Cholinesterase Inhibitory Activity, Kinetic and Molecular Docking Studies of N-(1-substituted-1H-1,2,3-triazole-4-yl)-aralkylamide Derivatives

Woralak PETRAT; Chatchai WATTANAPIROMSAKUL; Teerapat NUALNOI; Nadia Hanim SABRI; Vannajan Sanghiran LEE LEE; Luelak LOMLIM

Authors

Woralak PETRAT Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112
Chatchai WATTANAPIROMSAKUL Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112
Teerapat NUALNOI Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112
Nadia Hanim SABRI Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603
Vannajan Sanghiran LEE LEE Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603
Luelak LOMLIM Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112

Keywords:

1, 2, 3-triazole, acetylcholinesterase inhibitor, butyrylcholinesterase inhibitor, enzyme kinetic study, molecular docking

Abstract

Acetylcholinesterase (AChE) inhibitors are widely used for treatment of Alzheimer’s disease (AD). With the ultimate goal of improving the efficiency of AChE inhibitors currently used in AD treatment, in this study, a total number of 14 compounds of N-(1-substituted-1H-1,2,3-triazole-4-yl)-aralkylamide derivatives were designed, synthesized, and investigated for their AChE and butyrylcholinesterase (BuChE) inhibitory activities. The most potent AChE inhibitor in this series was 6e (IC₅₀ 15.01 mM against human AChE). The inhibition kinetics of 6e indicated that the compound was a noncompetitive inhibitor of acetylcholinesterase. A molecular docking study supported the idea that the aromatic moieties of 6e interacted with both a catalytic anionic site and a peripheral anionic site of acetylcholinesterase, while the 1,2,3-triazole ring also formed van der Waals and hydrogen bond interactions with the amino acid residues in the mid-gorge of the enzyme.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

References

A Lleó, SM Greengerg and JH Growdon. Current pharmacotherapy for Alzheimer’s disease. Annu.

Rev. Med. 2006; 57, 513-33.

NH Greig, T Utsuki, QS Yu, X Zhu, HW Holloway, TA Perry, B Lee, DK Ingram and DK Laniri. A

new therapeutic target in Alzheimer’s disease treatment: attention to butyrylcholinesterase. Curr. Med. Res. Opin. 2001; 17, 159-65.

GA Reid, N Chilukuri and S Darvesh. Butyrylcholinesterase and the cholinergic system. Neuroscience 2013; 234, 53-68.

JL Sussman, M Harel, F Frolow, and G Oefner, A Goldman, L Toker and I Silman. Atomic structure of acetylcholinesterase from Torpedo californica: A prototypic acetylcholine-binding protein. Science 1991; 253, 872-8.

D Muñoz-Torrero and P Camps. Dimeric and hybrid anti-alzheimer drug candidates. Curr. Med. Chem. 2006; 13: 399-22.

A Cavalli, ML Bolognesi, A Minarini, M Rosini, V Tumiatti, M Recanatini and C Melchiorre. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 2008; 51, 347-72.

TM Keck, AK Banala, RD Slack, C Burzynski, A Bonifazi, OM Okunola-Bakare, M Moore, JR Deschamps, R Rais, BS Slusher and AH Newman. Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands. Bioorg. Med. Chem. 2015; 23, 4000-12.

HM Faidallah, SS Panda, JC Serrano, AS Girgis, KA Khan, KA Alamry, T Therathanakorn, MJ Meyers, FM Sverdrup and CS Eickhoff. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates. Bioorg. Med. Chem. 2016; 24, 3527-39.

RR Ruddarraju, AC Murugulla, R Kotla, MCB Tirumalasetty, R Wudayagiri, S Donthabakthuni, R Maroju, K Baburao and LS Parasa. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives. Eur. J. Med. Chem. 2016; 123, 379-96.

A Ouach, F Pin, E Bertrand, J Vercouillie, Z Gulhan, C Mothes, JB Deloye, D Guilloteau, F Suzenet, S Chalon and S Routier. Design of 7 nicotinic acetylcholine receptor ligands using the (het) Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies. Eur. J. Med. Chem. 2016; 107, 153-64.

Y Bourne, HC Kolb, Z Radic, KB Sharpless, P Taylor and P Marchot. Freeze-frame inhibitors capture acetylcholinesterase in a unique conformation. Proc. Natl. Acad. Sci. USA. 2003; 101, 1449-54.

A Shi, L Huang, C Lu and X Li. Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and -amyloid aggregation inhibitors. Bioorg. Med. Chem. 2011; 19, 2298-305.

H Akrami, BF Mirjalili, M Khoobi, A Moradi, H Nadri, A Emami, A Foroumadi, M Vosooghi and A Shafiee. 9H-Carbazole derivatives containing the N-benzyl-1,2,3-triazole moiety as new acetylcholinesterase inhibitors. Arch. Pharm. Chem. Life Sci. 2015; 348, 366-74.

M Mohammadi-Khanaposhtani, M Saeedi, NS Zafarghandi, M Mahdavi, R Sabourian, EK Razkenari, H Alinezhad, M Khanavi, A Foroumadi, A Shafiee and T Akbarzadeh. Potent acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivatives. Eur. J. Med. Chem. 2015; 92, 799-806.

SM Bagheri, M Khoobi, H Nadri, A Moradi, S Emami, L Jalili-Balen, F Jafarpour, FH Moghadam, A Foroumadi and A Shafiee. Synthesis and anticholinergic activity of 4-hydroxycoumarin derivatives containing substituted benzyl-1,2,3-triazole moiety. Chem. Biol. Drug. Des. 2015; 86, 1215-20.

M Mohammadi-Khanaposhtani, M Mahdavi, M Saeedi, R Sabourian, M Safavi, M Khanavi, A Foroumadi, A Shafiee and T Akbarzadeh. Design, synthesis, biological evaluation, and docking study of acetylcholinesterase inhibitors: New acridone-1,2,4-oxadiazole-1,2,3-triazole hybrids. Chem. Biol. Drug. Des. 2015; 86, 1425-32.

JC Li, J Zhang, MC Rodrigues, DJ Ding, JPF Longo, RC Azevedo, LA Muehlmann and CS Jiang. Synthesis and evaluation of novel 1,2,3-triazole-based acetylcholinesterase inhibitors with neuroprotective activity. Bioorg. Med. Chem. Lett. 2016; 26, 3881-5.

W Petrat, C Wattanapiromsakul and L Lomlim. Design and synthesis of N-(1-benzyl-1H-1,2,3-triazole-4-yl)-benzamide derivatives as acetylcholinesterase inhibitor. In: Proceedings of the 1st ASEAN Plus Three Graduate Research Congress. Chiang Mai, Thailand, 2012, p. 539-44.

GL Ellman, KD Courtney, V Andres and RM Featherstone. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961; 7, 88-95.

MJ Frisch, GW Trucks, HB Schlegel, GE Scuseria, MA Robb, JR Cheeseman, G Scalmani, V Barone, B Mennucci, GA Petersson, H Nakatsuji, M Caricato, X Li, HP Hratchian, AF Izmaylov, J Bloino, G Zheng, JL Sonnenberg, M Hada, M Ehara, K Toyota, R Fukuda, J Hasegawa, M Ishida, T Nakajima, Y Honda, O Kitao, H Nakai, T Vreven, JA Montgomery, JE Peralta, F Ogliaro, M Bearpark, JJ Heyd, E Brothers, KN Kudin, VN Staroverov, R Kobayashi, J Normand, K Raghavachari, A Rendell, JC Burant, SS Iyengar, J Tomasi, M Cossi, N Rega, JM Millam, M Klene, JE Knox, JB Cross, V Bakken, C Adamo, J Jaramillo, R Gomperts, RE Stratmann, O Yazyev, AJ Austin, R Cammi, C Pomelli, JW Ochterski, RL Martin, K Morokuma, VG Zakrzewski, GA Voth, P Salvador, JJ Dannenberg, S Dapprich, AD Daniels, Ö Farkas, JB Foresman, JV Ortiz, J Cioslowski and DJ Fox. Gaussian 09, Revision C.01. Gaussian, Wallingford CT, 2010.

TA Halgren. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem. 1996; 17, 490-519.

H Sugimoto, H Ogura, Y Arai, Y Iimura and Y Yamanishi. Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn. J. Pharmacol. 2002; 89, 7-20.

S Simon, A Le Goff, Y Frobert, J Grassi and J Massoulie. The binding sites of inhibitory monoclonal antibodies on acetylcholinesterase. J. Biol. Chem. 1999; 274, 27740-6.

F Belluti, L Piazzi, A Bisi, S Gobbi, M Bartolini, A Cavalli, P Valenti and A Rampa. Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors. Eur. J. Med. Chem. 2009; 44, 1341-8.