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Design, synthesis and biological evaluation of novel indolinedione–coumarin hybrids as xanthine oxidase inhibitors

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Abstract

A library of indolinedione–coumarin hybrid molecules was rationally designed and synthesized against hyperuricemia. All of the synthesized hybrid molecules were tested to check their inhibitory activity against xanthine oxidase enzyme by using a spectrophotometric assay. The results revealed that the compound showed IC50 values within the range of 6.5–24.5 µM amongst which compound K-7 was found to be endowed with the most potent IC50 value against xanthine oxidase enzyme. Kinetic studies were also performed to check the mode of inhibition of most potent compound K-7, which revealed its mixed-type inhibition behavior. Structure-activity relationships revealed that electron-donating groups and small alkyl chains between the two active scaffolds might be beneficial in inhibiting xanthine oxidase enzyme. It was also shown that various electrostatic interactions stabilized the compound K-7 within the active site of xanthine oxidase enzyme, which confirmed that it can completely block its catalytic active site. Thus, K-7 is regarded as a potent xanthine oxidase inhibitor and can be served as a promising molecular architectural unit for anti-hyperuricemic drug design.

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Acknowledgements

Authors are grateful to the University Grants Commission for providing funds under Rajiv Gandhi National Fellowship (RGNF) and National Fellowships for Other Backword Classes (NFOBC), Department of Science & Technology (DST-PURSE), Council of Scientific and Industrial Research (CSIR): Project no. 02(0319)17/EMR-II, Women Scientists Scheme-A (WOS-A: DST) and DST-FIST. The authors are also thankful to Guru Nanak Dev University, Amritsar for providing various basic facilities to carry out the research work.

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  1. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India

    Harmandeep Kaur Gulati, Kavita Bhagat, Atamjit Singh, Nitish Kumar, Arshmeet Kaur, Akriti Sharma, Shilpa Heer, Harbinder Singh, Jatinder Vir Singh & Preet Mohinder S. Bedi

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  1. Harmandeep Kaur Gulati
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  2. Kavita Bhagat
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Correspondence to Harbinder Singh, Jatinder Vir Singh or Preet Mohinder S. Bedi.

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Gulati, H.K., Bhagat, K., Singh, A. et al. Design, synthesis and biological evaluation of novel indolinedione–coumarin hybrids as xanthine oxidase inhibitors. Med Chem Res 29, 1632–1642 (2020). https://doi.org/10.1007/s00044-020-02589-2

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