Computational and experimental exploration of the structure–activity relationships of flavonoids as potent glyoxalase‐I inhibitors

Hit, Lead & Candidate Discovery Glyoxalase‐I (Glo‐I) enzyme has emerged as a potential target for cancer treatment. Several classes of natural products including coumarins and flavonoids have shown remarkable Glo‐I inhibitory activity. In the present study, computational and experimental approaches were used to explore the structure–activity relationships of a panel of 24 flavonoids as inhibitors of the Glo‐1 enzyme. Scutellarein with an IC50 value of 2.04 μM was identified as the most potent inhibitor among the series studied. Di‐ or tri‐hydroxylation of the benzene rings A and B accompanied with a C2/C3 double bond in ring C were identified as essential structural features for enzyme inhibition. Moreover, the ketol system showed a minor role in the inhibitory power of these compounds. The structure‐activity relationships revealed in this study had deepened our understanding of the Glo‐I inhibitory activities of flavonoids and opened the door for further exploration of this promising compound class.