## 4 Discussion  
As the principal regulator of the redox homeostasis in cells, the cap 'n' collar basic leucine zipper (CNC-bZip) transcription factor, Nrf2 counterpoises the free radical production and maintains cellular redox homeostasis [47]. Depleted Nrf2, due to oxidative stress, senescence, or epigenetic suppression, drives the accumulation of free radicals in cells, lead  
Figure 9: Metabolism and absorption of key antioxidant esters and ketones of selected phenolic acids. ing to a pathogenic state. Since the discovery of Nrf in the 1990s, its physiological spectrum has expanded extensively [7; 33; 48; 49]. Currently, there are several botanicals and dietary supplements in the market with Nrf2-activation claim; however, only one FDA-approved Nrf2 activator, Tcedifera (dimethylfumarate), for the treatment of multiple sclerosis can be recognized [50]. Therefore, the design and development of Nrf2-based therapeutics to mitigate oxidative stress-associated diseases remain a much-needed area of study. Phenolic acids are among the vital antioxidant metabolites of a plant-based diet with the ability to activate the Nrf2 pathway [51]. Numerous studies indicate the antioxidant and other pharmacological properties of these plant secondary metabolites [8; 51]. Caffe acid, a vital antioxidant phenolic acid has been studied for more than 65 years [52; 53]. Initially identified as a fungistatic agent, it was found to be a bioavailable and rapidly metabolized bioactive compound [52; 54; 55]. The synthesis of its esters began in the 1950s as well and continues to date for more potent versions of the parent molecule [56]. Other phenolic acids used in this study _viz._ hydro caffe acid, ferulic, and gallic acid have also been well studied for more than 60 years and numerous analogs are available [57; 58; 59]. However, owing to their clinical significance, efforts are continuously underway to develop their novel and potent analogs of phenolic acids and this effort holds practical significance. In line with our work on polyphenol analogs, we synthesized an array of phenolic acid analogs with variable amide and ester moieties and assessed their antioxidant activity in situ, in cells, and _D. melanogaster_. We found that these compounds exhibit antioxidant capacity and induce cellular antioxidant enzymes at basal conditions. Our study identified unique polyphenol analogs with a strong ability to scavenge free radicals and stimulate GPx in cells (Figures 1, 4 and 6). We also found that the cytoprotective impacts of phenolic acid amides and esters are possibly interceded by their coordinated Nrf2 and ERK receptor activity (Figures 7 and 8). Our findings complement previous data on the pharmacological spectrum of phenolic acids and their derivatives. Esterification of caffe acid leads to the enhancement of its antioxidant capacities [60]. Likewise, novel amides of caffe acid improve cell survival and cytoprotection [61]. A similar impact on biological activity has been shown by amides and ketones of ferulic acid, gallic acid, and hydroxy ferulic acid [62; 63; 64]. These antioxidant activities of phenolic acid(s) and their derivatives transcend free radical mitigation and extend benefits in different disease states as well. Caffe acid amides have shown cytoprotective potential by inhibiting \(\beta\)-amyloid fibrillization and cytotoxicity [65]. Similarly, gallic acid amides have shown the ability to inhibit \(\alpha\)-synuclein, a protein involved in the pathogenesis of [PERSON]'s disease [66]. CAPE also protects neurons against cisplatin-induced neurotoxicity via activation of the AMPK/SIRT1 pathway [67]. However, we did not observe any significant increase in both SIRT1 (Figure S2) and AMPK (Figure S3) pathways by CAPE or other analogs. It might be attributed to treatment at the basal level and lack of oxidative stress. Apart from the neuroprotective spectrum, the pharmacological sphere of phenolic acid derivatives extends to infectious diseases as well.