Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity,anti-inflammatory activity and gastric safety profile |
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| Affiliation: | 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;2. Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Saudi Arabia;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt;4. Biochemistry Department, Cairo General Hospital, Cairo, Egypt;5. Pharmacology Department, Faculty of Veterinary, Cairo University, Cairo, Egypt;1. Department of Chemistry, St Berchmans College (Autonomous), Changanassery, Kerala, India;2. Department of Physics, Fatima Mata National College (Autonomous), Kollam, Kerala, India;3. Department of Chemistry, Mangalore University, Mangalagangothri, Karnataka, India;4. Department of Industrial Chemistry, Mangalore University, Mangalagangothri, Karnataka, India;5. Department of Chemistry, Arinagar Anna Government Arts College, Musiri PO, Thiruchirapalli, Tamil Nadu, India;6. Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020, Antwerp, Belgium;1. Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan;2. Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;3. School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;4. Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;5. Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;6. Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 41354, Taiwan;7. Division of Metabolism, Department of Internal Medicine, China Medical University, Taichung 40402, Taiwan;1. Cairo University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Cairo, Egypt;2. October 6 University (O6U), Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, 6th of October City, Giza, Egypt;3. Al-Azhar University, Faculty of Pharmacy, Organic Chemistry Department (Girls), Cairo, Egypt;4. Misr University for Science and Technology, Faculty of Pharmacy, Organic Chemistry Department, Giza, Egypt;5. Modern University for Technology and Information, Faculty of Pharmacy, Organic Chemistry Department, Cairo, Egypt;1. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India;2. Centre for Bioinformatics, M.D University, Rohtak, Haryana, India;1. Department of Pharmaceutical Chemistry, KLE University’s College of Pharmacy, Nehrunagar, Belgaum 590 010, Karnataka, India;2. Regional Medical Research Centre (ICMR), Nehrunagar, Belgaum, Karnataka, India;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Chennai 03, India |
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| Abstract: | Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50 = 15.06, 42.51 and 50.43 μmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 μmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72–3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features. |
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| Keywords: | Anti-inflammatory Pyrazole Lonazolac Cyclooxygenase-2 inhibitors |
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