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Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors

Received: 14 September 2019     Accepted: 15 October 2019     Published: 24 October 2019
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Abstract

Role of aldose reductase (ALR2) in diabetic complications such as retinopathy, nephropathy, neuropathy, and cataract etc. is well-evident. ALR2 in the first step of polyol pathway reduces glucose to sorbitol whose elevated level leads to diabetic cataract, characterize by clouding of the lens in the eye that affects vision. Inhibition of ALR2 enzyme with small molecules as inhibitor is a rapid approach for diabetic management. In the present study the synthetic route to synthesize desired benzopyrazines and a library of sixteen (16) methyl benzopyrazines were screened against aldose reductase. From the bioactivity results, the 3'-hydroxyphenyl benzopyrazine 6l was found most active (IC50 = 1.34 ± 0.07 µM) while 3'-bromophenyl analogue 6i showed comparable activity for ALR2 (IC50 = 3.48 ± 0.66 µM) as compared to standard sorbinil (IC50 = 3.14 ± 0.02 µM). Both compounds (6l and 6i) showed excellent selectivity for ALR2 over aldehyde reductase (ALR1) which has important role in detoxification of toxic aldehydes. The structure of two regio-isomers were fully characterize by 1H and 13C NMR two dimensional NMR techniques including COSY, NOESY, HSQC, and HMBC. Regio-isomers separation was proved to be difficult in different solvent systems. Only an isomer of 3'-bromo benzopyrazine 6i' was isolated that help to assign the structure of regioisomers from NMR data. All the benzopyrazines were fully characterized by using different spectral techniques including 1H, 13C NMR, IR spectroscopy, and mass spectrometry.

Published in Science Journal of Chemistry (Volume 7, Issue 5)

This article belongs to the Special Issue Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors

DOI 10.11648/j.sjc.20190705.11
Page(s) 90-97
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2019. Published by Science Publishing Group

Keywords

Aldose Reductase, Polyol Pathway, Aldehyde Reductase, Benzopyrazines, Diabetic Complications

References
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    Huma Aslam Bhatti, Qurat-Ul-Ain Zaheer, Yildiz Tehseen, Zahid Shaiq, Khalid Mohammed Khan, et al. (2019). Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors. Science Journal of Chemistry, 7(5), 90-97. https://doi.org/10.11648/j.sjc.20190705.11

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    ACS Style

    Huma Aslam Bhatti; Qurat-Ul-Ain Zaheer; Yildiz Tehseen; Zahid Shaiq; Khalid Mohammed Khan, et al. Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors. Sci. J. Chem. 2019, 7(5), 90-97. doi: 10.11648/j.sjc.20190705.11

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    AMA Style

    Huma Aslam Bhatti, Qurat-Ul-Ain Zaheer, Yildiz Tehseen, Zahid Shaiq, Khalid Mohammed Khan, et al. Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors. Sci J Chem. 2019;7(5):90-97. doi: 10.11648/j.sjc.20190705.11

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  • @article{10.11648/j.sjc.20190705.11,
      author = {Huma Aslam Bhatti and Qurat-Ul-Ain Zaheer and Yildiz Tehseen and Zahid Shaiq and Khalid Mohammed Khan and Abdul Hameed and Jamshed Iqbal},
      title = {Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors},
      journal = {Science Journal of Chemistry},
      volume = {7},
      number = {5},
      pages = {90-97},
      doi = {10.11648/j.sjc.20190705.11},
      url = {https://doi.org/10.11648/j.sjc.20190705.11},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.sjc.20190705.11},
      abstract = {Role of aldose reductase (ALR2) in diabetic complications such as retinopathy, nephropathy, neuropathy, and cataract etc. is well-evident. ALR2 in the first step of polyol pathway reduces glucose to sorbitol whose elevated level leads to diabetic cataract, characterize by clouding of the lens in the eye that affects vision. Inhibition of ALR2 enzyme with small molecules as inhibitor is a rapid approach for diabetic management. In the present study the synthetic route to synthesize desired benzopyrazines and a library of sixteen (16) methyl benzopyrazines were screened against aldose reductase. From the bioactivity results, the 3'-hydroxyphenyl benzopyrazine 6l was found most active (IC50 = 1.34 ± 0.07 µM) while 3'-bromophenyl analogue 6i showed comparable activity for ALR2 (IC50 = 3.48 ± 0.66 µM) as compared to standard sorbinil (IC50 = 3.14 ± 0.02 µM). Both compounds (6l and 6i) showed excellent selectivity for ALR2 over aldehyde reductase (ALR1) which has important role in detoxification of toxic aldehydes. The structure of two regio-isomers were fully characterize by 1H and 13C NMR two dimensional NMR techniques including COSY, NOESY, HSQC, and HMBC. Regio-isomers separation was proved to be difficult in different solvent systems. Only an isomer of 3'-bromo benzopyrazine 6i' was isolated that help to assign the structure of regioisomers from NMR data. All the benzopyrazines were fully characterized by using different spectral techniques including 1H, 13C NMR, IR spectroscopy, and mass spectrometry.},
     year = {2019}
    }
    

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  • TY  - JOUR
    T1  - Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors
    AU  - Huma Aslam Bhatti
    AU  - Qurat-Ul-Ain Zaheer
    AU  - Yildiz Tehseen
    AU  - Zahid Shaiq
    AU  - Khalid Mohammed Khan
    AU  - Abdul Hameed
    AU  - Jamshed Iqbal
    Y1  - 2019/10/24
    PY  - 2019
    N1  - https://doi.org/10.11648/j.sjc.20190705.11
    DO  - 10.11648/j.sjc.20190705.11
    T2  - Science Journal of Chemistry
    JF  - Science Journal of Chemistry
    JO  - Science Journal of Chemistry
    SP  - 90
    EP  - 97
    PB  - Science Publishing Group
    SN  - 2330-099X
    UR  - https://doi.org/10.11648/j.sjc.20190705.11
    AB  - Role of aldose reductase (ALR2) in diabetic complications such as retinopathy, nephropathy, neuropathy, and cataract etc. is well-evident. ALR2 in the first step of polyol pathway reduces glucose to sorbitol whose elevated level leads to diabetic cataract, characterize by clouding of the lens in the eye that affects vision. Inhibition of ALR2 enzyme with small molecules as inhibitor is a rapid approach for diabetic management. In the present study the synthetic route to synthesize desired benzopyrazines and a library of sixteen (16) methyl benzopyrazines were screened against aldose reductase. From the bioactivity results, the 3'-hydroxyphenyl benzopyrazine 6l was found most active (IC50 = 1.34 ± 0.07 µM) while 3'-bromophenyl analogue 6i showed comparable activity for ALR2 (IC50 = 3.48 ± 0.66 µM) as compared to standard sorbinil (IC50 = 3.14 ± 0.02 µM). Both compounds (6l and 6i) showed excellent selectivity for ALR2 over aldehyde reductase (ALR1) which has important role in detoxification of toxic aldehydes. The structure of two regio-isomers were fully characterize by 1H and 13C NMR two dimensional NMR techniques including COSY, NOESY, HSQC, and HMBC. Regio-isomers separation was proved to be difficult in different solvent systems. Only an isomer of 3'-bromo benzopyrazine 6i' was isolated that help to assign the structure of regioisomers from NMR data. All the benzopyrazines were fully characterized by using different spectral techniques including 1H, 13C NMR, IR spectroscopy, and mass spectrometry.
    VL  - 7
    IS  - 5
    ER  - 

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Author Information
  • Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan

  • Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan

  • Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan

  • Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan

  • Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan

  • Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan

  • Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan

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