Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors

• Published in: European journal of medicinal chemistry 2004-02, Vol.39 (2), p.141-151
• Main Authors: MARTIC, Miljen, TATIC, Iva, MARKOVIC, Stribor, KUJUNDZIC, Nedjeljko, KOSTRUN, Sanja
• Format: Article
• Language: English
• Subjects: ADME; Adsorption; Benzoates - chemistry; Benzoates - metabolism; Benzoates - pharmacology; Binding Sites; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; COX-1; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacokinetics; Cyclooxygenase Inhibitors - pharmacology; Docking; Drug Design; Enzyme Activation - drug effects; Ethane - analogs & derivatives; Ethane - chemistry; Ethane - metabolism; Ethane - pharmacology; Ibuprofen; Ibuprofen - pharmacology; Isoenzymes - antagonists & inhibitors; Ketoprofen; Ketoprofen - pharmacology; Ligands; Medical sciences; Models, Molecular; Molecular Conformation; NSAID; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2003.11.011

Synthesis of new potential COX-1 and/or COX-2 inhibitors, derivatives of 1,1-di-(3-carboxyphenyl)ethane, their biological activity, docking results on COX-1 enzyme and absorption, distribution, metabolism, excretion (ADME) properties are presented. In addition to known interactions between ketoprofen and ibuprofen, leading NSAID agents and COX-1 active site, the possibility of formation of additional interactions is explored. Interactions with Ala527, and with one of the water molecules situated within the active site are identified. Molecular mechanics and DFT calculations for studied compounds have revealed free rotation around two central bonds (C 1–C 3′ and C 1–C 3″), making them flexible, thus easier to enter and adjust to the active site. Further modifications of core structure have been undertaken to optimize biological activity and ADME properties. As a result, two of the compounds are indicated as novel COX-1 inhibitors.