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Medicinal Chemistry Research

, Volume 27, Issue 9, pp 2187–2198 | Cite as

Isoindolines/isoindoline-1,3-diones as AChE inhibitors against Alzheimer’s disease, evaluated by an improved ultra-micro assay

  • Erik Andrade-Jorge
  • Luis A. Sánchez-Labastida
  • Marvin A. Soriano-Ursúa
  • Juan A. Guevara-SalazarEmail author
  • José G. Trujillo-FerraraEmail author
Original Research
  • 75 Downloads

Abstract

Alzheimer’s disease (AD), the most common form of dementia, is characterized by a progressive degeneration of the brain that leads to loss of memory and deterioration of others cognitive functions. The only drugs currently approved for treating AD are AChE inhibitors (AChEIs). We previously tested a novel isoindoline-1,3-dione, finding potent inhibition of AChE, in part because the two carbonyl groups of phthalimide facilitate hydrogen bonds with the enzyme. The aims of the present study were: (A) To achieve a faster and cheaper technique with a reduced quantity of reactive, without significant difference in the validation of the results, by modifying the version of the method described by Bonting and Featherstone. (B) To test new isoindolines and dioxoisoindolines as AChEIs and see if the carbonyl group is really important for affinity. Both families of compounds (isoindolines and dioxoisoindolines) had an inhibitory effect. The enzymatic inhibitions produced by isoindolines were uncompetitive, whereas that evoked by dioxoisoindolines were competitive. One of the isoindoline derivatives (IsoB with a Ki of 88–160µM) showed about 5-fold greater inhibition of AChE than its corresponding dioxoisoindoline. According to molecular docking performed, dioxoisoindolines apparently interact with the catalytic active site, the peripheral anionic site, and the aromatic patch, which can explain the kind of inhibition observed. Due to the uncompetitive inhibition of isoindolines, their inhibitory behavior could not be explored in silico. We afforded a faster and more efficient method, while yielding similar results than Bonting and Featherstone method. Additionally, we demonstrated that carbonyl group affects the kind of inhibition and the affinity.

Keywords

Alzheimer’s disease AChE 2,3-Dihydro-1H-isoindoles N-substituted phthalimide Molecular docking 

Notes

Acknowledgements

This work was supported by SIP (m1930), Instituto Politécnico Nacional, and by CONACYT-Mexico.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Achary R, Jung I-A, Son S-M, Lee H-K (2017) Stereoselective synthesis of functionalized 1,3-disubstituted isoindolines via Rh(III)-catalyzed tandem oxidative olefination-cyclization of 4-aryl-cyclic sulfamidate-5-carboxylates. J Org Chem.  https://doi.org/10.1021/acs.joc.7b00799
  2. Aliabadi A, Foroumadi A, Mohammadi-Farani A (2013) Synthesis and evaluation of anti-acetylcholinesterase Alzheimer effects. Iran J Basic Med Sci 16:1049–1054PubMedPubMedCentralGoogle Scholar
  3. Alipour M, Khoobi M, Foroumadi A, Nadri H, Moradi A, Sakhteman A, Ghandi M, Shafiee A (2012) Novel coumarin derivatives bearing N-benzyl pyridinium moiety: potent and dual binding site acetylcholinesterase inhibitors. Bioorganic Med Chem 20:7214–7222.  https://doi.org/10.1016/j.bmc.2012.08.052 CrossRefGoogle Scholar
  4. Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer’s disease. Arch Pharm Res 36:375–399.  https://doi.org/10.1007/s12272-013-0036-3 CrossRefPubMedGoogle Scholar
  5. Andrade-Jorge E, Bahena-Herrera JR, Garcia-Gamez J, Padilla-Martínez II, Trujillo-Ferrara JG (2017) Novel synthesis of isoindoline/isoindoline-1,3-dione derivatives under solventless conditions and evaluation with the human D2 receptor. Med Chem Res 26:2420–2431.  https://doi.org/10.1007/s00044-017-1942-6 CrossRefGoogle Scholar
  6. Andrade-Jorge E, Bribiesca-Carlos J, Martínez-Martínez FJ, Soriano-Ursúa MA, Padilla-Martínez II, Trujillo-Ferrara JG (2018) Crystal structure, DFT calculations and evaluation of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione as AChE inhibitor. Chem Cent J 12:74.  https://doi.org/10.1186/s13065-018-0442-1 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bajda M, Więckowska A, Hebda M, Guzior N, Sotriffer C, Malawska B (2013) Structure-based search for new inhibitors of cholinesterases. Int J Mol Sci 14:5608–5632.  https://doi.org/10.3390/ijms14035608 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Barnard EA (1974) Neuromuscular transmission—enzymatic destruction of acetylcholine. In:Hubbard J.I. (eds) The peripheral nervous system. Springer, Boston, MA, pp 201–224Google Scholar
  9. Barrio P, Ibáñez I, Herrera L, Román R, Catalán S, Fustero S (2015) Asymmetric synthesis of fluorinated isoindolinones through palladium-catalyzed carbonylative amination of enantioenriched benzylic carbamates. Chemistry 21:11579–11584.  https://doi.org/10.1002/chem.201500773 CrossRefPubMedGoogle Scholar
  10. Birks JS (2006) Cholinesterase inhibitors for Alzheimer’s disease. In: Birks JS (ed) Cochrane database of systematic reviews. John Wiley & Sons, Ltd., Chichester, p CD005593Google Scholar
  11. Bonting SL, Featherstone RM (1956) Ultramicro assay of the cholinesterases. Arch Biochem Biophys 61:89–98.  https://doi.org/10.1016/0003-9861(56)90319-8 CrossRefPubMedGoogle Scholar
  12. Bourne Y, Grassi J, Bougis PE, Marchot P (1999) Conformational flexibility of the acetylcholinesterase tetramer suggested by X-ray crystallography. J Biol Chem 274:30370–30376.  https://doi.org/10.1074/jbc.274.43.30370 CrossRefPubMedGoogle Scholar
  13. Çizmecioğlu M, Pabuççuoğlu V, Ballar P, Pabuççuoğlu A, Soyer Z (2011) Synthesis and screening of cyclooxygenase inhibitory activity of some 1,3-dioxoisoindoline derivatives. Arzneimittelforschung 61:186–190.  https://doi.org/10.1055/s-0031-1296187 CrossRefGoogle Scholar
  14. Czarnecka K, Szymański P, Girek M, Mikiciuk-Olasik E, Skibiński R, Kabziński J, Majsterek I, Malawska B, Jończyk J, Bajda M (2017) Tetrahydroacridine derivatives with fluorobenzoic acid moiety as multifunctional agents for Alzheimer’s disease treatment. Bioorg Chem 72:315–322.  https://doi.org/10.1016/j.bioorg.2017.05.003 CrossRefPubMedGoogle Scholar
  15. Davood A, Shafaroodi H, Amini M, Nematollahi A, Shirazi M, Iman M (2012) Design, synthesis and protection against pentylenetetrazole-induced seizure of N-aryl derivatives of the phthalimide pharmacophore. Med Chem 8:953–963.  https://doi.org/10.2174/157340612802084289 CrossRefPubMedGoogle Scholar
  16. Duthey B (2013) Background Paper 6. 11 Alzheimer disease and other dementias, update on 2004. World Heal Organ 1–77Google Scholar
  17. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL (2010) Acetylcholinesterase: from 3D structure to function. Chem Biol Interact 187:10–22.  https://doi.org/10.1016/j.cbi.2010.01.042 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95.  https://doi.org/10.1016/0006-2952(61)90145-9 CrossRefPubMedGoogle Scholar
  19. Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ (2016) Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc 11:905–919CrossRefPubMedPubMedCentralGoogle Scholar
  20. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J (2009) Gaussian 09, Revision E. 01; Gaussian, Inc., Wallingford, CTGoogle Scholar
  21. Grathwohl SA, Kälin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12:1361–1363.  https://doi.org/10.1038/nn.2432 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gupta S, Mohan CG (2014) Dual binding site and selective acetylcholinesterase inhibitors derived from integrated pharmacophore models and sequential virtual screening. Biomed Res Int 2014:291214.  https://doi.org/10.1155/2014/291214 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Guzior N, Bajda M, Skrok M, Kurpiewska K, Lewiński K, Brus B, Pišlar A, Kos J, Gobec S, Malawska B (2015) Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties. Eur J Med Chem 92:738–749.  https://doi.org/10.1016/j.ejmech.2015.01.027 CrossRefPubMedGoogle Scholar
  24. Guzior N, Wieckowska A, Panek D, Malawska B (2014) Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr Med Chem 22:373–404.  https://doi.org/10.2174/0929867321666141106122628 CrossRefGoogle Scholar
  25. Hebda M, Bajda M, Więckowska A, Szałaj N, Pasieka A, Panek D, Godyń J, Wichur T, Knez D, Gobec S, Malawska B (2016) Synthesis, molecular modelling and biological evaluation of novel heterodimeric, multiple ligands targeting cholinesterases and amyloid beta. Molecules 21:1–24.  https://doi.org/10.3390/molecules21040410 CrossRefGoogle Scholar
  26. Heneka MT, Carson MJ, Khoury JEl, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405.  https://doi.org/10.1016/S1474-4422(15)70016-5 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38.  https://doi.org/10.1016/0263-7855(96)00018-5 CrossRefPubMedGoogle Scholar
  28. Ibach B, Haen E (2004) Acetylcholinesterase inhibition in Alzheimer’s disease. Curr Pharm Des 10:231–251.  https://doi.org/10.2174/1381612043386509 CrossRefPubMedGoogle Scholar
  29. Ignasik M, Bajda M, Guzior N, Prinz M, Holzgrabe U, Malawska B (2012) Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors. Arch Pharm 345:509–516.  https://doi.org/10.1002/ardp.201100423 CrossRefGoogle Scholar
  30. Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656–664.  https://doi.org/10.2174/156720510793611592 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kamkwalala A, Newhouse P (2016) Beyond acetylcholinesterase inhibitors: novel cholinergic treatments for Alzheimer’s disease. Curr Alzheimer Res 13:1–1.  https://doi.org/10.2174/1567205013666160930112625 CrossRefGoogle Scholar
  32. Kiametis AS, Silva MA, Romeiro LAS, Martins JBL, Gargano R (2017) Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction. J Mol Model 23:67–72.  https://doi.org/10.1007/s00894-017-3228-9 CrossRefPubMedGoogle Scholar
  33. Kim HS, Kim Y, Doddareddy MR, Seo SH, Rhim H, Tae J, Pae AN, Choo H, Cho YS (2007) Design, synthesis, and biological evaluation of 1,3-dioxoisoindoline-5-carboxamide derivatives as T-type calcium channel blockers. Bioorg Med Chem Lett 17:476–481.  https://doi.org/10.1016/j.bmcl.2006.10.042 CrossRefPubMedGoogle Scholar
  34. Korolev I (2014) Alzheimer’s disease: a clinical and basic science review. Med Stud Res J 4:24–33Google Scholar
  35. Kukkola PJ, Bilci NA, Ikler T, Savage P, Shetty SS, DelGrande D, Jeng AY (2001) Isoindolines: a new series of potent and selective endothelin—a receptor antagonists. Bioorg Med Chem Lett 11:1737–1740.  https://doi.org/10.1016/S0960-894X(01)00273-6 CrossRefPubMedGoogle Scholar
  36. Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67:195–203.  https://doi.org/10.1016/j.pharep.2014.09.004 CrossRefPubMedGoogle Scholar
  37. Lahiri DK, Farlow MR, Greig NH, Sambamurti K (2002) Current drug targets for Alzheimer’s disease treatment. Drug Dev Res 56:267–281.  https://doi.org/10.1002/ddr.10081 CrossRefGoogle Scholar
  38. Li F, Liu Y, Yuan Y, Yang B, Liu Z, Huang L (2017) Molecular interaction studies of acetylcholinesterase with potential acetylcholinesterase inhibitors from the root of Rhodiola crenulata using molecular docking and isothermal titration calorimetry methods. Int J Biol Macromol 104:527–532.  https://doi.org/10.1016/j.ijbiomac.2017.06.066 CrossRefPubMedGoogle Scholar
  39. Mandelkow E-M, Mandelkow E (1994) Tau protein and Alzheimer’s disease. Neurobiol Aging 15:85–86.  https://doi.org/10.1016/0197-4580(94)90178-3 CrossRefGoogle Scholar
  40. Mary A, Renko DZ, Guillou C, Thal C (1998) Potent acetylcholinesterase inhibitors: design, synthesis, and structure–activity relationships of bis-interacting ligands in the galanthamine series. Bioorg Med Chem 6:1835–1850.  https://doi.org/10.1016/S0968-0896(98)00133-3 CrossRefPubMedGoogle Scholar
  41. Mohammadi-Farani A, Abdi N, Moradi A, Aliabadi A (2017) 2-(2-(4-Benzoylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives: synthesis, docking and acetylcholinesterase inhibitory evaluation as anti-alzheimer agents. Iran J Basic Med Sci 20:59–66.  https://doi.org/10.22038/ijbms.2017.8095 PubMedPubMedCentralCrossRefGoogle Scholar
  42. Mohammadi-Farani A, Ahmadi A, Nadri H, Aliabadi A (2013) Synthesis, docking and acetylcholinesterase inhibitory assessment of 2- (2- (4-Benzylpiperazin- potential anti-Alzheimer effects. DARU J Pharm Sci 21:1–10.  https://doi.org/10.1186/2008-2231-21-47
  43. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662. 10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-BCrossRefGoogle Scholar
  44. Morris GM, Ruth H, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791.  https://doi.org/10.1002/jcc.21256 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Murphy MP, LeVine H (2010) Alzheimer’s disease and the amyloid-β peptide. J Alzheimer’s Dis 19:311–323.  https://doi.org/10.3233/JAD-2010-1221 CrossRefGoogle Scholar
  46. Musiał A, Bajda M, Malawska B (2007) Recent developments in cholinesterases inhibitors for Alzheimer’s disease treatment. Curr Med Chem 14:2654–2679.  https://doi.org/10.2174/092986707782023217 CrossRefPubMedGoogle Scholar
  47. Nwidu LL, Elmorsy E, Thornton J, Wijamunige B, Wijesekara A, Tarbox R, Warren A, Carter WG (2017) Anti-acetylcholinesterase activity and antioxidant properties of extracts and fractions of Carpolobia lutea. Pharm Biol 55:1875–1883.  https://doi.org/10.1080/13880209.2017.1339283 CrossRefPubMedGoogle Scholar
  48. Ozadali-Sari K, Tüylü Küçükkılınç T, Ayazgok B, Balkan A, Unsal-Tan O (2017) Novel multi-targeted agents for Alzheimer’s disease: synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles. Bioorg Chem 72:208–214.  https://doi.org/10.1016/j.bioorg.2017.04.018 CrossRefPubMedGoogle Scholar
  49. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9:63–75.e2.  https://doi.org/10.1016/j.jalz.2012.11.007 CrossRefPubMedGoogle Scholar
  50. Raveendra RS, Prashanth Pa, Prasad BD, Nayaka SC, Suresha GP, Nagabhushana BM, Bhagya NP (2014) Synthesis, characterization and antibacterial activity of isoindoline-1,3-dione derivatives. SOP Trans Org Chem 01:543–547Google Scholar
  51. Shakir R, Muhi-Eldeen Za, Matalka KZ, Qinna Na (2012) Analgesic and toxicity studies of aminoacetylenic isoindoline-1,3-dione derivatives. ISRN Pharmacol 2012:1–7.  https://doi.org/10.5402/2012/657472 CrossRefGoogle Scholar
  52. Shazi S (2012) Molecular interaction of the antineoplastic drug, methotrexate with human brain acetylcholinesterase: a docking study CNS Neurol Disord Drug Targets 11:142–147.  https://doi.org/10.2174/187152712800269669 CrossRefGoogle Scholar
  53. Si W, Zhang T, Zhang L, Mei X, Dong M, Zhang K, Ning J (2016) Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem Lett 26:2380–2382.  https://doi.org/10.1016/j.bmcl.2015.07.052 CrossRefPubMedGoogle Scholar
  54. Van Goethem S, Matheeussen V, Joossens J, Lambeir A-M, Chen X, De Meester I, Haemers A, Augustyns K, Van der Veken P (2011) Structure–activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal? J Med Chem 54:5737–5746.  https://doi.org/10.1021/jm200383j CrossRefPubMedGoogle Scholar
  55. Wenk GL (2003) Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64:7–10PubMedGoogle Scholar
  56. Zhao Q, Yang G, Mei X, Yuan H, Ning J (2009) Novel acetylcholinesterase inhibitors: synthesis and structure-activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives. Pestic Biochem Physiol 95:131–134.  https://doi.org/10.1016/j.pestbp.2009.04.018 CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Erik Andrade-Jorge
    • 1
  • Luis A. Sánchez-Labastida
    • 1
  • Marvin A. Soriano-Ursúa
    • 2
  • Juan A. Guevara-Salazar
    • 3
    Email author
  • José G. Trujillo-Ferrara
    • 1
    Email author
  1. 1.Laboratorio de Investigación en Bioquímica, Sección de Estudios de Posgrado e InvestigaciónEscuela Superior de Medicina del Instituto Politécnico NacionalMexico CityMexico
  2. 2.Laboratorio de Investigación en Fisiología, Sección de Estudios de Posgrado e InvestigaciónEscuela Superior de Medicina del Instituto Politécnico NacionalMexico CityMexico
  3. 3.Academia de FarmacologíaEscuela Superior de Medicina del Instituto Politécnico NacionalMexico CityMexico

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