Enhanced Antibacterial Activity of Ent-Labdane Derivatives of Salvic Acid (7α-Hydroxy-8(17)-ent-Labden-15-Oic Acid): Effect of Lipophilicity and the Hydrogen Bonding Role in Bacterial Membrane Interaction

Abstract

In the present study, the antibacterial activity of several ent-labdane derivatives of salvic acid (7α-hydroxy-8(17)-ent-labden-15-oic acid) was evaluated in vitro against the Gram-negative bacterium Escherichia coli and the Gram-positive bacteria Staphylococcus aureus and Bacillus cereus. For all of the compounds, the antibacterial activity was expressed as the minimum inhibitory concentration (MIC) in liquid media and minimum inhibitory amount (MIA) in solid media. Structure activity relationships (SAR) were employed to correlate the effect of the calculated lipophilicity parameters (logPow) on the inhibitory activity. Employing a phospholipidic bilayer (POPG) as a bacterial membrane model, ent-labdane-membrane interactions were simulated utilizing docking studies. The results indicate that (i) the presence of a carboxylic acid in the C-15 position, which acted as a hydrogen-bond donor (HBD), was essential for the antibacterial activity of the ent-labdanes; (ii) an increase in the length of the acylated chain at the C-7 position improved the antibacterial activity until an optimum length of five carbon atoms was reached; (iii) an increase in the length of the acylated chain by more than five carbon atoms resulted in a dramatic decrease in activity, which completely disappeared in acyl chains of more than nine carbon atoms; and (iv) the structural factors described above, including one HBD at C-15 and a hexanoyloxi moiety at C-7, had a good fit to a specific lipophilic range and antibacterial activity. The lipophilicity parameter has a predictive characteristic feature on the antibacterial activity of this class of compounds, to be considered in the design of new biologically active molecules.

Compound Prioritization through Meta-Analysis Enhances the Discovery of Antimicrobial Hits against Bacterial Pathogens

“…It was also shown that, for clusters X and W, the number of carboxylic acid groups and HBD per SM were positively correlated with the spectrum of activity, while the number of acyl groups per SM were negatively correlated. Similar observations were made with salvic acid derivatives in their antimicrobial properties when tested against E. coli , Staphylococcus aureus , and Bacillus cereus [ 37 , 47 ]. The in vitro analyses and docking studies revealed that the antimicrobial activity of salvic acid derivatives (labdanes and diterpenoids) was closely associated with the presence of the carboxylic acid groups in the molecules.…”

“…A total of the 34 PCP were correlated with the activity spectrum of the SM. Several of these parameters (e.g., MR [ 32 ], logP [ 30 , 36 ], HBD [ 37 ], hydroxyl groups [ 38 , 39 , 40 ], aromatic groups [ 41 ], MW [ 31 ], carbons atoms [ 42 ], pyrophosphate [ 43 ], double bonds [ 44 , 45 ], and boron [ 46 ]) are known to influence the antimicrobial activity of a molecule. It was also shown that, for clusters X and W, the number of carboxylic acid groups and HBD per SM were positively correlated with the spectrum of activity, while the number of acyl groups per SM were negatively correlated.…”

“…The in vitro analyses and docking studies revealed that the antimicrobial activity of salvic acid derivatives (labdanes and diterpenoids) was closely associated with the presence of the carboxylic acid groups in the molecules. The carboxylic group in the derivatives acted as HBD enhancing lipophilicity of the molecules, and thus modulated the interactions with the bacterial membrane [ 37 , 47 ]. It is important to notice that hydrogen bond acceptors (HBA) parameter was the only PCP strongly negatively correlated with the spectrum of activity of the SM, which coincides with the negative correlation observed between HBA and HBD (r 2 = –0.47).…”

Whey Proteins as a Potential Co-Surfactant with Aesculus hippocastanum L. as a Stabilizer in Nanoemulsions Derived from Hempseed Oil

“…A similar shift, visible as a change in shape, is present for vibrations from the O–H group. This shift may indicate a variation in the strength and configuration of the hydrogen bonds between polar components of the tested emulsions, suggesting the complex interactions between the emulsion components, which may then have impact on their physicochemical properties [ 50 , 51 ] and plausible biological activity of the samples [ 52 , 53 ].…”

“Haplopappus platylepis(Asteraceae) resin: an adhesive trap for pest control of crawling arthropods, with antimicrobial potential”

“…Labdane diterpenoids are also well known as antimicrobials [67,68]. It has been proved that the presence of a carboxylic acid in the C-15 position, which acted as a hydrogen-bond donor (HBD), is essential for the antibacterial activity of ent -labdanes [64]. Furthermore, derivatives of pinifolic acid, which were characterized in the H. platylepis sticky exudate, showed this main structural characteristic of labdanes.…”