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Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 7303096, 11 pages
https://doi.org/10.1155/2017/7303096
Research Article

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

1Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland
2Students Research Group, Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland
3Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland
4School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, POB 1627 70211 Kuopio, Finland

Correspondence should be addressed to Magdalena Markowicz-Piasecka; lp.zdol.demu@zciwokram.aneladgam

Received 11 March 2017; Revised 5 June 2017; Accepted 14 June 2017; Published 9 July 2017

Academic Editor: Eduardo L. G. Moreira

Copyright © 2017 Magdalena Markowicz-Piasecka et al. 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.

Abstract

The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer’s disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.