Novel Sunifiram-carbamate Hybrids As Potential Dual Acetylcholinesterase Inhibitor and NMDAR Co-agonist: Simulation-guided Analogue Design and Pharmacological Screening

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2022 Apr 29

PMID 35484855

Authors

Khalid A Agha

Nader E Abo-Dya

Abdul Rashid Issahaku

Clement Agoni

Mahmoud E S Soliman

Eatedal H Abdel-Aal

Zakaria K Abdel-Samii

Tarek S Ibrahim

Affiliations

Soon will be listed here.

Abstract

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields protecting group-free stepwise unsymmetric diacylation of piperazine using -acylbenzotiazole. Compounds , and exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid was found to exhibit higher potency than donepezil with IC = 18 ± 0.2 nM, 29.9 ± 0.15 nM for and donepezil, respectively. was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds and are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.

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References

Gualtieri F . Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings. J Enzyme Inhib Med Chem. 2015; 31(2):187-94. DOI: 10.3109/14756366.2015.1021252. View

Gumus M, Ozgur A, Tutar L, Disli A, Koca I, Tutar Y . Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis. Curr Pharm Biotechnol. 2016; 17(14):1231-1245. DOI: 10.2174/1389201017666161031105815. View

Lau J, Brown K, Dasgupta P . Measurement of Acetylcholine from Cell Lines. Bio Protoc. 2016; 3(24). PMC: 4932865. DOI: 10.21769/bioprotoc.1007. View

Cummings K, Popescu G . Glycine-dependent activation of NMDA receptors. J Gen Physiol. 2015; 145(6):513-27. PMC: 4442789. DOI: 10.1085/jgp.201411302. View

Hanwell M, Curtis D, Lonie D, Vandermeersch T, Zurek E, Hutchison G . Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform. 2012; 4(1):17. PMC: 3542060. DOI: 10.1186/1758-2946-4-17. View

Rowland L, Astur R, Jung R, Bustillo J, Lauriello J, Yeo R . Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology. 2005; 30(3):633-9. DOI: 10.1038/sj.npp.1300642. View

Scatena R, Martorana G, Bottoni P, Botta G, Pastore P, Giardina B . An update on pharmacological approaches to neurodegenerative diseases. Expert Opin Investig Drugs. 2006; 16(1):59-72. DOI: 10.1517/13543784.16.1.59. View

Stockert J, Horobin R, Colombo L, Blazquez-Castro A . Tetrazolium salts and formazan products in Cell Biology: Viability assessment, fluorescence imaging, and labeling perspectives. Acta Histochem. 2018; 120(3):159-167. DOI: 10.1016/j.acthis.2018.02.005. View

Dallakyan S, Olson A . Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015; 1263:243-50. DOI: 10.1007/978-1-4939-2269-7_19. View

10.

Klopman G, Stefan L, Saiakhov R . ADME evaluation. 2. A computer model for the prediction of intestinal absorption in humans. Eur J Pharm Sci. 2002; 17(4-5):253-63. DOI: 10.1016/s0928-0987(02)00219-1. View

11.

Manetti D, Ghelardini C, Bartolini A, Dei S, Galeotti N, Gualtieri F . Molecular simplification of 1,4-diazabicyclo[4.3.0]nonan-9-ones gives piperazine derivatives that maintain high nootropic activity. J Med Chem. 2000; 43(23):4499-507. DOI: 10.1021/jm000972h. View

12.

Yao L, Zhou Q . Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators. Neural Plast. 2017; 2017:2875904. PMC: 5253171. DOI: 10.1155/2017/2875904. View

13.

Lau J, Brown K, Thornhill B, Crabtree C, Dom A, Witte T . Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma. Cancer Res. 2012; 73(4):1328-39. PMC: 10461321. DOI: 10.1158/0008-5472.CAN-12-3190. View

14.

Perry E, Walker M, Grace J, Perry R . Acetylcholine in mind: a neurotransmitter correlate of consciousness?. Trends Neurosci. 1999; 22(6):273-80. DOI: 10.1016/s0166-2236(98)01361-7. View

15.

Jang C, Yadav D, Subedi L, Venkatesan R, Venkanna A, Afzal S . Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay. Sci Rep. 2018; 8(1):14921. PMC: 6175823. DOI: 10.1038/s41598-018-33354-6. View

16.

Martina M, Gorfinkel Y, Halman S, Lowe J, Periyalwar P, Schmidt C . Glycine transporter type 1 blockade changes NMDA receptor-mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels. J Physiol. 2004; 557(Pt 2):489-500. PMC: 1665089. DOI: 10.1113/jphysiol.2004.063321. View

17.

Lin J, Lu A . Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev. 1998; 49(4):403-49. View

18.

Pagadala N, Syed K, Tuszynski J . Software for molecular docking: a review. Biophys Rev. 2017; 9(2):91-102. PMC: 5425816. DOI: 10.1007/s12551-016-0247-1. View

19.

Olney J, Farber N . Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995; 52(12):998-1007. DOI: 10.1001/archpsyc.1995.03950240016004. View

20.

Deutsch S, Tang A, Burket J, Benson A . NMDA receptors on the surface of cancer cells: target for chemotherapy?. Biomed Pharmacother. 2014; 68(4):493-6. PMC: 5581960. DOI: 10.1016/j.biopha.2014.03.012. View