Design, Synthesis, and Evaluation of Organic and Organometallic Pyrazoline Derivatives as Selective Dual COX-2/5-LOX Inhibitors and Potential Anticancer Agents

Inspired by the structure of the anti-inflammatory drug Celecoxib, which is currently used in cancer prevention and treatment, we report the design, synthesis, and biological evaluation of organic and organometallic molecular hybrids based on pyrazolines (<b>4a</b>-<b>h</b>). Structure-Activity Relationship (SAR) analyses showed that the combination of catechol-benzenesulfonamide in <b>4a</b> (organic) and <b>4c</b> (ferrocenyl) derivatives acts as potent and highly selective dual inhibitors (IC₅₀ COX-2 = 4.58 and 2.88 μM; IC₅₀ 5-LOX = 0.23 and 0.10 μM, respectively; evaluated against COX-1 and 15-LOX isoforms). Molecular dynamics simulations of <b>4a</b> and <b>4c</b> in 5-LOX showed their preferential localization at the allosteric site and at the entry channel, respectively, consistent with their noncompetitive (<b>4a</b>) and mixed (<b>4c</b>) kinetics. Furthermore, the noncytotoxic complex <b>4c</b> (MRC-5, CC₅₀ = 38.13 μM) exhibited anticancer effects in ovarian cancer cells (A2780, CC₅₀ = 13.79 μM) that overexpress the proinflammatory enzymes COX-2 and 5-LOX (Western Blot), exceeding the activity of the drug Celecoxib.