Hydrogen bond formation as basis for radical scavenging activity: a structure-activity study of C-methylated...

A naturally occurring flavonoid, myrigalone B (2',6' -dihydroxy-4'-methoxy-3',5'-dimethyl-dihydrochal-cone) is an effective antioxidant and scavenger of the diphenylpicrylhydrazyl radical, while the closely related angoletin (2',4'-dihydroxy-6'-methoxy-3',5'-dimethyl-dihydrochalcone) is inactive. From NMR spectra, it appears that myrigalone B has a time-averaged conformation in which the substituted aromatic ring is orthogonal to the carbonyl group, while angoletin is coplanar. By donating a phenolic hydrogen in radical scavenging, myrigalone B will lose its symmetrical structure and may thereby change to a coplanar conformation forming a strong intramolecular hydrogen bond between the remaining phenolic hydrogen and the carbonyl group. The energy gain entailed would then appear to be a driving force for the radical scavenging by myrigalone B. Angoletin, being coplanar, lacks this driving force. To verify this hypothesis, the conformation and radical scavenging activity of a series of phenolic acetophenones were studied. All substances that had an orthogonal conformation and could form intramolecular hydrogen bonds by loss of a phenolic hydrogen were DPPH scavengers, while compounds lacking these properties were inactive. From this, we propose that formation of intramolecular hydrogen bonds may lead to radical scavenging activity.