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Bioorg Med Chem Lett. 2016 Nov 1;26(21):5193-5197. doi: 10.1016/j.bmcl.2016.09.070. Epub 2016 Sep 29.

Synthesis, structure determination, and biological evaluation of phenylsulfonyl hydrazide derivatives as potential anti-inflammatory agents.

Author information

1
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
2
Korea Institute of Science and Technology, PO Box 131, Cheongyang, Seoul 02792, Republic of Korea.
3
Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
4
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
5
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany.
6
Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
7
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ljy@khu.ac.kr.

Abstract

In our previous research, a novel series of phenylsulfonyl hydrazide derivatives were found to reduce LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. Recently, it was found that a regioisomeric mixture of phenylsulfonyl hydrazide was formed depending on the reaction conditions, which favor either of two regioisomers. One regioisomer corresponds to a kinetic product (7a-7c) and the other regioisomer corresponds to a thermodynamic product (8a-8c). Among them, the structure of kinetic product 7b was confirmed by measuring single X-ray crystallography. In vitro PGE2 assay studies showed that the kinetic product (7a and 7b; IC50=0.69 and 0.55μM against PGE2) is generally more potent than the thermodynamic product (8a and 8b; IC50=>10 and 0.79μM against PGE2). A molecular docking study also exhibited that the kinetic product (7a) has a higher MolDock Score (-147.4) than that of 8a (-142.4), which is consistent with the PGE2 assay results. A new potent phenylsulfonyl hydrazide (7d; IC50=0.06μM against PGE2) without affecting COX-1 and COX-2 enzyme activities was identified based on these overall results.

KEYWORDS:

Inflammation; Molecular docking study; Prostaglandin E(2); Regioisomers; X-ray crystallography

PMID:
27720548
DOI:
10.1016/j.bmcl.2016.09.070
[Indexed for MEDLINE]

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