## 5 Conclusions  
We adopt natural product supplementation as a strategy for managing oxidative stress-mediated pathophysiological conditions. The discovery of natural product inspired new Nrf2 activators and establishing their mechanism of action can be of great pharmacological value. We have shown that multiple esters and ketones of phenolic acids exhibit potent antioxidant activity and activate antioxidant enzymes such as GPx, and HO-1 via the Nrf2-ARE pathway. Importantly, selected derivatives of phenolic acids, which constitute the human diet, exhibit safe and non-toxic activity in cells. Further, Nrf2 activation of both parent molecules (CA and CAPE) and the derivatives, particularly analog **44** is ERK-dependent. The design of CAPE's analog series for the investigation of the effect of structural modifications on all parts of this molecule provided a clear picture. The effect of caffeic acid analogs, as well as CAPE, are not due only to the presence of the catechol moiety. Our experiments have identified ketone **44** as a novel activator of Nrf2 in vivo and in cells. The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/app12063062/s1](https://www.mdpi.com/article/10.3390/app12063062/s1)]([https://www.mdpi.com/article/10.3390/app12063062/s1](https://www.mdpi.com/article/10.3390/app12063062/s1)), Figure S1: Figures and tables showing detailed antioxidant activity and chemical characteristics of Caffeic acid and CAPE analogs (100 \(\upmu\)M) as measured using ABTS, FRAP, and ORAC antioxidant assays; Figure S2: The impact of Caffeic acid and CAPE analogs on cytochrome C levels as the toxicity indicator. WI-38 cells were pre-treatedwith 10 uM of the selected compounds for 24 h and then the cytochrome C levels were measured using ELISA; Figure S3: The impact of Caffeic acid and CAPE analogs on SIRT1 levels. 293T cells were pre-treated with 10 uM of the selected compounds for 24 h and then the selected biomarkers were observed using western blot; Figure S4: The impact of Caffeic acid and CAPE analogs on Nrf pathway activation. 293T cells were pre-treated with 10 uM of the selected compounds for 24 h and then the protein and RNA were extracted using RIPA buffer and TRIzol. (A-B) mRNA increase in HO-1 and (C) validation of p-NRF2 by analog 44. Ordinary one-way analysis of variance (ANOVA) was performed followed by [PERSON]'s multiple comparisons test to identify statistical difference **_p_ < 0.01, ***_p_ < 0.0001; Figure S5: The subcellular localization of Nrf2 following treatment with compound 44, the ketone analog of CAPE. 293T cells were pre-treated with 10 uM of the compound 44 for 24 h and then the nuclear protein was extracted, and immunoblotting was performed; Additional Supplementary Material: NMR data. K.S.B. : Conceptualization, Investigation, Data curation, Writing--original draft, and updated versions. M.A.N. : Investigation, Data curation, Writing--original draft, and updated versions. K.M.E. : Supervision, Writing--original draft & updated versions, corrections and editing. J.A.D. : Investigation and Data curation. L.M.L. : Investigation and Data curation. G.L.-C.: Investigation and Data curation. M.S. : Investigation, Resources, and Manuscript Revision. F.S.A. : Manuscript Revision. M.T. and H.P.V.R. : Supervision, Funding, Writing--original draft & updated versions, corrections and editing. All authors have read and agreed to the published version of the manuscript. M.T. and H.P.V.R. acknowledge funding from the Discovery Grant of the Natural Sciences and Engineering Research Council (NSERC) of Canada. M.T. also received funds from New Brunswick Innovation Foundation. Available on request from the corresponding author. The authors thank [PERSON] and [PERSON] for their help with western blots, cell culture, RNA extraction, and providing other resources. [PERSON] and [PERSON] for their help with fly study and qPCR, and [PERSON] and [PERSON] for help with flow cytometry analysis.