DDCH

Diclofenac, a widely used nonsteroidal anti-inflammatory drug (NSAID), is effective in treating pain and inflammation and has also shown potential as an anticancer agent, primarily through cyclooxygenase-2 (COX-2) inhibition. However, its therapeutic application is often limited by adverse effects, necessitating the development of new derivatives with improved pharmacological profiles. In this study, two novel diclofenac hydrazide-imine derivatives, DDCH (cyclohexanone-based) and DDAC (acetylacetone-based), were synthesized, structurally characterized, and evaluated through combined computational and experimental approaches. Density functional theory (DFT) calculations provided transition-state and energy profile analyses, while molecular docking and molecular dynamics (MD) simulations established stable interactions of both derivatives with COX-2 and heat shock protein 90 (HSP90), a key oncogenic chaperone. DDAC exhibited particularly strong binding to HSP90, suggesting enhanced anticancer potential compared with diclofenac. In silico drug-likeness and ADME assessments, including Lipinski's Rule of Five, predicted favorable pharmacokinetic properties. Experimental evaluation confirmed anti-inflammatory efficacy: in vitro protein denaturation assays showed that DDAC display inhibition comparable to diclofenac, while in vivo carrageenan-induced paw edema studies demonstrated significant activity for both derivatives. Collectively, these findings confirm that DDCH and DDAC retain anti-inflammatory properties while offering predicted anticancer potential, with DDAC emerging as the more promising dual-action candidate. This work establishes a rational framework for the further optimization and pharmacological development of diclofenac-based analogues targeting both inflammation and cancer.