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

  • J Med Chem. 2026 Jan 22;69(2):1387-1402. doi: 10.1021/acs.jmedchem.5c02815.
Elizabeth Navarrete  1 ,  Tomás Cáceres M  1 ,  Pilar Morales  1 ,  Michelle Muñoz-Osses  1  2 ,  Olivier Blacque  3 ,  Pierre Mesdom  4 ,  Kevin Cariou  4 ,  Fernando Godoy  5 ,  Gilles Gasser  4 ,  Erick Flores  6 ,  Carolina Mascayano  1
Affiliations
  • 1. Departamento de Ciencias del Ambiente, Universidad de Santiago de Chile, Santiago 9170022, Chile.
  • 2. Faculty of Chemistry and Biochemistry, Inorganic Chemistry I - Bioinorganic Chemistry, Ruhr-Universität Bochum, Universitätsstrasse 150, Bochum 44780, Germany.
  • 3. Department of Chemistry, X-ray Crystallography Facility, University of Zürich, Zürich 8057, Switzerland.
  • 4. Chimie ParisTech, PSL University, Centre National de la Recherche Scientifique (CNRS), Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, Paris 75005, France.
  • 5. Departamento Química de los Materiales, Universidad de Santiago de Chile, Santiago 9170022, Chile.
  • 6. Instituto de Química, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile.
PMID: 41500666 DOI: 10.1021/acs.jmedchem.5c02815
Abstract

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.

Products