TY - JOUR
T1 - Benzoflavone derivatives as potent antihyperuricemic agents
AU - Singh, Jatinder V.
AU - Mal, Gurbachan
AU - Kaur, Gurleen
AU - Gupta, Manish K.
AU - Singh, Amritpal
AU - Nepali, Kunal
AU - Singh, Harbinder
AU - Sharma, Sahil
AU - Bedi, S. Preet Mohinder
N1 - Funding Information:
The authors are grateful to the University Grants Commission for providing funds under the Rajiv Gandhi National Fellowship (RGNF) and they are thankful to Guru Nanak Dev University, Amritsar for providing various facilities to carry out the research work.
Publisher Copyright:
© 2019 The Royal Society of Chemistry.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Two series of benzoflavone derivatives were rationally designed, synthesized and evaluated for their xanthine oxidase (XO) inhibitory potential. Among both series, eight compounds (NF-2, NF-4, NF-9, NF-12, NF-16, NF-25, NF-28, and NF-32) were found to exert significant XO inhibition with IC50 values lower than 10 μM. Enzyme kinetic studies revealed that the most potent benzoflavone derivatives (NF-4 and NF-28) are mixed type inhibitors of the XO enzyme. Molecular modeling studies were also performed to investigate the binding interactions of these molecules (NF-4 and NF-28) with the amino acid residues present in the active site of the enzyme. Docking results confirmed that their favorable binding conformations in the active site of XO can completely block the catalytic activity of the enzyme. Benzoflavone derivatives exhibiting potent XO enzyme inhibition also showed promising results in a hyperuricemic mice model when tested in vivo.
AB - Two series of benzoflavone derivatives were rationally designed, synthesized and evaluated for their xanthine oxidase (XO) inhibitory potential. Among both series, eight compounds (NF-2, NF-4, NF-9, NF-12, NF-16, NF-25, NF-28, and NF-32) were found to exert significant XO inhibition with IC50 values lower than 10 μM. Enzyme kinetic studies revealed that the most potent benzoflavone derivatives (NF-4 and NF-28) are mixed type inhibitors of the XO enzyme. Molecular modeling studies were also performed to investigate the binding interactions of these molecules (NF-4 and NF-28) with the amino acid residues present in the active site of the enzyme. Docking results confirmed that their favorable binding conformations in the active site of XO can completely block the catalytic activity of the enzyme. Benzoflavone derivatives exhibiting potent XO enzyme inhibition also showed promising results in a hyperuricemic mice model when tested in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85060557304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060557304&partnerID=8YFLogxK
U2 - 10.1039/c8md00512e
DO - 10.1039/c8md00512e
M3 - Article
AN - SCOPUS:85060557304
SN - 2040-2503
VL - 10
SP - 128
EP - 147
JO - MedChemComm
JF - MedChemComm
IS - 1
ER -