Structure–activity relationship of tacrine and its analogues in relation to inhibitory activity against Alzheimer’s disease

  • Ingrid Vieira
  • Lilian T. F. M. CamargoEmail author
  • Luciano Ribeiro
  • Allane C. C. Rodrigues
  • Ademir J. Camargo
Original Paper
Part of the following topical collections:
  1. VII Symposium on Electronic Structure and Molecular Dynamics – VII SeedMol


Alzheimer’s disease is a widespread type of neurodegenerative dementia that mainly affects the elderly. Currently, this disease can only be treated palliatively. Existing drugs can only improve patients’ symptoms. The search for new drugs that can effectively treat this disease is an important field of research in medicinal chemistry. Here we report a structure–activity relationship study of tacrine and some of its analogues in relation to their inhibitory activities against Alzheimer’s disease. All of the molecular descriptors were calculated at the M062X/6–311++G(d,p) level of theory. Principal component analysis of the molecular descriptors showed that the compounds could be categorized into active and inactive compounds using just two descriptors: the HOMO and LUMO energies. These results should help us to explain the activities of tacrine derivatives and to model new tacrine analogues that are active against Alzheimer’s disease.

Graphical abstract

PCA score plot for tacrine and its analogues


Alzheimer’s Tacrine DFT PCA 



The authors acknowledge the Fund for Research Support of the State of Goiás (FAPEG) and the High-Performance Computing Center at the Universidade Estadual de Goiás (UEG).


  1. 1.
    McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944Google Scholar
  2. 2.
    Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P et al (2014) Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 75:21–30Google Scholar
  3. 3.
    Keri RS, Quintanova C, Chaves S, Silva DF, Cardoso SM et al (2016) New tacrine hybrids with natural-based cysteine derivatives as multitargeted drugs for potential treatment of Alzheimer’s disease. Chem Biol Drug Des 87:101–111Google Scholar
  4. 4.
    Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509Google Scholar
  5. 5.
    Qiang W, Yau W-M, Lu J-X, Collinge J, Tycko R (2017) Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541:217–221Google Scholar
  6. 6.
    Perry G, Cash AD, Smith M (2002) Alzheimer disease and oxidative stress. J Biomed Biotechnol 2:120–123Google Scholar
  7. 7.
    Brühlmann C, Ooms F, Carrupt P-AA, Testa B, Catto M et al (2001) Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase. J Med Chem 44:3195–3198Google Scholar
  8. 8.
    Samadi A, Valderas C, Ríos CDL, Bastida A, Chioua M et al (2011) Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles. Bioorg Med Chem 19:122–133Google Scholar
  9. 9.
    Jarrott B (2016) Tacrine: in vivo veritas. Pharmacol Res 116:29–31Google Scholar
  10. 10.
    Tai K, Shen T, Börjesson U, Philippopoulos M, McCammon JA et al (2001) Analysis of a 10-ns molecular dynamics simulation of mouse acetylcholinesterase. Biophys J 81:715–724Google Scholar
  11. 11.
    Bautista-Aguilera OM, Esteban G, Bolea I, Nikolic K, Agbaba D et al (2014) Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease. Eur J Med Chem 75:82–95Google Scholar
  12. 12.
    Gholivand K, Ebrahimi Valmoozi AA, Mahzouni HR, Ghadimi S, Rahimi R (2013) Molecular docking and QSAR studies: noncovalent interaction between acephate analogous and the receptor site of human acetylcholinesterase. J Agric Food Chem 61:6776–6785Google Scholar
  13. 13.
    Castilho MS, Guido R, Andricopulo AD (2007) Classical and hologram QSAR studies on a series of tacrine derivatives as butyrylcholinesterase inhibitors. Lett Drug Des Discov 4:106–113Google Scholar
  14. 14.
    Jeřábek J, Uliassi E, Guidotti L, Korábečný J, Soukup O et al (2017) Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur J Med Chem 127:250–262Google Scholar
  15. 15.
    Reddy EK, Remya C, Mantosh K, Sajith AM, Omkumar RV et al (2017) Novel tacrine derivatives exhibiting improved acetylcholinesterase inhibition: design, synthesis and biological evaluation. Eur J Med Chem 139:367–377Google Scholar
  16. 16.
    Proctor GR, Harvey AL (2000) Synthesis of tacrine analogues and their structure-activity relationships. Curr Med Chem 7:295–302Google Scholar
  17. 17.
    Nascimento ECM, Martins JBL, dos Santos ML, Gargano R (2008) Theoretical study of classical acetylcholinesterase inhibitors. Chem Phys Lett 458:285–289Google Scholar
  18. 18.
    Nascimento ECM, Martins JBL (2011) Electronic structure and PCA analysis of covalent and non-covalent acetylcholinesterase inhibitors. J Mol Model 17:1371–1379Google Scholar
  19. 19.
    Alam M, Lee DU (2016) Synthesis, spectroscopic and computational studies of 2-(thiophen-2-yl)-2,3-dihydro-1H-perimidine: an enzymes inhibition study. Comput Biol Chem 64:185–201Google Scholar
  20. 20.
    Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985) Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. J Am Chem Soc 107:3902–3909Google Scholar
  21. 21.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA et al (2009) Gaussian 09, revision A.02. Gaussian, Inc., WallingfordGoogle Scholar
  22. 22.
    Kohn W, Becke AD, Parr RG (1996) Density functional theory of electronic structure. J Phys Chem 100:12974–12980Google Scholar
  23. 23.
    Breneman CM, Wiberg KB (1990) Determining atom-centered monopoles from molecular electrostatic potentials. The need for high sampling density in formamide conformational analysis. J Comput Chem 11:361–373Google Scholar
  24. 24.
    Karelson M, Lobanov VS, Katritzky AR (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chem Rev 96:1027–1044Google Scholar
  25. 25.
    Camargo AJ, Honório KM, Mercadante R, Molfetta FA, Alves CN et al (2003) A study of neolignan compounds with biological activity against Paracoccidioides brasiliensis by using quantum chemical and chemometric methods. J Braz Chem Soc 14:809–814Google Scholar
  26. 26.
    Camargo LTFM, Sena MMM, Camargo AJJ (2009) A quantum chemical and chemometrical study of indolo[2,1-b]quinazoline and their analogues with cytotoxic activity against breast cancer cells. SAR QSAR Environ Res 20:537–549Google Scholar
  27. 27.
    Martins GR, Napolitano HB, Camargo LTFM, Camargo AJ (2012) Structure-activity relationship study of rutaecarpine analogous active against central nervous system cancer. J Braz Chem Soc 23:2183–2190Google Scholar
  28. 28.
    Sharaf MA, Illman DL, Kowalski BR (1986) Chemometrics. Wiley, New YorkGoogle Scholar
  29. 29.
    Jolliffe IT (1986) Principal Component Analysis. Springer, Berlin. Book, v 2, p 37–52Google Scholar
  30. 30.
    Acar N, Selçuki C, Coşkun E (2017) DFT and TDDFT investigation of the Schiff base formed by tacrine and saccharin. J Mol Model 23:17Google Scholar
  31. 31.
    Nepovimova E, Korabecny J, Dolezal R, Babkova K, Ondrejicek A et al (2015) Tacrine-trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity. J Med Chem 58:8985–9003Google Scholar
  32. 32.
    Eslami M, Hashemianzadeh SM, Bagherzadeh K, Seyed Sajadi SA (2016) Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer’s disease. J Biomol Struct Dyn 34:855–869Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Instituto Federal de EducaçãoCiência e Tecnologia de GoiásAnápolisBrazil
  2. 2.Grupo de Química Teórica e Estrutural de Anápolis (QTEA), Câmpus de Ciências Exatas e TecnológicasUniversidade Estadual de GoiásAnápolisBrazil

Personalised recommendations