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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 (<b>2</b>) and its hydrogenated derivative <b>8</b> (2′,3′,7,8-tetrahydro-plicatin B) were the most active compounds. Plicatin B (<b>2</b>) displayed strong activity against all the bacteria tested, with an MIC of 31.2 μg/mL against <i>Streptococcus mutans, S. sanguinis</i>, and <i>S. mitis.</i> On the other hand, compound <b>8</b> displayed strong activity against <i>S. mutans</i>, <i>S. salivarius</i>, <i>S. sobrinus</i>, <i>Lactobacillus paracasei</i> (MIC = 62.5 μg/mL), and <i>S. mitis</i> (MIC = 31.2 μg/mL), as well as moderate activity against <i>Enterococcus faecalis</i> and <i>S. sanguinis</i> (MIC = 125 μg/mL). Compounds <b>2</b> and <b>8</b> displayed bactericidal effects (MBC: MIC ≤ 4) against all the tested bacteria. In silico studies showed that the complexes formed by compounds <b>2</b> and <b>8</b> with the <i>S. mitis</i>, <i>S. sanguinis</i>, and <i>S. mutans</i> targets (<b>3LE0</b>, <b>4N82</b>, and <b>3AIC</b>, respectively) had energy score values similar to those of the native <i>S. mitis</i>, <i>S. sanguinis</i>, and <i>S. mutans</i> 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 <b>2</b> and <b>8</b> also had suitable ADMET parameters, as the online server pkCSM calculates. These results make compounds <b>2</b> and <b>8</b> good candidates as antibacterial agents against oral bacteria.