Synthesis and evaluation of dithiolethiones as novel cyclooxygenase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2009-01, Vol.19 (2), p.459-461
• Main Authors: Zanatta, Shannon D., Manallack, David T., Jarrott, Bevyn, Williams, Spencer J.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Catalytic Domain; Cyclooxygenase; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - drug effects; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - drug effects; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Dithiolethiones; Drug Evaluation, Preclinical; Hydrogen Bonding; Inhibitor; Medical sciences; Modelling; Models, Molecular; Pharmacology. Drug treatments; Thiones - chemical synthesis; Thiones - chemistry; Thiones - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.11.045

3 H-1,2-Dithiole-3-thiones substituted with a 3,5-di- tert-butyl-4-hydroxyphenyl (DTBHP) or a 3,5-di- tert-butyl-4-methoxyphenyl group at the C5 position were prepared and their ability to inhibit the cyclooxygenase isoenzymes, COX-1 and COX-2 was evaluated. Both compounds were potent inhibitors of COX-2 (relative to rofecoxib), and while the phenol was a weak inhibitor of COX-1, the methyl ether gave no measurable inhibition. Docking studies of the two compounds into the COX-1 and -2 active sites showed that the methyl ether could only fit in the COX-2 active site whereas the phenol could be docked into both COX-1 and -2. This study reports a new mode for inhibitor binding to COX-1 and -2 and a novel structural scaffold for the development of COX-2 selective inhibitors.