## 3 Results
### Selected Phenolic Acid Analogs Exhibit Stronger Metabolic Uptake  
The metabolic simulation studies supported our findings on the antioxidant activities of selected polyphenol analogs (Figure 9). All selected compounds exhibited TPSA between a healthy range of 20 and 130 A. Most analogs exhibited lower TPSA, thus aiding their polarity and ability to cross the biological barriers for absorption. Ketones **42** and **44** exhibited the lowest TPSA backed by high GI and brain availability (Figure 9). However, the skin permeability coefficient (log _Kp_ in cm/s) and bioavailability score of analyzed compounds were similar (Figure 9). Overall, when calculations were completed, the \"BOILED-Egg\" analysis confirmed the high bioavailability of analogs compared to the parent molecules in both GI and BBB settings (Figure 9). Figure 6: The impact of Caffe acid and CAPE analogs on Nrf pathway activation in _Drosophila Melanogaster_. (**A**) The virgin yellow white (_qu_) mutant female flies were fed the selected compounds for 2 weeks (10 nM) and then the total RNA was extracted using TRIzol. Changes in (**B**) Nrf (**C**) GPs (**D**) SOD mRNA levels were analyzed. Ordinary one-way analysis of variance (ANOVA) was performed followed by [PERSON]’s multiple comparisons test to identify statistical difference *_p_\(<\)0.05, *_p_\(<\)0.01, *_m_\(<\)0.001, ns non-significant. Figure 7: The impact of Caffe acid and CAPE analogs on key antioxidant parameter GPx is dependent on ERK phosphorylation. (**A**) ERK inhibitor SCH77/2984 (1 uM) was used to lower ERK phosphorylation levels in 2937 cells (immunoprecipitated). Next, 2937 cells were pre-treated with 10 uM of the selected compounds for 24 h, (**B**) without and (**C**) with ERK inhibitor SCH77/2984 (1 uM), and then the changes in selected biomarker, GPx, was observed using western blot. \(p<0.05\), \(\ast\)\(p<0.01\), \(\ast\)\(\ast\)\(p<0.001\), ns: non-significant. Figure 8: _Cont._  
Figure 8: The interaction of selected analogs of phenolic acids with ERK depicted by molecular docking. (**A**). The binding modes of the phenolic acid analogs. **I. ** Alignment of selected analogs in the active site of ERK2. **II. ** Caffe acid interaction model. **III**. Analog **12** interaction model. The protein is shown as cartoon, ligand as sticks, and the interacting amino acids as lines. (**B**). The interaction models of selected phenolic acid analogs; **16**, **26**, **35**, **42**, Caffeic acid, and **44**. The protein is shown as cartoon, ligand as sticks, and the interacting amino acids as lines. Caffeic acid is given as the reference frame for comparison. Caffeic acid interacts through HB with Asp106 and Met108. It shows electrostatic contacts with Lys54, Gln105, Asp106 and Lys114. It exerts several hydrophobic contacts with Ile31, Gly34, Ala35, Val39, Ala52, Ile84, Leu107, Met108 and Leu156. Compound 12 exhibits these types of interactions with the surrounding amino acids; hydrogen bonds with Gln105, Asp106, and Met108, electrostatic type with Glu33, Lys54, Gln105, Asp106, Asp111, Lys114, Lys151, Asn154, Ser153, and Asp167, and hydrophobic contacts with Ile31, Gly34, Ala35, Val39, Ala52, Ile84, Leu107, Met108, Met109, Met111, Lys114, Lys151, Asn154, Ser155, and Asp167, and hydrophobic contacts with Ile31, Gly34, Ala35, Val39, Ala52, Ile84, Leu107, Met1108, Met112, Lys114, Lys151, Asn154, Ser153, and Asp167, and hydrophobic contacts with Ile31, Gly34, Ala35, Val39,  
Met108, and Leu156. Compound 26 interacts with Gln105, Asp106, and Met108 by hydrogen bonds. The polar amino acids Glu33, Lys54, Gln105, Asp106, Asp111, Lys114, and Ser153 interact electrostatically with compound 26. The hydrophobic contacts involve Tyr30, Ile31, Gly32, Gly34, Val39, Ala52, Ile84, Leu107, Met108, and Leu156.