Synthesis, Pharmacological Evaluation, Molecular Docking, and In Silico ADMET Profiling of Novel Ibuprofen–Chalcone Hybrids as Potent Anti-Inflammatory Agents

Abstract

Abstract Objective: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are severely limited by systemic toxicities. To address these constraints, we designed and synthesized a novel series of ibuprofen–chalcone hybrid molecules, capitalizing on a molecular hybridization strategy to merge the core therapeutic pharmacophore of ibuprofen with the versatile, highly biocompatible scaffolds of chalcone derivatives. Methods: We comprehensively characterized the synthesized hybrids using robust spectroscopic techniques. Their biological efficacy was validated via systematic in vitro assays evaluating cyclooxygenase (COX-1/COX-2) inhibition and antioxidant capacities, followed by rigorous in vivo models of anti-inflammatory kinetics, analgesic potencies, and acute ulcerogenic safety profiles. Complementary mechanistic insights were obtained through in silico molecular docking experiments and predictive ADMET profiling. Results and Discussion: Our screening identified compound 6c as the lead candidate, exhibiting highly potent dual COX inhibition (COX-1 IC50 = 1.77 ± 0.01 μM; COX-2 IC50 = 9.17 ± 0.04 μM). Calculation of the selectivity index (SI = COX-2 IC50/COX-1 IC50 = 5.18) confirmed a pronounced preferential affinity for the COX-1 isoform. Crucially, in vivo functional assays demonstrated that compound 6c elicits superior anti-inflammatory and analgesic activities compared to parent ibuprofen, while concomitantly abrogating classic NSAID-induced gastric irritation. Radical scavenging metrics confirmed robust antioxidant functionality across the hybrid series. Molecular docking trajectories corroborated these phenotypic outcomes, revealing highly favorable structural binding conformations and optimal interaction energies within the catalytic pockets of both COX isoforms. Furthermore, predictive in silico ADMET simulations forecasted excellent drug-like characteristics, high oral bioavailability, and a favorable safety margin with minimal systemic toxicity indices for the lead hybrids. Conclusions: Taken together, our findings demonstrate that these novel ibuprofen–chalcone hybrids represent a highly promising therapeutic class of anti-inflammatory leads capable of circumventing the pathological side effects that typically hamper traditional NSAID regimens. These results strongly warrant subsequent preclinical validation and expanded structure–activity relationship (SAR) optimizations.