Eugenol is the main component of clove basil oil, mainly extracted from Syzygium aromaticum. In order to discover biorational natural product-based pesticides, 24 novel eugenol acyloxy/sulfonyloxy derivatives (3a-q and 4d,f,j-n) containing an isoxazoline ring were designed and synthesized by simultaneously introducing isoxazoline and acyloxy/sulfonyloxy pharmacophores, and their structures were characterized by 1H NMR, 13C NMR, and HRMS. The single-crystal X-ray diffraction of two titled compounds 3k and 4l usefully established the 5-substituted regiochemistry. Furthermore, we screened the bioactivities of these compounds as anti-oomycete, anti-fungal, and nematicidal agents. Three serious agricultural diseases that have a devastating impact on agricultural production were selected as the test subjects, namely Phytophthora capsici, Fusarium graminearum, and Heterodera glycines. Amongst evaluated derivatives, (1) Compounds 2 and 4f displayed potential anti-oomycete against the plant pathogen P. capsici, with EC50 values of 40.20 and 71.43 mg/L, respectively. (2) Compounds 2 and 4d also exhibited potential anti-fungal against the plant pathogen F. graminearum, with EC50 values of 49.19 and 61.29 mg/L, respectively. (3) Seven compounds (3a, 3i, 3l, 3n, and 4l-n) showed significant nematicidal activity against H. glycines, with LC50 values below 20 mg/L. Especially for compound 3a (R1 = CF3), its LC50 was 11.38 mg/L. It has been proven that the simultaneous introduction of isoxazoline ring and acyloxy/sulfonyloxy pharmacophores into the structural skeleton of eugenol (1) has been successful in enhancing its nematicidal activity.
Here, we report the discovery and optimization of 1-cinnamylpiperazine derivatives as antibiotic-potentiating agents inspired by the known RND efflux pump inhibitor 1-(1-naphthylmethyl)piperazine (NMP). A structurally diverse series of analogues was synthesized and evaluated for intrinsic antibacterial activity, cytotoxicity, and ability to potentiate antibiotic activity against Escherichia coli. Most derivatives showed low intrinsic antibacterial activity, consistent with an adjuvant mode of action. In combination assays, several compounds enhanced the antibiotic activity of erythromycin and linezolid, with halogenated derivatives showing the strongest potentiating effects. Compound 27 displayed the broadest potentiation profile, showing synergistic interactions with five of the seven tested antibiotics, namely linezolid, novobiocin, fusidic acid, pyridomycin, and clindamycin. Notably, it showed a superior potency to the structurally related reference inhibitor NMP. Experiments with AcrAB–TolC-deficient E. coli mutants, together with dye accumulation (Hoechst 33342) and membrane-permeabilization assays, suggested that 1-cinnamylpiperazine derivatives modulate efflux-associated resistance in a manner distinct from NMP, with increased membrane permeability likely contributing to their overall potentiating effect. Beyond planktonic cultures, compound 27 also potentiated erythromycin and linezolid against mature E. coli biofilms. These findings identify 1-cinnamylpiperazines as promising antibiotic adjuvant scaffolds for further optimization against drug-resistant Gram-negative infections.
