Molecular design,synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2 |
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Authors: | Ibrahim A Al-Suwaidan Amer M Alanazi Adel S El-Azab Abdulrahman M Al-Obaid Kamal EH ElTahir Azza R Maarouf Mohamed A Abu El-Enin Alaa A-M Abdel-Aziz |
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Institution: | 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;2. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;3. Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;4. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt |
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Abstract: | A group of cyclic imides (1–10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1–4.0 μM. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 8a as a highly potent (IC50 = 0.1 μM), and an extremely selective COX-2 (SI) > 1000] comparable to celecoxib COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50 = 72.4 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln192(2.95 Å), Phe518(2.82 Å) and Arg513(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. |
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Keywords: | Cyclic imides Benzenesulfonamide COX-2 inhibitors Anti-inflammatory activities Molecular docking |
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