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

被引：90
作者：
Abdellatif, Khaled R. A. [1 ,2 ]
Fadaly, Wael A. A. [1 ]
Kamel, Gehan M. [3 ]
Elshaier, Yaseen A. M. M. [4 ]
El-Magd, Mohammed A. [5 ]
机构：
[1] Beni Suef Univ, Fac Pharm, Pharmaceut Organ Chem Dept, Bani Suwayf, Egypt
[2] Ibn Sina Natl Coll Med Studies, Pharmaceut Sci Dept, Jeddah 21418, Saudi Arabia
[3] Cairo Univ, Fac Vet, Pharmacol Dept, Cairo, Egypt
[4] Al Azhar Univ, Pharmaceut Organ Chem Dept, Fac Pharm, Assiut 71524, Egypt
[5] Kafrelshiekh Univ, Anat Dept, Fac Vet Med, Kafrelshiekh 33516, Egypt
来源：
BIOORGANIC CHEMISTRY | 2019年 / 82卷
关键词：
Thiazolidine; Pyrazole; Cyclooxygenase-2; inhibitors; Anti-inflammatory; Anti-diabetic; PPAR gamma; PROLIFERATOR-ACTIVATED RECEPTORS; CYCLOOXYGENASE-2; INHIBITORS; MOLECULAR DOCKING; INFLAMMATION; GLUCOSIDASE; REGULATOR; DISCOVERY; ANALOGS; RAT;
D O I：
10.1016/j.bioorg.2018.09.034
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 antidiabetic 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 alpha-glucosidase, beta-glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPAR. 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 alpha- and beta-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for alpha-glucosidase and 57.42, 60.07, 58.19, 66.90 for beta-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for alpha-glucosidase and D-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for beta-glucosidase) and also showed good PPAR-gamma 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.
引用
收藏
页码：86 / 99
页数：14
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