Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 8, Pages 1658-1669Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.03.015
Keywords
Aldose reductase inhibitor; Quinoxalinone; Acyl trifluoromethanesulfonamide; Antioxidant; Molecular docking; Lipid-water partition coefficient
Funding
- National Natural Science Foundation of China [21572021]
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A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC50 value of 0.100 mu M, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox. Compounds 9 had higher lipid-water partition coefficients relative to the carboxylic acid compounds 8, indicating that they may have better lipophilicity and membrane permeability. Structure-activity relationship (SAR) studies found that acyl trifluoromethanesulfonamide group at N1 and the C3-dihydroxystyryl side chain were the key structure for improving the aldose reductase inhibitory activity and antioxidant activity.
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