α-Glucosidase inhibitory activity and cytotoxic effects of some cyclic urea and carbamate derivatives

Jelena B Popović-Djordjević,Ivana I Jevtić,Nadja Dj Grozdanić,Sandra B Šegan,Mario V Zlatović,Milovan D Ivanović,Tatjana P Stanojković

doi:10.1080/14756366.2016.1250754

Jelena B Popović-Djordjević, Ivana I Jevtić + Show 5 more

Open Access

https://doi.org/10.1080/14756366.2016.1250754

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Abstract

The inhibitory activities of selected cyclic urea and carbamate derivatives (1–13) toward α-glucosidase (α-Gls) in in vitro assay were examined in this study. All examined compounds showed higher inhibitory activity (IC50) against α-Gls compared to standard antidiabetic drug acarbose. The most potent was benzyl (3,4,5-trimethoxyphenyl)carbamate (12) with IC50 = 49.85 ± 0.10 µM. In vitro cytotoxicity of the investigated compounds was tested on three human cancer cell lines HeLa, A549 and MDA-MB-453 using MTT assay. The best antitumour activity was achieved with compound 2 (trans-5-phenethyl-1-phenylhexahydro-1H-imidazo[4,5-c]pyridin-2(3H)-one) against MDA-MB-453 human breast cancer cell line (IC50 = 83.41 ± 1.60 µM). Cyclic ureas and carbamates showed promising anti-α-glucosidase activity and should be further tested as potential antidiabetic drugs. The PLS model of preliminary QSAR study indicated that, in planing the future synthesis of more potent compounds, the newly designed should have the substituents capable of polar interactions with receptor sites in various positions, while avoiding the increase of their lipophilicity.

Highlights

Diabetes mellitus type 2 (DMT2) is an endocrine disease of global proportions which is currently affecting 1 out of 12 adults in the world, with still increasing prevalence[1]
Both the insulin resistance and the decrease in insulin production over time, allow the treatment of people suffering from DMT2 with a wide range of drugs that are available on the market[5]
Sulfonylureas, the metiglinides, insulin sensitizers, biguanides and a-glucosidase inhibitors belong to the group of traditional antidiabetics developed during the twentieth century[2,6] while the newer drugs such as GLP-1 analogs, DPP-VI inhibitors, amylin analogs and SGLT2 inhibitors emerged during the past decade[2,7]

Summary

Introduction

Diabetes mellitus type 2 (DMT2) is an endocrine disease of global proportions which is currently affecting 1 out of 12 adults in the world, with still increasing prevalence[1]. World Health Organization (WHO) declared this worldwide health problem as an epidemic disease to be the only noninfectious disease with such categorization[2] This deadly disease is associated with numerous side effects such as impairment of functions of kidneys, heart, eye and nervous system affecting carbohydrate, protein and fat metabolism[3]. The main classes of oral antidiabetic drugs accessible today for DMT2 vary in their chemical composition, modes of action, safety profiles and tolerability[4]. Both the insulin resistance and the decrease in insulin production over time, allow the treatment of people suffering from DMT2 with a wide range of drugs that are available on the market[5]. Sulfonylureas, the metiglinides, insulin sensitizers, biguanides and a-glucosidase inhibitors belong to the group of traditional antidiabetics developed during the twentieth century[2,6] while the newer drugs such as GLP-1 analogs, DPP-VI inhibitors, amylin analogs and SGLT2 inhibitors emerged during the past decade[2,7]

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