2,3-dihydrobenz-imidazole, A Novel Reissert Compound, Tetrahedron Lett., 32, 2997 (1991); https://doi.org/10.1016/0040-4039(91)80670-2
J. Chen, J. Qu and Y. Zhang, Metal-Free Construction of Tricyclic or Tetracyclic Compounds-Acid Promoted Synthesis of Benzo[4,5]-imidazo[2,1-a]isoindole and 1,2-Dialkyl-2,3-dihydrobenzimidazoles, Tetrahedron, 69, 316 (2013); https://doi.org/10.1016/j.tet.2012.10.030
A. Verma, S. Joshi and D. Singh, Imidazole: Having Versatile Biological Activities, J. Chem., 2013, 329412 (2013); https://doi.org/10.1155/2013/329412
R.S. Keri, A. Hiremathad, S. Budagumpi and B.M. Nagaraja, Compre-hensive Review in Current Developments of Benzimidazole-based Medicinal Chemistry, Chem. Biol. Drug. Des., 86, 65 (2015); https://doi.org/10.1111/cbdd.12462
C.H. Sridevi, K. Balaji, A. Naidu and R. Sudhakaran, Synthesis of Some Phenylpyrazolo Benzimidazolo Quinoxaline Derivatives as Potent Anti-histaminic Agents, E-J. Chem., 7, 234 (2010).
P.K. Ranjith, P. Rajeesh, K.R. Haridas, N.K. Susanta, T.N. Guru Row, R. Rishikesan and N.S. Kumari, Design and Synthesis of Positional Isomers of 5 and 6-Bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)-methyl]-1H-benzimidazoles as Possible Antimicrobial and Antitubercular Agents, Bioorg. Med. Chem. Lett., 23, 5228 (2013); https://doi.org/10.1016/j.bmcl.2013.06.072
R.K. Arora, N. Kaur, Y. Bansal and G. Bansal, Novel Coumarin-Benzi-midazole Derivatives as Antioxidants and Safer Anti-inflammatory Agents, Acta Pharm. Sin. B, 4, 368 (2014); https://doi.org/10.1016/j.apsb.2014.07.001
T. Pan, X. He, B. Chen, H. Chen, G. Geng, H. Luo, H. Zhang and C. Bai, Development of Benzimidazole Derivatives to Inhibit HIV-1 Replication through Protecting APOBEC3G Protein, Eur. J. Med. Chem., 95, 500 (2015); https://doi.org/10.1016/j.ejmech.2015.03.050
K. Vasantha, G. Basavarajaswamy, M. Vaishali Rai, P. Boja, V.R. Pai, N. Shruthi and M. Bhat, Rapid ‘One-Pot’ Synthesis of a Novel Benzi-midazole-5-carboxylate and Its Hydrazone Derivatives as Potential Anti-inflammatory and Antimicrobial Agents, Bioorg. Med. Chem. Lett., 25, 1420 (2015); https://doi.org/10.1016/j.bmcl.2015.02.043
M. Gaba, P. Gaba, D. Uppal, N. Dhingra, M.S. Bahia, O. Silakari and C. Mohan, Benzimidazole Derivatives: Search for GI-Friendly Anti-inflammatory Analgesic Agents, Acta Pharm. Sin. B, 5, 337 (2015); https://doi.org/10.1016/j.apsb.2015.05.003
J. Wen, Y. Luo, H. Zhang, H. Zhao, C. Zhou and G. Cai, A Green and Convenient Approach Toward Benzimidazole Derivatives and their Antimicrobial Activity, Chin. Chem. Lett., 27, 391 (2016); https://doi.org/10.1016/j.cclet.2015.12.014
Y. Bansal and O. Silakari, The Therapeutic Journey of Benzimidazoles: A Review, Bioorg. Med. Chem., 20, 6208 (2012); https://doi.org/10.1016/j.bmc.2012.09.013
R.A. Haque, S. Budagumpi, S.Y. Choo, M.K. Choong, B.E. Lokesh and K. Sudesh, Nitrile-Functionalized Hg(II)- and Ag(I)-N-Heterocyclic Carbene Complexes: Synthesis, Crystal Structures, Nuclease and DNA Binding Activities, Appl. Organomet. Chem., 26, 689 (2012); https://doi.org/10.1002/aoc.2912
K.F. Ansari and C. Lal, Synthesis, Physicochemical Properties and Antimicrobial Activity of Some New Benzimidazole Derivatives, Eur. J. Med. Chem., 44, 4028 (2009); https://doi.org/10.1016/j.ejmech.2009.04.037
S.J. Park, J.C. Lee and K.I. Lee, A Facile Synthesis of 4-Hydroxy-coumarin and 4-Hydroxy-2-quinolone Derivatives, Bull. Korean Chem. Soc., 28, 1205 (2007); https://doi.org/10.5012/bkcs.2007.28.7.1203
S.I. Alaqeel, Synthetic Approaches to Benzimidazoles from o-Phenylene-diamine: A Literature Review, J. Saudi Chem. Soc., 21, 229 (2017); https://doi.org/10.1016/j.jscs.2016.08.001
J.G. Cappucino and N. Sherman, Microbiology: A Laboratory Mannual, Addison Wesley Longman Inc.: California, p. 263 (1999).
H.D. Isenberg, Clinical Microbiology Procedures Handbook, American Society for Microbiology, Washington, D.C. vol. 1(1992).
Pharmacopoeia of India, Ministry of Health Department, Government of India: New Delhi, vol. 2, p. A-88 (1996).
T. Parish and N.G. Stroker, Mycobacteria Protocols: Methods in Molecular Biology, Humana Press: NJ p. 395 (1998).
V. Klimesová, L. Zahajská, K. Waisser, J. Kaustová and U. Möllmann, IL Farmaco, 59, 288 (2004); https://doi.org/10.1016/j.farmac.2004.01.006
L.A. Collins and S.G. Franzblau, Microplate Alamar Blue Assay versus BACTEC 460 System for High-throughput Screening of Compounds against M. tuberculosis and M. avium, Antimicrob. Agents Chem., 41, 1004 (1997).
P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J.T. Warren, H. Bokesch, S. Kenney and M.R. Boyd, New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening, J. Natl. Cancer Inst., 82, 1107 (1990); https://doi.org/10.1093/jnci/82.13.1107
V. Vichai and K. Kirtikara, Sulforhodamine B Colorimetric Assay for Cytoxicity Screening, Nat. Protocol, 1, 1116 (2006); https://doi.org/10.1038/nprot.2006.179

References

S.S. Morse, Factors in the Emergence of Infectious Diseases, Emerg. Infect. Dis., 1, 7 (1995); https://doi.org/10.3201/eid0101.950102

A. Matsos and I.N. Johnston, Chemotherapy-Induced Cognitive Impair-ments: A Systematic Review of the Animal Literature, Neurosci. Biobehav. Rev., 102, 382 (2019); https://doi.org/10.1016/j.neubiorev.2019.05.001

S. Saeed, N. Rashid, P.G. Jones and M.A. Hussain, Synthesis, Charact-erization and Biological Evaluation of Some Thiourea Derivatives Bearing Benzothiazole Moiety as Potential Antimicrobial and Anti-cancer Agents, Eur. J. Med. Chem., 45, 1323 (2010); https://doi.org/10.1016/j.ejmech.2009.12.016

S.K. Mohanty, A. Khuntia, N. Yellasubbaiah, C. Ayyanna, B.N. Sudha and M.S. Harika, Design, Synthesis of Novel Azo Derivatives of Benzimidazole as Potent Antibacterial and Anti-Tubercular Agents, Beni-Suef Univ. J. Basic Appl. Sci., 7, 646 (2018); https://doi.org/10.1016/j.bjbas.2018.07.009

S.E. Knudson, K. Kumar, D. Awasthi, I. Ojima and R.A. Slayden, in vitro-in vivo Activity Relationship of Substituted Benzimidazole Cell Division Inhibitors with Activity Against Mycobacterium tuberculosis, Tuberculosis, 94, 271 (2014); https://doi.org/10.1016/j.tube.2014.03.007

Y.K. Yoon, M.A. Ali, A.C. Wei, T.S. Choon and R. Ismail, Synthesis and Evaluation of Antimycobacterial Activity of New Benzimidazole Aminoesters, Eur. J. Med. Chem., 93, 624 (2015); https://doi.org/10.1016/j.ejmech.2013.06.025

C.R. Sears and P.J. Mazzone, Clin. Chest Med., 41, 115 (2020); https://doi.org/10.1016/j.ccm.2019.10.004

K.L. Shelton, M.A. DeBord, P.O. Wagers, M.R. Southerland, T.M. Williams, N.K. Robishaw, L.P. Shriver, C.A. Tessier, M.J. Panzner, W.J. Youngs, T.M. Williams, N.K. Robishaw, L.P. Shriver, C.A. Tessier, M.J. Panzner and W.J. Youngs, Synthesis, Anti-Proliferative Activity, SAR Study and Preliminary in vivo Toxicity Study of Substituted N,N'-bis(arylmethyl)-Benzimidazolium Salts Against a Panel of Non-small Cell Lung Cancer Cell Lines, Bioorg. Med. Chem., 25, 421 (2017); https://doi.org/10.1016/j.bmc.2016.11.009

Y.K., Yoon, M.A. Ali, A.C. Wei and A.N. Shirazi, K. Parang and T.S. Choon, Benzimidazoles as New Scaffold of Sirtuin Inhibitors: Green Synthesis, in vitro Studies, Molecular Docking Analysis and Evaluation of their Anticancer Properties, Eur. J. Med. Chem., 83, 448 (2014); https://doi.org/10.1016/j.ejmech.2014.06.060

Y.H.R. Jois, M.A.G. Berg, J.S. Merola and H.W. Gibson, X-Ray Crystal Structure and Reactions of 2-Cyano-1,3-dibenzoyl-2,3-dihydrobenz-imidazole, A Novel Reissert Compound, Tetrahedron Lett., 32, 2997 (1991); https://doi.org/10.1016/0040-4039(91)80670-2

J. Chen, J. Qu and Y. Zhang, Metal-Free Construction of Tricyclic or Tetracyclic Compounds-Acid Promoted Synthesis of Benzo[4,5]-imidazo[2,1-a]isoindole and 1,2-Dialkyl-2,3-dihydrobenzimidazoles, Tetrahedron, 69, 316 (2013); https://doi.org/10.1016/j.tet.2012.10.030

A. Verma, S. Joshi and D. Singh, Imidazole: Having Versatile Biological Activities, J. Chem., 2013, 329412 (2013); https://doi.org/10.1155/2013/329412

R.S. Keri, A. Hiremathad, S. Budagumpi and B.M. Nagaraja, Compre-hensive Review in Current Developments of Benzimidazole-based Medicinal Chemistry, Chem. Biol. Drug. Des., 86, 65 (2015); https://doi.org/10.1111/cbdd.12462

C.H. Sridevi, K. Balaji, A. Naidu and R. Sudhakaran, Synthesis of Some Phenylpyrazolo Benzimidazolo Quinoxaline Derivatives as Potent Anti-histaminic Agents, E-J. Chem., 7, 234 (2010).

P.K. Ranjith, P. Rajeesh, K.R. Haridas, N.K. Susanta, T.N. Guru Row, R. Rishikesan and N.S. Kumari, Design and Synthesis of Positional Isomers of 5 and 6-Bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)-methyl]-1H-benzimidazoles as Possible Antimicrobial and Antitubercular Agents, Bioorg. Med. Chem. Lett., 23, 5228 (2013); https://doi.org/10.1016/j.bmcl.2013.06.072

R.K. Arora, N. Kaur, Y. Bansal and G. Bansal, Novel Coumarin-Benzi-midazole Derivatives as Antioxidants and Safer Anti-inflammatory Agents, Acta Pharm. Sin. B, 4, 368 (2014); https://doi.org/10.1016/j.apsb.2014.07.001

T. Pan, X. He, B. Chen, H. Chen, G. Geng, H. Luo, H. Zhang and C. Bai, Development of Benzimidazole Derivatives to Inhibit HIV-1 Replication through Protecting APOBEC3G Protein, Eur. J. Med. Chem., 95, 500 (2015); https://doi.org/10.1016/j.ejmech.2015.03.050

K. Vasantha, G. Basavarajaswamy, M. Vaishali Rai, P. Boja, V.R. Pai, N. Shruthi and M. Bhat, Rapid ‘One-Pot’ Synthesis of a Novel Benzi-midazole-5-carboxylate and Its Hydrazone Derivatives as Potential Anti-inflammatory and Antimicrobial Agents, Bioorg. Med. Chem. Lett., 25, 1420 (2015); https://doi.org/10.1016/j.bmcl.2015.02.043

M. Gaba, P. Gaba, D. Uppal, N. Dhingra, M.S. Bahia, O. Silakari and C. Mohan, Benzimidazole Derivatives: Search for GI-Friendly Anti-inflammatory Analgesic Agents, Acta Pharm. Sin. B, 5, 337 (2015); https://doi.org/10.1016/j.apsb.2015.05.003

J. Wen, Y. Luo, H. Zhang, H. Zhao, C. Zhou and G. Cai, A Green and Convenient Approach Toward Benzimidazole Derivatives and their Antimicrobial Activity, Chin. Chem. Lett., 27, 391 (2016); https://doi.org/10.1016/j.cclet.2015.12.014

Y. Bansal and O. Silakari, The Therapeutic Journey of Benzimidazoles: A Review, Bioorg. Med. Chem., 20, 6208 (2012); https://doi.org/10.1016/j.bmc.2012.09.013

R.A. Haque, S. Budagumpi, S.Y. Choo, M.K. Choong, B.E. Lokesh and K. Sudesh, Nitrile-Functionalized Hg(II)- and Ag(I)-N-Heterocyclic Carbene Complexes: Synthesis, Crystal Structures, Nuclease and DNA Binding Activities, Appl. Organomet. Chem., 26, 689 (2012); https://doi.org/10.1002/aoc.2912

K.F. Ansari and C. Lal, Synthesis, Physicochemical Properties and Antimicrobial Activity of Some New Benzimidazole Derivatives, Eur. J. Med. Chem., 44, 4028 (2009); https://doi.org/10.1016/j.ejmech.2009.04.037

S.J. Park, J.C. Lee and K.I. Lee, A Facile Synthesis of 4-Hydroxy-coumarin and 4-Hydroxy-2-quinolone Derivatives, Bull. Korean Chem. Soc., 28, 1205 (2007); https://doi.org/10.5012/bkcs.2007.28.7.1203

S.I. Alaqeel, Synthetic Approaches to Benzimidazoles from o-Phenylene-diamine: A Literature Review, J. Saudi Chem. Soc., 21, 229 (2017); https://doi.org/10.1016/j.jscs.2016.08.001

J.G. Cappucino and N. Sherman, Microbiology: A Laboratory Mannual, Addison Wesley Longman Inc.: California, p. 263 (1999).

H.D. Isenberg, Clinical Microbiology Procedures Handbook, American Society for Microbiology, Washington, D.C. vol. 1(1992).

Pharmacopoeia of India, Ministry of Health Department, Government of India: New Delhi, vol. 2, p. A-88 (1996).

T. Parish and N.G. Stroker, Mycobacteria Protocols: Methods in Molecular Biology, Humana Press: NJ p. 395 (1998).

V. Klimesová, L. Zahajská, K. Waisser, J. Kaustová and U. Möllmann, IL Farmaco, 59, 288 (2004); https://doi.org/10.1016/j.farmac.2004.01.006

L.A. Collins and S.G. Franzblau, Microplate Alamar Blue Assay versus BACTEC 460 System for High-throughput Screening of Compounds against M. tuberculosis and M. avium, Antimicrob. Agents Chem., 41, 1004 (1997).

P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J.T. Warren, H. Bokesch, S. Kenney and M.R. Boyd, New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening, J. Natl. Cancer Inst., 82, 1107 (1990); https://doi.org/10.1093/jnci/82.13.1107

V. Vichai and K. Kirtikara, Sulforhodamine B Colorimetric Assay for Cytoxicity Screening, Nat. Protocol, 1, 1116 (2006); https://doi.org/10.1038/nprot.2006.179

Synthesis and in vitro Evaluation of Dihydrobenzimidazole Thiopyranooxazinone Derivatives as a Potent Biological Agents

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