Structure–activity relationships studies of quinoxalinone derivatives as aldose reductase inhibitors

• The SAR study of quinoxalinone derivatives as aldose reductase inhibitors.
• The C3-phenethyl and C6-nitro substitutions enhancing the activity and selectivity.
• Aldose reductase inhibitors are a promising and an attractive therapeutic strategy.

Novel quinoxalinone derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Among them, N1-acetate derivatives had significant activity in a range of IC50 values from low micromolar to submicromolar, and compound 15a bearing a C3-phenethyl side chain was identified as the most potent inhibitor with an IC50 value of 0.143 μM. The structure–activity studies suggested that both C3-phenethyl and C6-NO2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based inhibitors.

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