Discovery of novel thiazole derivatives containing pyrazole scaffold as PPAR-γ Agonists, α-Glucosidase, α-Amylase and COX-2 inhibitors; Design, synthesis and in silico study.

Autor: Fadaly WAA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt., Elshewy A; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini street 11562, Cairo, Egypt; Department of Natural and Applied Sciences, College of Arts and Sciences, The American University of Iraq-Baghdad (AUIB), Baghdad, Iraq., Nemr MTM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini street 11562, Cairo, Egypt. Electronic address: Mohamed.nemr@pharma.cu.edu.eg., Abdou K; Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Sayed AM; Department of Pharmacognosy, Collage of Pharmacy, Almaaqal University, 61014 Basrah, Iraq., Kahk NM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Nov; Vol. 152, pp. 107760. Date of Electronic Publication: 2024 Aug 25.
DOI: 10.1016/j.bioorg.2024.107760
Abstrakt: A novel series of thiazole derivatives with pyrazole scaffold 16a-l as hybrid rosiglitazone/celecoxib analogs was designed, synthesized and tested for its PPAR-γ activation, α-glucosidase, α-amylase and COX-2 inhibitory activities. Regarding the anti-diabetic activity, all compounds were assessed in vitro against PPAR-γ activation, α-glucosidase and α-amylase inhibition in addition to in vivo hypoglycemic activity (one day and 15 days studies). Compounds 16b, 16c, 16e and 16 k showed good PPAR-γ activation (activation % ≈ 72-79 %) compared to that of the reference drug rosiglitazone (74 %). In addition, the same derivatives 16b, 16c, 16e and 16 k showed the highest inhibitory activities against α-glucosidase (IC 50  = 0.158, 0.314, 0.305, 0.128 μM, respectively) and against α-amylase (IC 50  = 32.46, 23.21, 7.74, 35.85 μM, respectively) compared to the reference drug acarbose (IC 50  = 0.161 and 31.46 μM for α-glucosidase and α-amylase, respectively). The most active derivatives 16b, 16c, 16e and 16 k also revealed good in vivo hypoglycemic effect comparable to that of rosiglitazone. In addition, compounds 16b and 16c had the best COX-2 selectivity index (S.I. = 18.7, 31.7, respectively) compared to celecoxib (S.I. = 10.3). In vivo anti-inflammatory activity of the target derivatives 16b, 16c, 16e and 16 k supported the results of in vitro screening as the derivatives 16b and 16c (ED 50  = 8.2 and 24 mg/kg, respectively) were more potent than celecoxib (ED 50  = 30 mg/kg). In silico docking, ADME, toxicity, and molecular dynamic studies were carried out to explain the interactions of the most active anti-diabetic and anti-inflammatory compounds 16b, 16c, 16e and 16 k with the target enzymes in addition to their physiochemical parameters.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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