Table 2.

Structure activity relationship (SAR) of previously studied STX inhibitors.

Compound	Structure Activity Relationship (SAR)
Flavone	Carbonyl moiety is crucial for activity, interacts with adjacent amino acid residues in CrtM receptor by conventional hydrogen bond. Yet, the exact mechanism of action for anti-virulence activity remains to be determined. [10,20,74]
Myricetin	Hydroxyl moiety enhances the binding affinity to adjacent amino acid residues of the CrtM receptor through conventional hydrogen bonds. Carbonyl group is essential for activity, binds to adjacent amino acids of the receptor via hydrogen bonds [21,74].
Rhodomyrtone	Alkyl interactions with CrtM receptor at CH3 terminals. Carbonyl moiety is crucial for activity, interacts with VAL in CrtM receptor by hydrogen bond. Hydroxyl moiety enhances the binding affinity to LYS residues through conventional hydrogen bonds [24,25].
E-nerolidol	The alcoholic moiety is essential for activity, binds to CrtM through hydrogen bond. The backbone of the structure interacts with the hydrophobic pocket of the receptor [28].
Carvacrol	Essential phenolic hydroxyl group for activity, binds with conventional hydrogen bond to CrtM. Oxygen involved in the hydroxyl group interacts with GLY A:161 through carbon hydrogen bond. Phenyl ring binds by Pi–Pi T-shaped bond to PHE A:22. Terminal methyl groups bind to ALA A:157, ILE A:241 and PHE A:22 [25].
Thymol	Essential phenolic hydroxyl group for activity, binds with conventional hydrogen bond to CrtM. Oxygen involved in the hydroxyl group interacts with PHE A:117 through carbon hydrogen bond. Methyl terminals bind to TYR A:129, LYS A:113 and PHE A:120 through alkyl interactions [49].
Hesperidin	In case of CrtM, hesperidin actively interacts through (Arg 158, Tyr 154 and Gln 102). Carbonyl moiety interacts with amino acid residues via hydrogen bond. Hydroxyl groups enhances the activity [51].
Tetrangomycin	Hydrogen acceptor groups are crucial for activity. Lipophilic moieties decorating the naphthoquinone ring enhance STX inhibition [55,56].
7-benzyloxyindole	The presence of ether group (acidic moiety) enhances the activity of the compound. The addition of a second hydrophobic ring enhances the activity [53,75].
2-isopropylnaphtho [2,3-b]furan-4,9-dione	Hydrogen acceptor groups are crucial for activity. Lipophilic moieties decorating the naphthoquinone ring enhance STX inhibition [55,56].
Lapaquistat acetate	Carbonyl groups interact with adjacent amino acid residues in CrtM receptor via conventional hydrogen bonds. Aromatic ring interaction with adjacent amino acid residues via alkyl interactions. Methyl group interacts with PHE A:267 on the receptor via Pi–alkyl interaction [25].
Squalestatin	Interaction of carbonyl groups, hydroxyl groups and aromatic benzene ring with His18, Arg45, Asp48, Asp52, Tyr129, Gln165, Asn168 and Asp172 residues on CrtM receptor [60].
Glyceryl trinitrate	GTN has nine hydrogen bonds with Arg45, Tyr129, Gln165, Asn168, Val 133 and Tyr248 electrostatic interaction with Arg45 and Asp48 and pi-cation interaction of the nitrogen atom with Tyr183 [61].
Naftifine	The naphthalenyl moiety of NTF is not indispensable for pigment inhibitory activity, the N-methyl group is critical for high potency on CrtN receptor [66].
5M analog	The naphthalenyl moiety of NTF is not indispensable for pigment inhibitory activity, the N-methyl group is critical for high potency, the 4-substituted phenyl moiety is critical for high potency on CrtN receptor. The para-position is the best substituted position at the phenyl ring [66].
Derivative 47	The N-methyl group is critical for high potency. Unsubstituted alkenyl linker was critical for improving pigment inhibitory activity. The 4-substituted phenyl moiety is critical for high potency on CrtN receptor. The para-position is the best substituted position at the phenyl ring [66,68].