Design,synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors |
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| Institution: | 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. Pharmacology Department, Faculty of Veterinary, Cairo University, Cairo, Egypt;4. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit 71524, Egypt;5. Anatomy Department, Faculty of Veterinary Medicine, Kafrelshiekh University, Kafrelshiekh, 33516, Egypt;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. Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan;2. Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan;3. Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;4. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan;1. Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Chodzki 4A, 20-093, Lublin, Poland;2. Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Medical University of Lublin, Chodzki 1, 20-093, Lublin, Poland;1. Department of Pharmaceutical Chemistry, Institute of Pharmacy, MET’s Bhujbal Knowledge City, Nashik, Maharashtra, India;2. Department of Applied Chemistry, Priydarshini College of Engineering, Nagpur, Maharashtra, India;3. Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India;1. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur, MS, 416013, India;2. Department of Quality Assurance, Bharati Vidyapeeth College of Pharmacy, Kolhapur, MS, 416013, India;3. Annasaheb Dange College of D. Pharmacy, Ashta, MS, 416301, India;1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Universitario Annunziata, Viale SS. Annunziata, 98168 Messina, Italy;2. Department of Biology, Biochemistry Unit, University of Pisa, Via S. Zeno, 51, 56123 Pisa, Italy;3. Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy;4. Institute of Pharmacy, Computer-Aided Molecular Design, Freie Universitaet Berlin, Koenigin-Luisestr. 2+4, 14195 Berlin, Germany |
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| Abstract: | Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, β- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69–9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and β-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for β-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for β-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs. |
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| Keywords: | Thiazolidine Pyrazole Cyclooxygenase-2 inhibitors Anti-inflammatory Anti-diabetic PPARγ |
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