Skip to main content
SpringerLink
Log in

Acetylcholinesterase inhibition by products generated in situ from the transformation of N-arylisomaleimides

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

When N-arylisomaleimides were transformed under enzymatic reaction conditions, the transformation reaction proved to be influenced by electronic effects. This was demonstrated qualitatively by 1H NMR spectroscopy and quantitatively by monitoring the kinetic of isomerization of N-phenylisomaleimide to N-phenylmaleimide. Subsequently, the first pseudo-order and activation energy (E a) of the process were determined. The compounds showed in situ influence on AChE inhibition. The derivatives with electron-withdrawing groups exhibited a better effect than those having electron-donating groups. The in silico experiments show that the ligands evaluated established interactions with the CAS site. This suggests that these compounds could be useful for generating better reversible and competitive inhibitors of AChE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Scheme 3
Scheme 4
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Apweiler R, Bairoch A, Wu C (2004) Protein sequence databases. Curr Opin Chem Biol 8:76–80

    Article  CAS  PubMed  Google Scholar 

  • Barba V, Hernández C, Rojas-Lima S, Farfán N, Santillán R (1999) Preparation of N-aryl-substituted spiro-β-lactames via Staudinger cycloaddition. Can J Chem 77:2025–2032

    Article  CAS  Google Scholar 

  • Berman H, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne P (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonting SL, Featherstone RM (1956) Ultramicro assay of the cholinesterases. Arch Biochem Biophys 61:89–98

    Article  CAS  PubMed  Google Scholar 

  • Bourne Y, Grassi J, Bougis P, Marchot P (1999) Conformational flexibility of the acetylcholinesterase tetramer suggested by X-ray crystallography. J Biol Chem 274:30370–30376

    Article  CAS  PubMed  Google Scholar 

  • Breine U, Henderberg I, Liljedahl SO (1958) Treatment of paralytic ileus with cholinesterase inhibitors in intravenous drip. Acta Chir Scand 114:172–180

    CAS  PubMed  Google Scholar 

  • Constantinescu M, Ivanov D (2005) Computational study of maleamic acid cyclodehydration with acetic anhydride. Intern J Quantum Chem 106:1330–1337

    Article  Google Scholar 

  • Correa-Basurto J, Espinosa-Raya J, González-May M, Espinoza-Fonseca LM, Vázquez-Alcántara I, Trujillo-Ferrara J (2006) Inhibition of acetylcholinesterase by two arylderivatives: 3a-acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione and cis-N-p-acetoxy-phenylisomaleimide. J Enzym Inhib Med Chem 21:133–138

    Article  CAS  Google Scholar 

  • Correa-Basurto J, Flores-Sandoval C, Marín-Cruz J, Rojo-Domínguez A, Espinoza-Fonseca M, Trujillo-Ferrara J (2007) Docking and quantum mechanic studies on cholinesterases and their inhibitors. Eur J Med Chem 42:10–19

    Article  CAS  PubMed  Google Scholar 

  • Cotter RJ, Sauers CK, Whelan JM (1961) The synthesis of N-substituted isomaleimides. J Org Chem 26(10):10–15

    Article  CAS  Google Scholar 

  • Cummings J, Lai TJ, Hemrungrojn S, Mohandas E, Yun Kim S, Mair G, Dash A (2016) Role of donepezil in the management of neuropsychiatric symptoms in Alzheimer’s disease and demetia with Lewy bodies. CNS Neurosci Ther 22:159–166

    Article  CAS  PubMed  Google Scholar 

  • Dassault Systèmes BIOVIA (2016) Discovery studio, v.16. Dassault Systèmes, San Diego

    Google Scholar 

  • Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403

    Article  CAS  PubMed  Google Scholar 

  • Desmidt T, Hommet C, Camus V (2016) Pharmacological treatments of behavioral and psychological symptoms of dementia in Alzheimer’s disease: role of acetylcholinesterase inhibitors and memantine. Geriatr Psychol Neuropsychiatr Vieil 14:300–306

    PubMed  Google Scholar 

  • Durai R (2009) Colonic pseudo-obstruction. Singapore Med J 50:237–244

    CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Andres Jr V, Featherstone RM (1961) A new rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  • Fersht A (1999) Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding. WH Freeman and Company, New York

    Google Scholar 

  • Fortier LP, McKeen D, Turner K, de Médicis É, Warriner B, Jones PM, Chaput A, Pouliot JF, Galarneau A (2015) The RECITE study: a Canadian prospective, multicenter study of the incidence and severity of residual neuromuscular blockade. Anesth Analg 121:366–372

    Article  PubMed  Google Scholar 

  • Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, Scalmani G, Barone V, Mennucci B, Petersson G, Nakatsuji H, Caricato M, Li X, Hratchian H, Izmaylov A, Bloino J, Zheng G, Sonnenberg J et al. (2009) Gaussian 09W, 9.5 Version. Gaussian Inc., Wallingford, CT

    Google Scholar 

  • Fruk L, Graham D (2003) The electronic effects on the formation of N-aryl-maleimides and isomaleimides. Heterocycles 60(10):2305–2313

    Article  CAS  Google Scholar 

  • Graipaspong N, Thaipisuttikul P, Vallipakorn SA (2016) Cholinesterase inhibitors and behavioral & psychological symptoms of Alzheimer’s disease. J Med Assoc Thai 99:433–440

    PubMed  Google Scholar 

  • Guevara-Salazar JA, Espinoza-Fonseca M, Beltrán HI, Correa-Basurto J, Quintana-Zavala D, Trujillo-Ferrara J (2007) The electronic influence on the active site-directed inhibition of acetylcholinesterase by N-aryl-substituted-succinimides. J Mex Chem Soc 51:222–227

    CAS  Google Scholar 

  • Guevara-Salazar JA, Quintana-Zavala D, Jiménez-Vázquez HA, Trujillo-Ferrara J (2011) Synthesis of Diels-Alder adducts of N-arylmaleimides by a multicomponent reaction between maleic anhydride, dienes, and anilines. Monatsh Chem 142:827–836

    Article  CAS  Google Scholar 

  • Gupta S, Mohan CG (2014) Dual binding site and selective acetylcholinesterase inhibitors derived from integrated pharmacophore models and sequential virtual screening. BioMed Res Int. https://doi.org/10.1155/2014/291214.

  • Inestrosa NC, Sagal JP, Colombres M (2005) Acetylcholinesterase interaction with Alzheimer amyloid beta. Subcell Biochem 38:299–317

    Article  CAS  PubMed  Google Scholar 

  • Ivanov D, Constantinescu M (2005) Computational study of maleamic acid cyclodehydration. J Phys Org Chem 16:348–354

    Article  Google Scholar 

  • Joseph-Nathan P, Mendoza V, García E (1974) Aziridine induced isomerization of isomaleimides to maleimides. Can J Chem 52:129–131

    Article  CAS  Google Scholar 

  • Kelly JS (1999) Alzheimer's disease the tacrine legacy. TiPS 20:127–129

    CAS  PubMed  Google Scholar 

  • Kiametis A, Monica-Silva A, Luiz-Romeiro A, Martins J, Gargano R (2017) Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction. J Mol Model 23:67

    Article  PubMed  Google Scholar 

  • Kirino O, Baruch R, Casida JE (1985) N-phenyl-maleimides, -isomaleimides and –maleamic acids as selective herbicide antidotes. Agric Biol Chem 49:267–268

    CAS  Google Scholar 

  • Kolko M (2015) Present and new treatment strategies in the management of glaucoma. Open Ophthalmol J 15:89–100

    Google Scholar 

  • Mehndiratta MM, Pandey S, Kuntzer T (2014) Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD006986.pub3

  • Morris G, Goodsell D, Halliday R, Huey R, Hart W, Belew R, Olson A (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comp Chem 19:1639–1662

    Article  CAS  Google Scholar 

  • Morris G, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J Comput Chem 16:2785–2791

    Article  Google Scholar 

  • Oishi T, Fujimoto M, Yoshimoto N, Kimura T (1989) Anionic polymerization of N-substituted isomaleimide. Polym J 21(8):655–659

    Article  CAS  Google Scholar 

  • Pakaski M, Kasa P (2003) Role of acetylcholinesterase inhibitors in the metabolism of amyloid precursor protein. Curr Drug Targets CNS Neurol Disord 2:163–171

    Article  CAS  PubMed  Google Scholar 

  • Perry EK (1986) The cholinergic hypothesis—ten years on. Br Med Bull 42:63–69

    Article  CAS  PubMed  Google Scholar 

  • Sadigh-Eteghad S, Sabermrouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J (2015) Amyloid-beta: a crucial factor in Alzheimer’s disease. Med Princ Pract 24:1–10

    Article  PubMed  Google Scholar 

  • Sauers CK (1969) The dehydration of N-arylmaleamic acids with acetic anhydride. J Org Chem 34:2275–2279

    Article  CAS  Google Scholar 

  • Schreiber JU (2014) Management of neuromulscular blocakade in ambulatory patients. Curr Opin Anaesthesiol 27:583–588

    Article  CAS  PubMed  Google Scholar 

  • Shakil S, Kamal M, Tabrez S, Abuzenadah A (2012) Molecular interaction of the antineoplastic drug methotrexate with human brain acetylcholinesterase: a docking study. CNS Neurol Disord Drug Targets 11:142–147

    Article  CAS  PubMed  Google Scholar 

  • Standaert DG, Roberson ED (2011) Tratamiento de enfermedades degenerativas del sistema nervioso central. In: Brunton LL, Chabner BA, Knollmann BC (eds) Goodman & Gilman: Las bases farmacológicas de la terapéutica. McGraw-Hill, China, pp 619–622

  • Taylor P (1991) The cholinesterases. J Biol Chem 266:4025–4028

    CAS  PubMed  Google Scholar 

  • Trujillo-Ferrara J, Montoya L, Espinoza-Fonseca M (2003a) Synthesis, anticholinesterase activity and structure-activity relationships m-aminobenzoic acid derivatives. Bioorg Med Chem Lett 13:1825–1827

    Article  CAS  PubMed  Google Scholar 

  • Trujillo-Ferrara J, Vázquez I, Espinosa J, Santillán R, Farfán N, Höpfl H (2003b) Reversible and irreversible activity of succinic and maleic acid derivatives on acetylcholinesterase. Eur J Pharm Sci 18:313–322

    Article  CAS  PubMed  Google Scholar 

  • Zeinali F, Stulberg JJ, Delaney CP (2009) Pharmacological management of postoperative ileus. Can J Surg 52:153–157

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the Comisión de Operación y Fomento de Actividades Académicas (COFAA) of the Secretaría de Investigación y Posgrado of the IPN (SIP).

Author information

Authors and Affiliations

  1. Academy of Pharmacology, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México, D.F., Mexico

    Juan A. Guevara

  2. Department of Biochemistry and Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México, D.F., Mexico

    José G. Trujillo, José R. Bahena & Feliciano Tamay

  3. Laboratory of Organic Chemistry, CICATA Unidad Legaria, Instituto Politécnico Nacional, Legaria No. 694, 11500, México, D.F., Mexico

    Delia Quintana

  4. Department of Organic Chemistry, ENCB, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala, 11350, México, D.F., Mexico

    Hugo A. Jiménez

  5. Laboratory of Chronic-Degenerative Diseases and Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México, D.F., Mexico

    Mónica G. Arellano

  6. Academy of Physiology and Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México, D.F., Mexico

    Fabiola J. Ciprés

Authors
  1. Juan A. Guevara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José G. Trujillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Delia Quintana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugo A. Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mónica G. Arellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José R. Bahena
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feliciano Tamay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fabiola J. Ciprés
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Juan A. Guevara or José G. Trujillo.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guevara, J.A., Trujillo, J.G., Quintana, D. et al. Acetylcholinesterase inhibition by products generated in situ from the transformation of N-arylisomaleimides. Med Chem Res 27, 989–1003 (2018). https://doi.org/10.1007/s00044-017-2122-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-017-2122-4

Keywords

Search

Navigation