3.1.1. Chalcones

Several studies have suggested that chalcones with a lipophilic group such as isoprenoid and methoxy groups at positions 3, 5, and 2 of ring A are the most potent inhibitors of MRSA strains [49]. Based on the activity of isobavachalcone (MIC: 30 μg/mL), (Figure 1A), the authors of [50] suggested the that A ring with a prenyl group displays adequate antimicrobial activity, but cyclization or addition of the prenyl group to B ring in addition to the A ring decreases this activity. Likewise, the hydroxy group at 4, 4, and 6 of A and B rings increase the antimicrobial activity. For example, kuraridin and 7,9,2,4-tetrahydroxy-8-isopentenyl-5-methoxychalcone (THIPMC) compounds with the same structure, with only one difference in the OH of the B ring (2 and 4 instead of 4 and 6), showed high activity against the MRSA strain [51].

**Figure 1.** Structure–activity (SAR) relationship of important flavonoids: (**a**) in chalcones, substitution of OMe, OH, and prenyl group in ring A, OH group in ring B, and OH groups in 2 and 4 position of ring C enhances antimicrobial activity; (**b**) on flavanes, substitution of prenyl and OH groups at 5and 7 positions in ring A and OH, OMe groups at 3 and 5 position and prenyl at 4 position in ring C enhances antimicrobial activity; (**c**) in flavanols, substituting OH group at 5 position and prenyl at 8 position of ring A, and OH groups at 2, 4 position can enhance antimicrobial activity; (**d**) in flavonols, replacing OH and Me group in ring A, OH, O-glycoside group in ring B and OH groups in ring C can improve antimicrobial activity; (**e**) In flavones substitution of OH group at 5, OH, Me groups at 6, and OH, OMe group at 7 of ring A can improve antimicrobial activity.

### 3.1.2. Flavanes and Flavanols

Flavanes with a prenyl group at the A ring have been found to be the most potent antibacterial compounds against *S*. *aureus*. It is established that the number and position of prenyl groups on this ring increase antimicrobial activity [52]. The presence of the hydroxy groups at different positions on A and B rings has also been reported to improve antibacterial activity (Figure 1B,C). The compound 3-O-methydiplacol with OH at the 5, 3, and 4 positions of the A and B rings, respectively, as well as the geranyl group at C-6 and OMe at C-5, showed satisfactory (i.e., MIC value of 4 μg/mL) activity against *S. aureus* [53]. additionally, sophoraflavanone with isogeranyl at C-8 and OH at 3, 2, and 4 at A and B rings were active (i.e., MIC value of 7.3 μg/mL) against *S. aureus* [51]. The position of prenyl, hydroxyl, and especially methoxy groups at positions 5 and 7 of the A ring, increased the antibacterial effect of flavanes and flavones [54]. Furthermore, different substitutions on position 3 of the C ring with a hydroxyl or an *O*-glycoside group could enhance the antimicrobial activity of certain flavones [46]. One of the earlier findings also suggested that the tetraflavonoids without OH on the C ring showed moderate activity against *E. coli* [55].
