Dehydrodieugenol Neolignans as Multitarget Anti-Inflammatory Agents: sPLA2 Inhibition and Therapeutic Implications

Background/Objectives: The study investigated the anti-inflammatory potential of neolignan derivatives of dehydrodieugenol (CP1–CP5), focusing on the inhibition of secretory phospholipase A2 (sPLA2), a key enzyme in inflammation. Methods: Comprehensive quantitative docking analysis using four independent algorithms (PLP, ASP, ChemScore, GoldScore) revealed exceptional multitarget binding profiles for CP1 and CP2, with scores consistently above activity thresholds for acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2), and sPLA2 from Crotalus durissus terrificus in both monomeric (Mcdt) and quaternary (Tcdt) forms. Results: Among the compounds, CP1 demonstrated the highest predicted affinity (AChE: 78.5, COX-2: 83.8, sPLA2: 82.7–83.4) and most potent experimental activity, reducing sPLA2 catalytic velocity through mixed-type inhibition involving the active site (His47, Asp48) and Ca2+ binding loop. In vivo assays in sPLA2-induced paw edema demonstrated that CP1 and CP2 achieved remarkable anti-inflammatory effects (up to 68.3% reduction), significantly exceeding their protective potential by direct enzyme inhibition, confirming the multitarget mechanism. The strong correlation between predicted docking scores and paw edema reduction (R2 = 0.89, p < 0.01) creates a firm foundation for establishing structure–activity relationship explanations. Conclusions: These findings highlight an integrated mechanism involving: (1) partial sPLA2 modulation, (2) neuroimmune regulation via AChE inhibition, and (3) prostaglandin synthesis blockade through COX-2 inhibition. This multitarget approach, combined with the natural origin of the compounds, positions dehydrodieugenol derivatives as promising candidates for developing therapies against complex inflammatory diseases, offering significant advantages over single-target strategies.