Development of indanones and isatins as non-cytotoxic inhibitors of cholinesterases

Authors

  • Josephine M. Gießel Martin-Luther Universitaet Halle-Wittenberg
  • Anne Loesche Martin-Luther Universitaet Halle-Wittenberg
  • Sophie Hoenke Martin-Luther Universitaet Halle-Wittenberg
  • Immo Serbian Martin-Luther Universitaet Halle-Wittenberg
  • Ahmed Al-Harrasi University of Nizwa
  • Rene Csuk Martin-Luther Universitaet Halle-Wittenberg http://orcid.org/0000-0001-7911-290X

DOI:

https://doi.org/10.13171/mjc10202002161233rc

Abstract

A small library of indanone-amides and substituted isatin derivatives has been prepared; these compounds have been investigated for their ability to act as inhibitors for the enzymes acetyl- and butyrylcholinesterase (AChE, BChE). Several of them were moderate inhibitors for AChE and not cytotoxic for a variety of human tumor cell lines as well as for non-malignant mouse fibroblasts. In this library consisting of 49 derivatives, 5,7-dibromo-4-iodoisatin was shown to be a good mixed-type inhibitor for AChE (K­i = 2.52 ± 0.61 µM and Ki´ = 11.74 ± 1.31 µM) but this compound also acted as a dual inhibitor for BChE (Ki = 4.49 ± 0.32 µM and Ki´ = 6.56 ± 0.57 µM). Interestingly, N-hexyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide was cytotoxic especially for MCF-7 breast adenocarcinoma cells (EC50 = 4.28 ± 0.5 µM).

Author Biography

Rene Csuk, Martin-Luther Universitaet Halle-Wittenberg

Organic ChemistryHead of Department

References

- I. Łozińska, A. Świerczyńska, Z. Molęda, A. M. Hartman, A. K. H. Hirsch, Z. Czarnocki, Donepezil-melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments, Arch. Pharm., 2018, 1800194.

- P. Costanzo, L. Cariati, D. Desiderio, R. Sgammato,

A. Lamberti, R. Arcone, R. Salerno, M. Nardi, M. Masullo, M. Oliverio, Design, Synthesis, and Evaluation of Donepezil-Like Compounds as AChE and BACE-1 Inhibitors, ACS Med. Chem. Lett., 2016, 7, 470-475.

- K. O. Yerdelen, M. Koca, B. Anil, H. Sevindik, Z. Kasap, Z. Halici, K. Turkaydin, G. Gunesacar, Synthesis of donepezil-based multifunctional agents for the treatment of Alzheimer’s disease, Bioorg. Med. Chem. Lett., 2015, 25, 5576-5582.

- M. Koca, K. O. Yerdelen, B. Anil, Z. Kasap, H. Sevindik, I. Ozyurek, G. Gunesacar, K. Turkaydin, Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents, J. Enzyme Inhib. Med. Chem., 2016, 31, 13-23.

- M. S. Altowyan, M. Ali, S. M. Soliman, A. M. Al-Majid, M. S. Islam, S, Yousuf, M. I. Choudhary, H. A. Ghabbour, A. Barakat, Synthesis, computational studies and biological activity of oxamohydrazide derivatives bearing isatin and ferrocene scaffolds, J. Mol. Struct., 2020, 1202, 127372.

- A. V. Bogdanov, I. F. Zaripova, A. D. Voloshina, A. S. Sapunova, N. V. Kulik, I. V. Tsivunina, A. B. Dorbrynin, V. F. Mironov, J. Fluorine Chem., 2019, 227, 109345.

- M. M. H. Arief, W. I. A. El-Dougdoug, M. A. Sayed, Synthesis of some new isatin derivatives of expected biological activities, J. Basic Environm. Sci., 2019, 6, 149-155.

- T. Sandmeyer, Über Isonitrosoacetanilide und deren Kondensation zu Isatinen, Helv. Chim. Acta, 1919, 2, 234-242.

- Y. S. Tingare, M. T. Shen, C. Su, S. Y. Ho, S. H. Tsai, B. -R. Chen, W. R. Li, Novel Oxindole Based Sensitizers: Synthesis and Application in Dye-Sensitized Solar Cells, Org. Lett., 2013, 15, 4292-4295.

- J. B. Campbell, E. J. Warawa, Preparation and formulation of heterocyclic fused tricyclic compounds as anxiolytics, EP245053A119871111.

- L. -S. Feng, M. -L. Liu, S. Zhang, Y. Chai, B. Wang, Y.-B. Zhang, K. Lv, Y. Guan, H. -Y. Guo, C. -L. Xiao, Synthesis and in vitro antimycobacterial activity of 8-OCH3 ciprofloxacin methylene and ethylene isatin derivatives, Eur. J. Med. Chem., 2011, 46, 341-348.

- Z. Wang, C. Wang, Y. Sun, N. Zhang, Z. Liu, J. Liu, A novel strategy to the synthesis of 4-anilinoquinazoline derivatives, Tetrahedron, 2014, 70, 906-913.

- P. Polychronopoulos, P. Magiatis, A. L. Skaltsounis, V. Myrianthopoulos, E. Mikros, A. Tarricone, A. Musacchio, S.M. Roe, L. Pearl, M. Leost, P. Greengard, L. Meijer, Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases, J. Med. Chem., 2004, 47, 935-946.

- G. L. Ellman, K. D. Courtney, V. J. Andres, R. M. Featherstone, A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem. Pharmacol., 1961, 7, 88-95.

- A. Loesche, A. Kowitsch, R. Csuk, S. D. Lucas, Z. Al-Halabi, W. Sippl, A. Al-Harrasi, Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential, Bioorg. Chem., 2018, 85, 23-32.

- S. Liu, W. Wei, Y. Li, X. Liu, X. Cao, K. Lei, M. Zhou, Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents, Eur. J. Med. Chem., 2015, 95, 473-482.

- Suresh, D. Kumar, J. S. Sandhu, Bismuth(III) Chloride–Mediated, Efficient, Solvent-Free, MWI-Enhanced Doebner Condensation for the Synthesis of (E)-Cinnamic Acids, Synth. Commun., 2010, 40, 1915-1919.

- T. Takahashi, M. Miyazawa, Tyrosinase inhibitory activities of cinnamic acid analogues, Pharmazie, 2010, 65, 913-918.

- K. Kindler, K. Lührs, Studien über den Mechanismus chemischer Reaktionen, XXII. (Über Hydrierungen und über spezifische Hydrierungen mittels gebundenen Wasserstoffs, VI). Hydrierungen mittels Terpenen, Ann. Chem., 1965, 685, 36-48.

- J. Koo, The Synthesis of 4,5,6-Trimethoxyindene- and 4,5,6-Trimethoxyindanecarboxylic Acids and Esters, J. Am. Chem. Soc., 1953, 75, 1889-1891.

- C. Pan, X. Zeng, Y. Guan, X. Jiang, L. Li, H. Zhang, Design and Synthesis of Brazilin-Like Compounds, Synlett, 2011, 425-429.

- T. M. Harris, C. R. Hauser, Benzylation at the Terminal Methyl Group of Certain Unsymmetrical β-Diketones Through One of Two Possible Intermediate Dicarbanions, J. Am. Chem. Soc., 1959, 81, 1160-1164.

- T. Dohi, N. Takenaga, A. Goto, H. Fujioka, Y. Kita, Clean and Efficient Benzylic C−H Oxidation in Water Using a Hypervalent Iodine Reagent: Activation of Polymeric Iodosobenzene with KBr in the Presence of Montmorillonite-K10, J. Org. Chem., 2008, 73, 7365-7368.

- A. Romeo, H. Corrodi, E. Hardegger, Umsetzungen des

o-Nitrophenylessigesters und des 2-Chlor-6-nitro-phenyl-brenztraubensäureesters, Helv. Chim. Acta, 1955, 38, 463-467.

- S. B. Kadin, Preparation and formulation of analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds, US4690943A19870901.

- M. E. Matheus, F. D. A. Violante, S. J. Garden, A. C. Pinto, P. D. Fernandes, Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line, Eur. J. Pharmacol., 2007, 556, 200-206.

- K. C. Joshi, V. N. Pathak, S. K. Jain, Studies of potential organo-fluorine antibacterial agents. Part 5: Synthesis and antibacterial activity of some new fluorine-containing indole-2,3-dione derivatives, Pharmazie, 1980, 35, 677-679.

- B. R. Baker, R. E. Schaub, J. P. Joseph, F. J. McEvoy, J. H. Williams, An antimalarial alkaloid from hydrangea. XV. Synthesis of 5-, 6-, 7-, and

-derivatives with two identical substituents, J. Org. Chem., 1952, 17, 149-156.

- L. Ettinger, P. Friedländer, Über 6.6′-Dibrom-indirubin, Ber. Dt. Chem. Ges., 1912, 45, 2081-2083.

- S. Inagaki, Diphenylisatin and its derivatives. IV. Monobromo derivatives of dianisoleisatin and its oxidation product, Yakugaku Zasshi, 1938, 58,

-975.

- A. Beauchard, H. Laborie, H. Rouillard, O. Lozach, Y. Ferandin, R. L. Guével, C. Guguen-Guillouzo, L. Meijer, T. Besson, V. Thiéry, Synthesis and kinase inhibitory activity of novel substituted indigoids, Bioorg. Med. Chem., 2009, 17, 6257-6263.

- F. Ziegler, T. Kappe, R. Salvador, Synthesen von Heterocyclen, 44. Mitt.: Eine Synthese des Isatins, Monatsh. Chem., 1963, 94, 453-459.

- C. A. Fetscher, M. T. Bogert, Researches on quinaolines. XLIV. The synthesis of some new quinazoline derivatives of veratrole akin to alkaloids, J. Org. Chem., 1939, 4, 71-87.

- J. Gray, D. R. Waring, 3-Amino-2,1-benzoisothiazole. Synthesis of some chloro and trifluoromethyl derivatives, J. Heterocycl. Chem., 1980, 17, 65-67.

- D. H. Klaubert, J. H. Sellstedt, C. J. Guinosso, R. J. Capetola, S. C. Bell, N-(Aminophenyl)oxamic acids and esters as potent, orally active antiallergy agents, J. Med. Chem., 1981, 24, 742-748.

- G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew, D. S. Goodsell, A. J. Olson, AutoDock and AutoDockTools: Automated docking with selective receptor flexibility, J. Comput. Chem., 2009, 30, 2785-2791

Downloads

Published

2020-02-18

Issue

Vol. 10 No. 2 (2020)

Section

Medicinal Chemistry

License

Authors who publish with this journal agree to the following terms:

    1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal
    2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal
    3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).