Generic placeholder image

Current Organic Synthesis


ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Research Article

Indol-2-Carboxylic Acid Esters Containing N-Phenylpiperazine Moiety - Preparation and Cholinesterase-inhibiting Activity

Author(s): Tereza Padrtová*, Pavlína Marvanová, Renáta Kubínová, Jozef Csöllei, Oldřich Farsa, Tomáš Goněc, Klára Odehnalová, Radka Opatřilová, Jiří Pazourek, Alice Sychrová, Karel Šmejkal and Petr Mokrý*

Volume 17 , Issue 7 , 2020

Page: [576 - 587] Pages: 12

DOI: 10.2174/1570179417666200619132218

Price: $65


Background: The indole derivatives and the N-phenylpiperazine fragment represent interesting molecular moieties suitable for the research of new potentially biologically active compounds. This study was undertaken to identify if indol-2-carboxylic acid esters containing N-phenylpiperazine moiety possess acetylcholinesterase and butyrylcholinesterase inhibitory activity.

Materials and Methods: The study dealt with the synthesis of a novel series of analogs of 1H-indole-2- carboxylic acid and 3-methyl-1H-indole-2-carboxylic acid. The structure of the derivatives was represented by the indolylcarbonyloxyaminopropanol skeleton with the attached N-phenylpiperazine or diethylamine moiety, which formed a basic part of the molecule. The final products were synthesized as dihydrochloride salts, fumaric acid salts, and quaternary ammonium salts. The first step of the synthetic pathway led to the preparation of esters of 1H-indole-2-carboxylic acid from the commercially available 1H-indole-2-carboxylic acid. The Fischer indole synthesis was used to synthesize derivatives of 3-methyl-1H-indole-2-carboxylic acid.

Results and Discussion: Final 18 indolylcarbonyloxyaminopropanols in the form of dihydrochlorides, fumarates, and quaternary ammonium salts were prepared using various optimization ways. The very efficient way for the formation of 3-methyl-1H-indole-2-carboxylate (Fischer indole cyclization product) was the one-pot synthesis of phenylhydrazine with methyl 2-oxobutanoate with acetic acid and sulphuric acid as catalysts.

Conclusion: Most of the derivatives comprised of an attached N-phenylpiperazine group, which formed a basic part of the molecule and in which the phenyl ring was substituted in position C-2 or C-4. The synthesized compounds were subjected to cholinesterase-inhibiting activity evaluation, by modified Ellman method. Quaternary ammonium salt of 1H-indole-2-carboxylic acid which contain N-phenylpiperazine fragment with nitro group in position C-4 (7c) demonstrated the most potent activity against acetylcholinesterase.

Keywords: Acetylcholinesterase, butyrylcholinesterase, Fischer indole synthesis, indoles, N-phenylpiperazine, T3P®.

Graphical Abstract
de Oliveira, J.S.; Abdalla, F.H.; Dornelles, G.L.; Adefegha, S.A.; Palma, T.V.; Signor, C.; da Silva Bernardi, J.; Baldissarelli, J.; Lenz, L.S.; Magni, L.P.; Rubin, M.A.; Pillat, M.M.; de Andrade, C.M. Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death. Neurotoxicology, 2016, 57, 241-250.
[] [PMID: 27746125]
Christen, Y. Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr., 2000, 71(2), 621S-629S.
[] [PMID: 10681270]
Hartman, D. Free radical theory of aging: Alzheimer’s disease pathogenesis. Age (Omaha), 1995, 18, 97-119.
Padrtova, T.; Marvanova, P.; Odehnalova, K.; Kubinova, R.; Parravicini, O.; Garro, A.; Enriz, R.D.; Humpa, O.; Oravec, M.; Mokry, P. Synthesis, Analysis, cholinesterase-inhibiting activity and molecular modelling studies of 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxy-carbonyl)amino]benzoates and their quaternary ammonium salts. Molecules, 2017, 22(12), 2048.
[] [PMID: 29168793]
Dvir, H.; Silman, I.; Harel, M.; Rosenberry, T.L.; Sussman, J.L. Acetylcholinesterase: From 3D structure to function. Chem. Biol. Interact., 2010, 187(1-3), 10-22.
[] [PMID: 20138030]
Colović, M.B.; Krstić, D.Z.; Lazarević-Pašti, T.D.; Bondžić, A.M.; Vasić, V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol., 2013, 11(3), 315-335.
[] [PMID: 24179466]
Ban, J.; Phillips, W.D. Mouse models of myasthenia gravis. Curr. Pharm. Des., 2015, 21(18), 2468-2486.
[] [PMID: 25777761]
Angelopoulou, E.; Paudel, Y.N.; Piperi, C. Unraveling the role of receptor for advanced glycation end products (RAGE) and its ligands in myasthenia gravis. ACS Chem. Neurosci., 2020, 11(5), 663-673.
[] [PMID: 32017530]
Gilhus, N.E.; Verschuuren, J.J. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol., 2015, 14(10), 1023-1036.
[] [PMID: 26376969]
Karasova, J.Z.; Hroch, M.; Musilek, K.; Kuca, K. Small quaternary inhibitors K298 and K524: Cholinesterases inhibition, absorption, brain distribution, and toxicity. Neurotox. Res., 2016, 29(2), 267-274.
[] [PMID: 26646154]
Farmakidis, C.; Pasnoor, M.; Dimachkie, M.M.; Barohn, R.J. Treatment of Myasthenia Gravis. Neurol. Clin., 2018, 36(2), 311-337.
[] [PMID: 29655452]
Lambrianides, S.; Kinnis, E.; Cleanthous, M.; Papacharalambous, R.; Panayiotou, E.; Zamba-Papanicolaou, E.; Kyriakides, T. A novel case of inclusion body myositis and myasthenia gravis. Neuromuscul. Disord., 2019, 29(10), 771-775.
[] [PMID: 31604651]
Chadha, N.; Silakari, O. Indoles as therapeutics of interest in medicinal chemistry: Bird’s eye view. Eur. J. Med. Chem., 2017, 134, 159-184.
[] [PMID: 28412530]
Dadashpour, S.; Emami, S. Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. Eur. J. Med. Chem., 2018, 150, 9-29.
[] [PMID: 29505935]
Desroses, M.; Wieckowski, K.; Stevens, M.; Odell, L.R. A microwave-assisted, propylphosphonic anhydride (T3P®) mediated one-pot Fischer indole synthesis. Tetrahedron Lett., 2011, 52(34), 4417-4420.
McAusland, D.; Seo, S.; Pintori, D.G.; Finlayson, J.; Greaney, M.F. The benzyne Fischer-indole reaction. Org. Lett., 2011, 13(14), 3667-3669.
[] [PMID: 21671610]
Gore, S.; Baskaran, S.; König, B. Fischer indole synthesis in low melting mixtures. Org. Lett., 2012, 14(17), 4568-4571.
[] [PMID: 22905733]
Maia, Rdo. C.; Tesch, R.; Fraga, C.A. Phenylpiperazine derivatives: A patent review (2006 - present). Expert Opin. Ther. Pat., 2012, 22(10), 1169-1178.
[] [PMID: 22957817]
Ritchie, T.J.; Macdonald, S.J. The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design? Drug Discov. Today, 2009, 14(21-22), 1011-1020.
[] [PMID: 19729075]
Pałczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C.A.; Motoshima, H.; Fox, B.A.; Le Trong, I.; Teller, D.C.; Okada, T.; Stenkamp, R.E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science, 2000, 289(5480), 739-745.
[] [PMID: 10926528]
Goněc, T.; Malík, I.; Csöllei, J.; Jampílek, J.; Stolaříková, J.; Solovič, I.; Mikuš, P.; Keltošová, S.; Kollár, P.; O’Mahony, J.; Coffey, A. Synthesis and in vitro antimycobacterial activity of novel n-arylpiperazines containing an ethane-1,2-diyl connecting chain. Molecules, 2017, 22(12), 2100.
[] [PMID: 29189762]
Marvanova, P.; Padrtova, T.; Pekarek, T.; Brus, J.; Czernek, J.; Mokry, P.; Humpa, O.; Oravec, M.; Jampilek, J. Synthesis and characterization of new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates and their hydrochloride salts. Molecules, 2016, 21(6), 707.
[] [PMID: 27258242]
Rüther, T.; Harris, K.R.; Horne, M.D.; Kanakubo, M.; Rodopoulos, T.; Veder, J-P.; Woolf, L.A. Transport, electrochemical and thermophysical properties of two N-donor-functionalised ionic liquids. Chemistry, 2013, 19(52), 17733-17744.
[] [PMID: 24288151]
Lu, X.; Cao, Q.; Wu, X.; Xie, H.; Lei, Q.; Fang, W. Conformational isomerism influence on the properties of piperazinium bis (trifluoromethylsulfonyl)imide. J. Phys. Chem. B, 2014, 118(30), 9085-9095.
[] [PMID: 25014126]
Pizova, H.; Bobal, P. An optimized and scalable synthesis of propylphosphonic anhydride for general use. Tetrahedron Lett., 2015, 56(15), 2014-2017.
Basavaprabhu; Vishwanatha, T.M.; Panguluri, N.R.; Sureshbabu, V.V. propanephosphonic acid anhydride (T3P®) - A benign reagent for diverse applications inclusive of large-scale synthesis. Synthesis, 2013, 45(12), 1569-1601.
Sakakura, T.; Hara, M.; Tanaka, M. Reaction of silyl enol ethers with arenediazonium salts. Part 2. α-Amination of esters. J. Chem. Soc., Perkin Trans. 1, 1994, 0(3), 289-293.
Fan, P.; Terrier, L.; Hay, A-E.; Marston, A.; Hostettmann, K. Antioxidant and enzyme inhibition amyloidogenesis. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 659-671.
[PMID: 28274151]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7(88), 88-95.
[] [PMID: 13726518]
Xie, Q.; Zheng, Z.; Shao, B.; Fu, W.; Xia, Z.; Li, W.; Sun, J.; Zheng, W.; Zhang, W.; Sheng, W.; Zhang, Q.; Chen, H.; Wang, H.; Qiua, Z. Pharmacophore-based design and discovery of (−)-meptazinol carbamates as dual modulators of cholinesterase and activities and chemical profiles of Polygonum sachalinensis F.Schmidt ex Maxim (Polygonaceae). Fitoterapia, 2010, 81(2), 124-131.
[] [PMID: 19698767]
Mokrý, P.; Zemanová, M.; Csöllei, J.; Racanská, E.; Tumová, I. Synthesis and pharmacological evaluation of novel potential ultrashort-acting beta-blockers. Pharmazie, 2003, 58(1), 18-21.
[PMID: 12622246]
Porcheddu, A.; Mura, M.G.; De Luca, L.; Pizzetti, M.; Taddei, M. From alcohols to indoles: A tandem Ru catalyzed hydrogen-transfer Fischer indole synthesis. Org. Lett., 2012, 14(23), 6112-6115.
[] [PMID: 23190207]
Scapecchi, S.; Marucci, G.; Matucci, R.; Angeli, P.; Bellucci, C.; Buccioni, M.; Dei, S.; Gualtieri, F.; Manetti, D.; Romanelli, M.N.; Teodori, E. Structure-activity relationships in 2,2-diphenyl-2-ethylthioacetic acid esters: Unexpected agonistic activity in a series of muscarinic antagonists. Bioorg. Med. Chem., 2001, 9(5), 1165-1174.
[] [PMID: 11377175]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy