In Vitro and In Silico Studies of the Antimicrobial Activity of Prenylated Phenylpropanoids of Green Propolis and Their Derivatives against Oral Bacteria

Abstract

Artepillin C, drupanin, and plicatin B are prenylated phenylpropanoids that naturally occur in Brazilian green propolis. In this study, these compounds and eleven of their derivatives were synthesized and evaluated for their in vitro antimicrobial activity against a representative panel of oral bacteria in terms of their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. Plicatin B (2) and its hydrogenated derivative 8 (2',3',7,8-tetrahydro-plicatin B) were the most active compounds. Plicatin B (2) displayed strong activity against all the bacteria tested, with an MIC of 31.2 μg/mL against Streptococcus mutans, S. sanguinis, and S. mitis. On the other hand, compound 8 displayed strong activity against S. mutans, S. salivarius, S. sobrinus, Lactobacillus paracasei (MIC = 62.5 μg/mL), and S. mitis (MIC = 31.2 μg/mL), as well as moderate activity against Enterococcus faecalis and S. sanguinis (MIC = 125 μg/mL). Compounds 2 and 8 displayed bactericidal effects (MBC: MIC ≤ 4) against all the tested bacteria. In silico studies showed that the complexes formed by compounds 2 and 8 with the S. mitis, S. sanguinis, and S. mutans targets (3LE0, 4N82, and 3AIC, respectively) had energy score values similar to those of the native S. mitis, S. sanguinis, and S. mutans ligands due to the formation of strong hydrogen bonds. Moreover, all the estimated physicochemical parameters satisfied the drug-likeness criteria without violating the Lipinski, Veber, and Egan rules, so these compounds are not expected to cause problems with oral bioavailability and pharmacokinetics. Compounds 2 and 8 also had suitable ADMET parameters, as the online server pkCSM calculates. These results make compounds 2 and 8 good candidates as antibacterial agents against oral bacteria.

Keywords: artepillin C; molecular docking; oral bacteria; oral pathogens; plicatin B.

Figure 1

Chemical structures of drupanin (I) and artepillin C (II).

Scheme 1

Synthesis of compounds 1–14.

Figure 2

Three- and two-dimensional diagrams of the interaction between the S. mitis target (3LE0) and compound 2 (a), compound 8 (b), and the native ligand (GOL) (c).

Figure 3

Three- and two-dimensional diagrams of the interactions between the S. sanguinis target (4N82) and compound 2 (a), compound 8 (b), and the native ligand (FMN) (c).

Figure 4

Three- and two-dimensional diagrams of the interactions between the S. mutans target (4N82) and compound 2 (a), compound 8 (b), and the native ligand (FMN) (c).

Figure 5

Three-dimensional diagrams of the best pose found by molecular docking (green) and molecular dynamics (yellow) for 3LE0–compound 8 (a), 4N82–compound 2 (b), and 3AIC–compound 2 (c).

Figure 6

Potential energy (U) as a function of time for three complexes; (a) 3LE0–compound 8, (b) 4N82–compound 2, and (c) 3AIC–compound 2.