Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile

被引：60

作者：

Abdellatif, Khaled R. A. ^{[1
,2
]}

Fadaly, Wael A. A. ^{[1
]}

Elshaier, Yaseen A. M. M. ^{[3
]}

Ali, Waleed A. M. ^{[4
]}

Kamel, Gehan M. ^{[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] Al Azhar Univ, Fac Pharm, Pharmaceut Organ Chem Dept, Assiut 71524, Egypt

[4] Cairo Gen Hosp, Biochem Dept, Cairo, Egypt

[5] Cairo Univ, Fac Vet, Pharmacol Dept, Cairo, Egypt

来源：

BIOORGANIC CHEMISTRY | 2018年 / 77卷

关键词：

Anti-inflammatory; Pyrazole; Lonazolac; Cyclooxygenase-2; inhibitors; CYCLOOXYGENASE INHIBITION; ULCEROGENIC LIABILITY; BIOLOGICAL EVALUATION; AGENTS; CELECOXIB; DESIGN;

D O I：

10.1016/j.bioorg.2018.02.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 mu mol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 mu mol/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. (C) 2018 Elsevier Inc. All rights reserved.

引用

页码：568 / 578

页数：11

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