International Journal of Drug Delivery Technology
Volume 15, Issue 3

Design, Synthesis, In-silico Study and Biological Evaluation of Some Heterocyclic Derivatives as Cholinesterase Inhibitors

Rupali Jinturkar*, Pallavi Patil

PES Modern College of Pharmacy, Nigdi, Pune- Savitribai Phule Pune University, Pune, Maharashtra, India

Received: 11th Jul, 2025; Revised: 17th Aug, 2025; Accepted: 31st Aug, 2025; Available Online: 25th Sep, 2025 

ABSTRACT

The study involves design, in-silico evaluation and synthesis of new Tacrine-based heterocyclic derivatives as neuroprotective agents. The need for efficient treatments that can target several pathogenic pathways is vital given the rising incidence of numerous disorders involving neuronal degeneration and subsequent neuronal death, which need neuroprotective agents.  By combining Tacrine with a heterocyclic scaffold, the study seeks to take advantage of its dual binding ability of the enzyme acetylcholinesterase (AChE). A comprehensive literature survey was conducted, to identify suitable heterocyclic moieties with reported cholinesterase (ChE) inhibitory and neuroprotective activity. In the present research new Tacrine-thiazolidine derivatives were designed and has been synthesized and later checked for AChE inhibitory activity. The structural characterization was done using various spectroscopic techniques, including IR, ¹H-NMR and Mass Spectroscopy. Acetylcholinesterase inhibitory activities of the synthesized compounds were diagnosed. Among the synthesized compounds, compound S2M1, which contains unsubstituted phenyl ring on thiazolidinone linked to Tacrine-Nitrogen through Ethylene Bridge, exhibited the most significant inhibitory effects against AChE, with 56.41% as a percent inhibition of AChE compared to that of scopolamine. In-silico insights shown very good binding interactions of compound S2M1 with AChE enzyme. Additionally, in silico assessments indicated that all synthesized compounds possess favourable drug-like characteristics and are predicted to be non-toxic, but amongst all S2M1 proves to be the most competent derivative as AChE inhibitor.

Keywords: Neuroprotectives, Heterocyclic, Design, in-silico, Synthesis.

How to cite this article: Rupali Jinturkar, Pallavi Patil. Design, Synthesis, In-silico Study and Biological Evaluation of Some Heterocyclic Derivatives as Cholinesterase Inhibitors. International Journal of Drug Delivery Technology. 2025;15(3):1347-53. doi: 10.25258/ijddt.15.3.57

REFERENCES

  1. Elkina NA, Grishchenko MV, Shchegolkov EV, Makhaeva GF, Kovaleva NV, Rudakova EV, Boltneva NP, Lushchekina SV, Astakhova TY, Radchenko EV, Palyulin VA. New multifunctional agents for potential Alzheimer’s disease treatment based on tacrine conjugates with 2-arylhydrazinylidene-1, 3-diketones. Biomolecules. 2022 Oct 24;12(11):1551. DOI: 10.3390/biom12111551.
  2. Fares S, El Husseiny WM, Selim KB, Massoud MA. Modified tacrine derivatives as multitarget-directed ligands for the treatment of Alzheimer’s disease: Synthesis, biological evaluation, and molecular modeling study. ACS omega. 2023 Jul 12;8(29):26012-34. DOI: 10.1021/acsomega.3c02051
  3. Šachlevičiūtė U, Gonzalez G, Kvasnicová M, Štěpánková Š, Kleizienė N, Bieliauskas A, Zatloukal M, Strnad M, Sløk FA, Kvasnica M, Šačkus A. Synthesis and neuroprotective activity of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives. Archiv der Pharmazie. 2023 Dec;356(12):2300378. DOI:10.1002/ardp.202300378.
  4. Makhaeva GF, Grigoriev VV, Proshin AN, Kovaleva NV, Rudakova EV, Boltneva NP, Serkov IV, Bachurin SO. Novel conjugates of tacrine with 1, 2, 4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants. In Doklady Biochemistry and Biophysics 2017 Nov (Vol. 477, No. 1, pp. 405-409). Moscow: Pleiades Publishing. DOI:10.1134/S1607672917060163.
  5. Dos Santos A, Teixeira FC, da Silva DS, Veleda TA, de Mello JE, Luduvico KP, Tavares RG, Stefanello FM, Cunico W, Spanevello RM. Thiazolidin-4-one prevents against memory deficits, increase in phosphorylated tau protein, oxidative damage and cholinergic dysfunction in Alzheimer disease model: Comparison with donepezil drug. Brain Research Bulletin. 2023 Feb 1;193:1-0. DOI:10.1016/j.brainresbull.2022.11.015.
  6. das Neves AM, Berwaldt GA, Avila CT, Goulart TB, Moreira BC, Ferreira TP, Soares MS, Pedra NS, Spohr L, dE Souza AA, Spanevello RM. Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl) pyrrolidine as acetylcholinesterase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry. 2020 Jan 1;35(1):31-41. DOI: 10.1080/14756366.2019.1680659
  7. Hemaida AY, Hassan GS, Maarouf AR, Joubert J, El-Emam AA. Synthesis and biological evaluation of thiazole-based derivatives as potential acetylcholinesterase inhibitors. ACS omega. 2021 Jul 19;6(29):19202-11. DOI: 10.1021/acsomega.1c02549
  8. Pérez MJ, Quintanilla RA. Therapeutic actions of the thiazolidinediones in Alzheimer’s disease. PPAR research. 2015;2015(1):957248. DOI: 10.1155/2015/957248
  9. Aggarwal N, Jain S, Chopra N. Hybrids of thiazolidin-4-ones and 1, 3, 4-thiadiazole: Synthesis and biological screening of a potential new class of acetylcholinesterae inhibitors. Biointerface Res. Appl. Chem. 2022;12:2800-12. DOI: 10.33263/BRIAC123.28002812
  10. Naz S, Al Kury LT, Nadeem H, Shah FA, Ullah A, Paracha RZ, Imran M, Li S. Synthesis, In Silico and Pharmacological Evaluation of New Thiazolidine-4-Carboxylic Acid Derivatives Against Ethanol-Induced Neurodegeneration and Memory Impairment. Journal of Inflammation Research. 2022 Jan 1:3643-60. DOI: 10.2147/JIR.S395876
  11. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera—a visualization system for exploratory research and analysis. Journal of computational chemistry. 2004 Oct;25(13):1605-12. DOI: 10.1002/ jcc.20084.
  12. Dassault BI. Systemes, Discovery studio visualizer, version v21. 1.0. 20298. Dassault Systemes, San Diego. 2021.
  13. Release S. 1: Maestro; Schrödinger, LLC. New York, NY, USA. 2018.
  14. Panwar R, Jakhmola V, Saha S, Jawla S, Mishra R. Molecular Docking, MD Simulation, and Antiproliferative Activity of Pyridazine Derivatives. International Journal of Drug Delivery Technology. 2025;15(2):748-56. DOI: 10.25258/ijddt.15.2.48
  15. Samiya SS, Jakhmola V, Gairola N, Singh M. Molecular Docking, Synthesis, Antiproliferative Activity against MCF-7, and In-vitro Alpha Amylase Activities of Newer Generation Pyrimidino Hydroxamic Acid Derivatives. International Journal of Drug Delivery Technology. 2024;14:649-59. DOI: 10.25258/ijddt.14.2.06
  16. Zhu J, Yang H, Chen Y, Lin H, Li Q, Mo J, Bian Y, Pei Y, Sun H. Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease. Journal of enzyme inhibition and medicinal chemistry. 2018 Jan 1;33(1):496-506. DOI: 1080/14756366.2018.1430691
  17. Spilovska K, Korabecny J, Kral J, Horova A, Musilek K, Soukup O, Drtinova L, Gazova Z, Siposova K, Kuca K. 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer’s disease treatment—synthesis, biological evaluation and molecular modeling studies. Molecules. 2013 Feb 20;18(2):2397-418. DOI:10.3390/molecules18022397.
  18. Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology. 1961 Jul 1;7(2):88-95. DOI:10.1016/0006-2952(61)90145-9.
  19. Kawsar SMA, Munia NS, Saha S, Ozeki Y. In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Simulation Studies of Nucleoside Analogs for Drug Discovery- A Mini Review. Mini Reviews in Medicinal Chemistry. 2023. DOI: 10.2174/0113895575258033231024073521.
  20. Almehmadi M, Alsaiari AA, Allahyani M, Alsharif A, Aljuaid A, Saha S, Asif M. Computational Studies and Antimicrobial Activity of 1-(benzo[d]oxazol-2-yl)-3,5-Diphenylformazan Derivatives. Current Computer Aided Drug Design. 2024;20(6): 835-846.DOI: 10.2174/15734099196662307 03103135.
  21. Kayes MR, Saha S, Alanazi MM, Ozeki Y, Pal D, Hadda TB, Legssyer A, Kawsar SMA. Macromolecules: Synthesis, antimicrobial, POM analysis and computational approaches of some glucoside derivatives bearing acyl moieties. Saudi Pharmaceutical Journal. 2023;31(11):101804.DOI: 10.1016/j.jsps.2023.101804.