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

Abstract

In our previous research, a novel series of phenylsulfonyl hydrazide derivatives were found to reduce LPS-induced PGE(2) 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 PGE(2) assay studies showed that the kinetic product (7a and 7b; IC50 = 0.69 and 0.55 mu M against PGE(2)) is generally more potent than the thermodynamic product (8a and 8b; IC50 = >10 and 0.79 mu M against PGE(2)). 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 PGE(2) assay results. A new potent phenylsulfonyl hydrazide (7d; IC50 = 0.06 mu M against PGE2) without affecting COX-1 and COX-2 enzyme activities was identified based on these overall results. (C) 2016 Elsevier Ltd. All rights reserved.