Design, synthesis, biological evaluation and molecular modeling of dihydropyrazole sulfonamide derivatives as potential COX-1/COX-2 inhibitors

Zhong Chen; Zhong-Chang Wang; Xiao-Qiang Yan; Peng-Fei Wang; Xiao-Yuan Lu; Long-Wang Chen; Hai-Liang Zhu; Hong-Wei Zhang

doi:10.1016/j.bmcl.2015.03.022

Design, synthesis, biological evaluation and molecular modeling of dihydropyrazole sulfonamide derivatives as potential COX-1/COX-2 inhibitors

Bioorg Med Chem Lett. 2015 May 1;25(9):1947-51. doi: 10.1016/j.bmcl.2015.03.022. Epub 2015 Mar 22.

Authors

Zhong Chen¹, Zhong-Chang Wang², Xiao-Qiang Yan², Peng-Fei Wang², Xiao-Yuan Lu², Long-Wang Chen², Hai-Liang Zhu³, Hong-Wei Zhang⁴

Affiliations

¹ Department of Plastic and Burn Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 21003, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
⁴ Department of Plastic and Burn Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 21003, People's Republic of China. Electronic address: zhanghw1966@aliyun.com.

PMID: 25866240
DOI: 10.1016/j.bmcl.2015.03.022

Abstract

Novel dihydropyrazole sulfonamide derivatives (30-56) were designed, synthesized, and evaluated for their biological activities as COX-1 and COX-2 inhibitors. In vitro biological evaluation against three human tumor cell lines revealed that most target compounds showed antiproliferative activities. Among the compounds, compound 48 exhibited the most potent and selective COX-2 inhibitor (COX-2 IC50=0.33 μM; COX-1 IC50=68.49 μM) relative to the reference drugs celecoxib (IC50=0.052 μM). Docking simulation was performed to position compound 48 into the COX-2 active site and the result showed that compound 48 could bind well at the COX-2 active site and it indicated that compound 48 could be a potent and selective COX-2 inhibitor.

Keywords: Anticancer; COX-1/COX-2; Dihydropyrazole sulfonamide; Docking; MTT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclooxygenase 1 / metabolism*
Cyclooxygenase 2 / metabolism*
Cyclooxygenase Inhibitors / chemical synthesis
Cyclooxygenase Inhibitors / chemistry*
Cyclooxygenase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
HeLa Cells
Humans
MCF-7 Cells
Models, Molecular*
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Antineoplastic Agents
Cyclooxygenase Inhibitors
Pyrazoles
Sulfonamides
Cyclooxygenase 1
Cyclooxygenase 2