2. Academic Validation
  3. Synthesis, biological evaluation, and docking analysis of a novel family of 1-methyl-1H-pyrrole-2,5-diones as highly potent and selective cyclooxygenase-2 (COX-2) inhibitors

Synthesis, biological evaluation, and docking analysis of a novel family of 1-methyl-1H-pyrrole-2,5-diones as highly potent and selective cyclooxygenase-2 (COX-2) inhibitors

  • Bioorg Med Chem Lett. 2014 Apr 15;24(8):1958-62. doi: 10.1016/j.bmcl.2014.02.074.
Kyung Ju Kim 1,  Min Ji Choi 1,  Ji-Sun Shin 2,  Minju Kim 1,  Hye-Eun Choi 2,  Seoung Mook Kang 1,  Jae Ho Jin 1,  Kyung-Tae Lee 3,  Jae Yeol Lee 4
Affiliations

Affiliations

  • 1 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea.
  • 2 Department of Life and Nanopharmaceutical Science, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
  • 3 Department of Life and Nanopharmaceutical Science, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
  • 4 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: ljy@khu.ac.kr.
PMID: 24656662 DOI: 10.1016/j.bmcl.2014.02.074
Abstract

As a continuous research for discovery of new COX-2 inhibitors, we present the simple chemical synthesis, in vitro biological screening, and molecular docking study of 1H-pyrrole-2,5-dione derivatives. New synthetic compounds were evaluated for the inhibitory activities on LPS-induced PGE2 production in RAW 264.7 macrophage cells as well as the COX-1 and COX-2 inhibitory potency. Among them, compound 9d (MPO-0029) was identified as more potent and selective COX-2 Inhibitor [PGE2 IC50=8.7 nM, COX-2 IC50=6.0 nM; COX-2 selectivity index (SI)=>168] than celecoxib. Molecular docking experiments were further performed against COX-2 and COX-1 isozymes to determine their probable binding models. Results of molecular docking studies revealed that compound 9d (MPO-0029) has stronger binding interaction with COX-2 than with COX-1 isozyme, and provided successfully complementary theoretical support for the obtained experimental biological data.

Keywords

1-Methyl-1H-pyrrole-2,5-dione; Cyclooxygenase-2; Inflammation; Molecular docking study; Prostaglandin E(2).

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