Synthesis and evaluation of dithiolethiones as novel cyclooxygenase inhibitors |
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Authors: | Shannon D Zanatta David T Manallack Bevyn Jarrott Spencer J Williams |
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Institution: | 1. Howard Florey Institute, Parkville, Vic. 3010, Australia;2. School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Rd, Parkville, Vic. 3010, Australia;3. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde Parkville, Vic. 3052, Australia;4. Department of Pharmacology, University of Melbourne, Parkville, Vic. 3010, Australia |
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Abstract: | 3H-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. |
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