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The Ameliorating Effect of Phenylsulfonamide Derivatives on Scopolamine-Induced Memory Impairment in Mice via Inhibition of mPGES-1

1
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Korea
2
Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 02447, Korea
3
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea
*
Author to whom correspondence should be addressed.
Presented at the 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery, Barcelona, Spain, 15–17 May 2019.
Proceedings 2019, 22(1), 36; https://doi.org/10.3390/proceedings2019022036
Published: 7 August 2019
(This article belongs to the Proceedings of The Molecules Medicinal Chemistry Symposium)
PDF [146 KB, uploaded 7 August 2019]

Abstract

Our previous research showed that a novel series of phenylsulfonyl hydrazide derivatives reduced LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. As a continuous work, new phenylsulfonamide derivatives (5a-5k) as methylene analogues of phenylsulfonyl hydrazide derivatives, including MPO-0063, were synthesized and biologically evaluated in vitro. Among synthetic compounds, 5a (MPO-0112) showed decreased inhibitory activity against PGE2 production (IC50: 0.34 µM) compared to MPO-0063 (IC50: 0.04 µM) but inhibited the mPGES-1 enzyme (IC50: 7.37 µM) similar to MPO-0063 (IC50: 0.10 µM) together with excellent selectivity over COX-enzymes (COX-1 and 2). According to recent studies on the close correlation between up-regulation of mPGES-1 and Alzheimer's disease, we investigated whether 5a could ameliorate scopolamine-induced memory impairment using the passive avoidance test. The memory impairment-ameliorating effect of 5a (1.0 mg/kg, p.o.) was found to be effective, comparable to that of donepezil (5 mg/kg, p.o.) as a positive control. On the other hand, 5a exhibited little or weak AChE and BuChE inhibitory activity, which implies that 5a could ameliorate scopolamine-induced memory impairment by inhibiting mPGES-1 enzyme instead of cholinesterase enzymes. In addition, MPO-0112 exhibited a favorable in vitro CYP profile, which is suggestive of no potential drug–drug interactions. Therefore, these overall results suggest that 5a as a selective mPGES-1 inhibitor may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer’s disease.
Keywords: mPGES-1; phenylsulfonamide derivatives; Memory Impairment mPGES-1; phenylsulfonamide derivatives; Memory Impairment
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Ryu, K.D.; Moon, Y.H.; Ko, D.H.; Lee, K.-T.; Lee, J.Y. The Ameliorating Effect of Phenylsulfonamide Derivatives on Scopolamine-Induced Memory Impairment in Mice via Inhibition of mPGES-1. Proceedings 2019, 22, 36.

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