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 (4a–h). Structure–Activity Relationship (SAR) analyses
showed that the combination of catechol-benzenesulfonamide in 4a (organic) and 4c (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 4a and 4c in 5-LOX showed their preferential localization at the allosteric
site and at the entry channel, respectively, consistent with their
noncompetitive (4a) and mixed (4c) kinetics.
Furthermore, the noncytotoxic complex 4c (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.