Determination of the inhibitory effects of N-methylpyrrole derivatives on glutathione reductase enzyme

Esma Kocaoğlu,Oktay Talaz,Hüseyin Çavdar,Murat Şentürk,Claudiu T Supuran,Deniz Ekinci

doi:10.1080/14756366.2018.1520228

Abstract

Glutathione reductase (GR) is a crucial antioxidant enzyme which is responsible for the maintenance of antioxidant GSH molecule. Antimalarial effects of some chemical molecules are attributed to their inhibition of GR, thus inhibitors of this enzyme are expected to be promising candidates for the treatment of malaria. In this work, GR inhibitory properties of N-Methylpyrrole derivatives are reported. It was found that all compounds have better inhibitory activity than the strong GR inhibitor N,N-bis(2-chloroethyl)-N-nitrosourea, especially three molecules, 8 m, 8 n, and 8 q, were determined to be the most powerful among them. Findings of our study indicates that these Schiff base derivatives are strong GR inhibitors which can be used as leads for designation of novel antimalarial candidates.

Highlights

In aerobic organisms, free radicals are produced via normal reactions in the metabolism and can be generated in the form of reactive oxygen species (ROS), such as superoxide anion radicals (O2À), hydroxyl radical (OH), hydrogen peroxide (H2O2), and etc
If the equilibrium between ROS and antioxidant defence system stops working properly, the reactive oxygen species cause cell damage which results in several diseases including cancer, cardiovascular diseases, age related degenerative diseases, arthritis, and diabetes[1,2,3]
A new irreversible Glutathione reductase (GR) inhibitor 2-acetylamino-3-[4–(2-acetylamino-2-carboxyethyl sulfanyl thiocarbonyl amino) phenyl thiocarbamoyl sulfanyl] propionic acid (2-AAPA) was selected in this study and this study showed that 2-AAPA increased anticancer activity, NADPH/ NADPþ and NADH/NADþ ratios, increased GSSG and decreased GSH and inhibited yeast GR8–11

Summary

Introduction

Free radicals are produced via normal reactions in the metabolism and can be generated in the form of reactive oxygen species (ROS), such as superoxide anion radicals (O2À), hydroxyl radical (OH), hydrogen peroxide (H2O2), and etc. Glutathione reductase reduces GSSG to GSH with NADPH and the intracellular ratio of GSH/GSSG remains above 99%. A new irreversible GR inhibitor 2-acetylamino-3-[4–(2-acetylamino-2-carboxyethyl sulfanyl thiocarbonyl amino) phenyl thiocarbamoyl sulfanyl] propionic acid (2-AAPA) was selected in this study and this study showed that 2-AAPA increased anticancer activity, NADPH/ NADPþ and NADH/NADþ ratios, increased GSSG and decreased GSH and inhibited yeast GR8–11.

Results

Conclusion