Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold |
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| Institution: | 1. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf-2014, Saudi Arabia;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;3. Chemistry Department, Faculty of Science, Jouf University, P.O. Box, 2014, Aljouf, Saudi Arabia;4. Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt;5. Department of Pharmacology and Toxicology, Beni-Suef University, Beni-Suef 62514, Egypt;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Chemistry, Faculty of Science and Technology, Al-Neelain University, Khartoum, Sudan;3. Department of Biochemistry, College of Science, King Saud University, PO Box 22452, Riyadh 11451, Saudi Arabia;1. Laboratório de Química Aplicada à Bioativos, Centro de Ciências Químicas, Farmacêuticas e de Alimento, Universidade Federal de Pelotas, Brazil;2. Laboratório do Grupo de Estudos em Doenças Transmitidas por Animais, Faculdade de Veterinária, Universidade Federal de Pelotas, Brazil;3. Laboratório de Virologia, Faculdade de Veterinária, Universidade Federal de Pelotas, Brazil;4. Laboratório de Desenvolvimento de Fármacos, Instituto de Química e Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, Brazil;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt;1. College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt;3. Department of Veterinary Medicine, College of Agricultural and Veterinary Medicine, Qassim University, Saudi Arabia;4. Department of Pharmacology, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt;5. Department of Chemistry, University of Prince Edward Island, Charlottetown, Prince Edward Island C1A 4P3, Canada |
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| Abstract: | Novel candidates of thiazolo4,5-d]pyrimidines (9a-l) were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g) was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC50 = 0.87–3.78 µM), in particular, the derivatives 9e (IC50 = 0.92 µM), 9g (IC50 = 0.87 µM) and 9k (IC50 = 1.02 µM) recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC50 = 1.11 µM). The in vivo potent compounds (9e, 9g and 9k) caused variable ulceration effect (ulcer index = 5–12.25) in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k) to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme. |
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| Keywords: | Thiazolidine Anti-inflammatory Cox-2 inhibitors |
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