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Synthesis, X-ray crystallographic study, pharmacology and docking of hydrazinyl thiazolyl coumarins as dengue virus NS2B/NS3 serine protease inhibitors

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Abstract

A series of total twenty-one thiazole-coumarin derivatives 7a-u, linked via hydrazine linkage were synthesized through Hantzsch cyclisation. Out of twenty-one derivatives, fourteen derivatives viz. 7b-d, 7g, 7i-k, 7n and 7p-u are the novel derivatives. The structures of the synthesized compounds were established by extensive spectroscopic studies (FTIR, 1H NMR, 13C NMR, 2D NMR, LC-MS) and elemental analysis. The structure of (E)-6-methoxy-3-(1-(2-(4-p-tolylthiazol-2-yl)hydrazono)ethyl)-2H-chromen-2-one (7d) was unambiguously confirmed by X-ray crystallography analysis. Hybrid molecules were evaluated for their potential as anti-tubercular agents against Mycobacterium tuberculosis H37Rv ATCC 25618, and anti-bacterial agents against Eschericia coli, Enterobacter aerogenes, Salmonella typhi, Streptococcus pneumoniae and Staphylococcus aureus. All the compounds displayed considerable potency against all the pathogens with MIC values ranging from 31.25 to 250 μg/mL, therein compounds 7i, 7j, 7k, 7q and 7t displayed superior inhibitory activities compared to standard drugs streptomycin, kanamycin, vancomycin and isoniazid. Molecular docking studies were performed to check the potential as dengue virus NS2B/NS3 serine protease inhibitors, by comparing to standards 4-hydroxypanduratin, panduratin and ethyl 3-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy)propanoate with DS of −3.379, −3.189 and −3.381, respectively. All the compounds were found to exhibit potency against the DENV virus. In particular, compound 7c (DS –5.141) and 7l (DS –3.894) were found to be even better than the standards followed by compounds 7j (DS –3.113) and 7q (DS –3.561).

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Acknowledgements

We would like to thank the Malaysian Government and Universiti Sains Malaysia (USM) for providing necessary research facilities and Research University Grant (FRGS 203/PKIMIA/6711462). Samina Khan Yusufzai (SKY) thanks the Institute of Postgraduate Studies (IPS), USM for the Graduate Assistance fellowship support. SKY expresses the gratitude to the School of Biological Sciences, USM and Faculty of Science and Natural Resources, Universiti Malaysia Sabah for providing facilities for biological studies.

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Authors and Affiliations

  1. School of Chemical Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia

    Samina Khan Yusufzai & Hasnah Osman

  2. School of Industrial Technology, Universiti Sains Malaysia, 11800, Penang, Malaysia

    Samina Khan Yusufzai & Othman Sulaiman

  3. Industrial Chemistry Programme, Faculty of Science and Natural Resources, Universiti Malaysia Sabah, 88400, Sabah, Malaysia

    Mohammad Shaheen Khan

  4. College of Pharmacy, Al-Mustansiriyah University, 10001, Baghdad, Iraq

    Basma M. Abd Razik

  5. School of Biological Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia

    Suriyati Mohamad

  6. Biotechnology Programme, Faculty of Science and Natural Resources, Universiti Malaysia Sabah, 88400, Kota Kinabalu, Sabah, Malaysia

    Jualang Azlan Gansau & Norhaniza Johansah

  7. College of Education for Women, University of Anbar, 31001, Ramadi, Anbar, Iraq

    Mohammed Oday Ezzat

  8. School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia

    Thaigarajan Parumasivam

  9. X-Ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800, Penang, Malaysia

    Mohd Mustaqim Rosli & Ibrahim Abdul Razak

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  1. Samina Khan Yusufzai
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  2. Hasnah Osman
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Correspondence to Hasnah Osman.

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Yusufzai, S.K., Osman, H., Khan, M.S. et al. Synthesis, X-ray crystallographic study, pharmacology and docking of hydrazinyl thiazolyl coumarins as dengue virus NS2B/NS3 serine protease inhibitors. Med Chem Res 27, 1647–1665 (2018). https://doi.org/10.1007/s00044-018-2179-8

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