N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2.

Maria A Theodoropoulou,Martin Erhardt,Andrea Huwiler,George Kokotos,Anna-Dimitra D Gerogiannopoulou,Daiki Hayashi,Anastasia Psarra,Dimitra Hadjipavlou-Litina,Edward A Dennis,Aikaterini Nikolaou

doi:10.3390/biom12020267

Abstract

The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. 2-Aminobenzothiazoles, either acylated by the 3-(naphthalen-2-yl)propanoyl moiety (GK510) or N-alkylated by a chain carrying a naphthalene (GK543) or a phenyl moiety (GK562) at a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. Thus, N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation.

Highlights

IntroductionThe quest for novel agents to regulate the generation of prostaglandin E2 (PGE2 ) is of high importance because this eicosanoid is a key player in inflammatory diseases
Inspired by thiazolyl ketones exhibiting an interesting ability to inhibit prostaglandin E2 (PGE2) formation and in vivo anti-inflammatory properties [19], we have most recently presented a series of α-ketoheterocycles and we have demonstrated that the α-ketobenzothiazole derivative GK181 (1, Figure 1a) and α-ketobenzoxazole derivative GK491 (2, Figure 1a) inhibit PGE2 formation in rat mesangial cells with half maximal effective concentrations (EC50 ) values of 0.71 μM and 0.79 μM, respectively [21]
A series of N-acylated 2-aminobenzothiazoles, benzoxazoles and benzimidazoles were synthesized by the general coupling procedures depicted in Scheme 1

Summary

Introduction

The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2 ) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. At a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation.

Methods

Results

Conclusion