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

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 th...

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Bibliographic Details
Published in:Medicinal chemistry research 2020-09, Vol.29 (9), p.1632-1642
Main Authors: Gulati, Harmandeep Kaur, Bhagat, Kavita, Singh, Atamjit, Kumar, Nitish, Kaur, Arshmeet, Sharma, Akriti, Heer, Shilpa, Singh, Harbinder, Singh, Jatinder Vir, Bedi, Preet Mohinder S.
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Chemical synthesis
Coumarin
Drug development
Electrostatic properties
Enzymes
Hybrids
Hyperuricemia
Inorganic Chemistry
Medicinal Chemistry
Original Research
Pharmacology/Toxicology
Spectrophotometry
Structure-activity relationships
Xanthine oxidase
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Summary: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 IC 50 values within the range of 6.5–24.5 µM amongst which compound K-7 was found to be endowed with the most potent IC 50 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.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-020-02589-2