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. 2021 Apr 15;26(8):2293.
doi: 10.3390/molecules26082293.

Quorum Sensing and NF-κB Inhibition of Synthetic Coumaperine Derivatives from Piper nigrum

Yael Kadosh  1 , Subramani Muthuraman  2 , Karin Yaniv  1 , Yifat Baruch  1 , Jacob Gopas  3   4 , Ariel Kushmaro  1 , Rajendran Saravana Kumar  2
Affiliations

Quorum Sensing and NF-κB Inhibition of Synthetic Coumaperine Derivatives from Piper nigrum

Yael Kadosh et al. Molecules. .

Abstract

Bacterial communication, termed Quorum Sensing (QS), is a promising target for virulence attenuation and the treatment of bacterial infections. Infections cause inflammation, a process regulated by a number of cellular factors, including the transcription Nuclear Factor kappa B (NF-κB); this factor is found to be upregulated in many inflammatory diseases, including those induced by bacterial infection. In this study, we tested 32 synthetic derivatives of coumaperine (CP), a known natural compound found in pepper (Piper nigrum), for Quorum Sensing Inhibition (QSI) and NF-κB inhibitory activities. Of the compounds tested, seven were found to have high QSI activity, three inhibited bacterial growth and five inhibited NF-κB. In addition, some of the CP compounds were active in more than one test. For example, compounds CP-286, CP-215 and CP-158 were not cytotoxic, inhibited NF-κB activation and QS but did not show antibacterial activity. CP-154 inhibited QS, decreased NF-κB activation and inhibited bacterial growth. Our results indicate that these synthetic molecules may provide a basis for further development of novel therapeutic agents against bacterial infections.

Keywords: NF-kB; Piper nigrum; amide alkaloids; antibacterial; coumaperine; plant natural-based compounds; quorum sensing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Few examples of natural product-based quorum sensing inhibitors.
Figure 2
Figure 2
Synthesis of monoconjugated coumaperine derivatives.
Figure 3
Figure 3
Di and triconjugated coumaperine derivatives synthesized.
Figure 4
Figure 4
Diconjugated coumaperine derivatives synthesized.
Figure 5
Figure 5
Dose response of Nuclear Factor kappa B (NF-κB) activation using the NF-κB reporter gene luciferase assay. L428 cells were stably transfected with the NF-κB luciferase reporter gene. The cells were incubated with the compounds at different concentrations for 2 h. Only compounds that showed NF-κB inhibition are shown here. The results represent the percentage of NF-kB activation as compared to vehicle (DMSO)-treated cells. All samples were normalized to the protein concentration. Mean + SD, Two-way ANOVA and Tukey’s multiple comparison test. 95% confidence interval (p-values * ≤ 0.0332, ** ≤ 0.0021 and *** ≤ 0.0002).
Figure 6
Figure 6
NF-κB inhibition in A549 cells. A549 cells were fixed in paraformaldehyde and immunostained with mouse-anti p65 and fluorescent goat anti-mouse IgG. Localization of p65 (A) without treatment- inactive p65 in the cytoplasm. (B) After activation with 2.5 ng/mL TNFα for 15 min, activated p65 in the nucleus. All derivatives were added to the cells at 160 µM for 120 min in DMSO (0.16%) then TNFα at 2.5 ng/mL was added for 15 min. (C) Activated cells (strong nuclear green fluorescence) as a percentage of all the cells in the analyzed field. (D) Ratio of the mean nuclear/cytoplasm fluorescence intensity values in the analyzed fields. Curcumin (CU). Mean ± SD of triplicate samples in two independent experiments. One-way ANOVA comparison of the treatment groups to the control groups DMSO TNF. 95% confidence interval (p-values * ≤ 0.0332, ** ≤ 0.0021, *** ≤ 0.0002). For the comparison between the CU and the CU TNF groups- unpaired two tailed t-test with 95% confidence interval, p-value is 0.0419 (*).
Figure 7
Figure 7
Florescent images of NF-κB inhibition. A549 cells were treated with TNFα (2.5 ng/mL) and/or different positive QS CP derivatives then fixed and immunostained with anti-p65 and anti-mouse IgG conjugate to Alexa AF488 (green) and nuclear staining with DAPI (blue). (A) The negative controls were: untreated, treated with the solvent DMSO (0.16%) for 120 min, TNFα (2.5 ng/mL) for 15 min, DMSO (0.16 %) for 120 min with TNFα (2.5 ng/mL) for 15 min. (B) CP-154 and CP-158 at 160 μM for 120 min with and without TNFα (2.5 ng/mL) for 15 min. (C) CP-286 and CP-215 at 160 μM for 120 min with and without TNFα (2.5 ng/mL) for 15 min. (D). Curcumin (CU) was used as a positive control with the same experimental design as in (B) or (C).
Figure 7
Figure 7
Florescent images of NF-κB inhibition. A549 cells were treated with TNFα (2.5 ng/mL) and/or different positive QS CP derivatives then fixed and immunostained with anti-p65 and anti-mouse IgG conjugate to Alexa AF488 (green) and nuclear staining with DAPI (blue). (A) The negative controls were: untreated, treated with the solvent DMSO (0.16%) for 120 min, TNFα (2.5 ng/mL) for 15 min, DMSO (0.16 %) for 120 min with TNFα (2.5 ng/mL) for 15 min. (B) CP-154 and CP-158 at 160 μM for 120 min with and without TNFα (2.5 ng/mL) for 15 min. (C) CP-286 and CP-215 at 160 μM for 120 min with and without TNFα (2.5 ng/mL) for 15 min. (D). Curcumin (CU) was used as a positive control with the same experimental design as in (B) or (C).
Figure 8
Figure 8
Structure activity relationship of methoxy (CP-38) and thiomethyl (CP-147)-diconjugated coumaperine derivatives.
Figure 9
Figure 9
Mono-, di- and triconjugated coumaperine derivatives.
Figure 10
Figure 10
Synthesis of monoconjugated coumaperine derivatives, CP-237.
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