Skip to content
2000
image of Cholinesterase Inhibition and Anticancer Properties of [4-(Benzyloxy)phenyl]{Methylidene}hydrazinylidene]-1,3-dihydro-2H-Indol-2-ones Using Swiss Target-guided Prediction

Abstract

Introduction

Our group previously reported isatin-based hydrazones () were further evaluated for their acetylcholine esterase, butylcholinestrase and cytotoxic effects on cancer cell lines. The compounds successfully suppressed AChE and BChE, with Ki values ranging from 1.06±0.07 to 23.57±1.64 nM for AChE and 15.31±1.28 to 84.41±8.04 nM for BChE. However, the IC values of these compounds for AChE and BChE were found to be in the ranges of 1.45-25.51 nM and 16.38-92.90 nM, respectively.

Method

Furthermore, to explore the anti-tumor potential of our newly synthesized compounds, we conducted a cytotoxic MTT assay to assess their impact on two different cancer cell lines: MCF7 and A2780.

Results

Our findings highlight diverse cytotoxic profiles among the compounds. Specifically, , , and demonstrated potential cytotoxicity in the A2780 cell line, while exhibited significant cytotoxicity in the MCF7 cell line. This suggests that these compounds have different effects on cancer cell types, indicating the need for further investigation into their potential applications in cancer therapy.

Conclusion

Finally, molecular docking and dynamic study revealed that lead molecule provides stability in the AChE and BChE protein-ligand complex.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cad/10.2174/0115734099359621250320073543
2025-04-07
2025-09-09

  • From This Site

    /content/journals/cad/10.2174/0115734099359621250320073543
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Kumar S. Manoharan A. J J. Abdelgawad M.A. Mahdi W.A. Alshehri S. Ghoneim M.M. Pappachen L.K. Zachariah S.M. Aneesh T.P. Mathew B. Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation. RSC Advances 2023 13 14 9513 9529 10.1039/D3RA00526G 36968055
    [Google Scholar]
  2. Manoharan A. Oh J.M. Benny F. Kumar S. Abdelgawad M.A. Ghoneim M.M. Shaker M.E. El-Sherbiny M. Almohaimeed H.M. Gahtori P. Kim H. Mathew B. Assembling a cinnamyl pharmacophore in the C3-position of substituted isatins via microwave-assisted synthesis: Development of a new class of monoamine oxidase-b inhibitors for the treatment of parkinson’s disease. Molecules 2023 28 16 6167 10.3390/molecules28166167 37630420
    [Google Scholar]
  3. Kısa D. Imamoglu R. Genc N. Taslimi P. Kaya Z. Taskin-Tok T. HPLC analysis, phytochemical content, and biological effects of Centaurea kilae against some metabolic enzymes: In vitro and in silico studies. ChemistrySelect 2023 8 6 e202204196 10.1002/slct.202204196
    [Google Scholar]
  4. Karimov A. Taslimi P. Orujova A. Mammadova K. Kısa D. Farzaliyev V. Sujayev A. Sadeghian N. Taskin-Tok T. Alwasel S. Gulcin I. Design, synthesis, characterization and biological activities of novel S‐(Acyloxy)butyl‐N,N‐Diethyldithiocarbamate compounds. ChemistrySelect 2023 8 18 e202300286 10.1002/slct.202300286
    [Google Scholar]
  5. Gök Y. Taslimi P. Şen B. Bal S. Aktaş A. Aygün M. Sadeghi M. Gülçin İ. Design, synthesis, characterization, crystal structure, in silico studies, and inhibitory properties of the PEPPSI type Pd(II)NHC complexes bearing chloro/fluorobenzyl group. Bioorg. Chem. 2023 135 106513 10.1016/j.bioorg.2023.106513 37030104
    [Google Scholar]
  6. Tariq Riaz M. Taslimi P. Yaqub M. al-Rashida M. Alharthy R.D. El-Gokha A. Shafiq Z. Functionalized Diazabenzo[a]anthracenediones: Regioselective multicomponent synthesis and biological and computational studies as potential cholinesterase inhibitors. ChemistrySelect 2023 8 22 e202300648 10.1002/slct.202300648
    [Google Scholar]
  7. Tokalı F.S. Taslimi P. Sadeghi M. Şenol H. Synthesis and evaluation of Quinazolin‐4(3 H )‐one derivatives as multitarget metabolic enzyme inhibitors: A biochemistry‐oriented drug design. ChemistrySelect 2023 8 25 e202301158 10.1002/slct.202301158
    [Google Scholar]
  8. Resende R.R. Adhikari A. Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation. Cell Commun. Signal. 2009 7 1 20 10.1186/1478‑811X‑7‑20 19712465
    [Google Scholar]
  9. Marucci G. Buccioni M. Ben D.D. Lambertucci C. Volpini R. Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 2021 190 108352 10.1016/j.neuropharm.2020.108352 33035532
    [Google Scholar]
  10. Martin F. A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int. Psychogeriatr. 2002 14 Suppl 1 93 126 10.1017/S1041610203008688 12636182
    [Google Scholar]
  11. Kabir M.T. Uddin M.S. Begum M.M. Thangapandiyan S. Rahman M.S. Aleya L. Mathew B. Ahmed M. Barreto G.E. Ashraf G.M. Cholinesterase inhibitors for Alzheimer’s disease: Multitargeting strategy based on anti-alzheimer’s drugs repositioning. Curr. Pharm. Des. 2019 25 33 3519 3535 10.2174/1381612825666191008103141 31593530
    [Google Scholar]
  12. Kuzirian M.S. Paradis S. Emerging themes in GABAergic synapse development. Prog. Neurobiol. 2011 95 1 68 87 10.1016/j.pneurobio.2011.07.002 21798307
    [Google Scholar]
  13. Erdmann O.L. Investigations into Indigo. J. Prakt. Chem. 1840 19 1 321 362 10.1002/prac.18400190161
    [Google Scholar]
  14. Ibrahim S. Elsaman T. Cytotoxic and anticancer activities of indoline-2,3-dione (Isatin) and its derivatives. J. Pharm. Res. Int. 2018 21 2 1 19 10.9734/JPRI/2018/39708
    [Google Scholar]
  15. Lelyukh M. Havrylyuk D. Lesyk R. Synthesis and anticancer activity of isatin, oxadiazole and 4-thiazolidinone based conjugates. Chem. Chem. Technol. 2015 9 1 29 36 10.23939/chcht09.01.029
    [Google Scholar]
  16. Kumar S. Nair A.S. Abdelgawad M.A. Mathew B. Exploration of the detailed structure–activity relationships of isatin and their isomers as monoamine oxidase inhibitors. ACS Omega 2022 7 19 16244 16259 10.1021/acsomega.2c01470 35601305
    [Google Scholar]
  17. Varun V. Sonam S. Kakkar R. Isatin and its derivatives: A survey of recent syntheses, reactions, and applications. MedChemComm 2019 10 3 351 368 10.1039/C8MD00585K 30996856
    [Google Scholar]
  18. Silva J.F.M. Garden S.J. Pinto A.C. The chemistry of isatins: A review from 1975 to 1999. J. Braz. Chem. Soc. 2001 12 3 273 324 10.1590/S0103‑50532001000300002
    [Google Scholar]
  19. Kumar S. Oh J.M. Prabhakaran P. Awasti A. Kim H. Mathew B. Isatin-tethered halogen-containing acylhydrazone derivatives as monoamine oxidase inhibitor with neuroprotective effect. Sci. Rep. 2024 14 1 1264 10.1038/s41598‑024‑51728‑x 38218887
    [Google Scholar]
  20. Nain S. Mathur G. Anthwal T. Sharma S. Paliwal S. Synthesis, characterization, and antibacterial activity of new isatin derivatives. Pharm. Chem. J. 2023 57 2 196 203 10.1007/s11094‑023‑02867‑4 37313436
    [Google Scholar]
  21. Raj R. Biot C. Carrère-Kremer S. Kremer L. Guérardel Y. Gut J. Rosenthal P.J. Forge D. Kumar V. 7-chloroquinoline-isatin conjugates: Antimalarial, antitubercular, and cytotoxic evaluation. Chem. Biol. Drug Des. 2014 83 5 622 629 10.1111/cbdd.12273 24341638
    [Google Scholar]
  22. Paul B.K. Ray D. Guchhait N. Unraveling the binding interaction and kinetics of a prospective anti-HIV drug with a model transport protein: Results and challenges. Phys. Chem. Chem. Phys. 2013 15 4 1275 1287 10.1039/C2CP42539D 23232916
    [Google Scholar]
  23. Prakash C.R. Raja S. Saravanan G. Design and synthesis of 4-(1-(4-chlorobenzyl)-2,3-dioxoindolin-5-yl)-1-(4-substituted/unsubstituted benzylidene) semicarbazide: Novel agents with analgesic, anti-inflammatory and ulcerogenic properties. Chin. Chem. Lett. 2012 23 5 541 544 10.1016/j.cclet.2012.03.014
    [Google Scholar]
  24. Khan K.M. Khan M. Ali M. Taha M. Rasheed S. Perveen S. Choudhary M.I. Synthesis of bis-Schiff bases of isatins and their antiglycation activity. Bioorg. Med. Chem. 2009 17 22 7795 7801 10.1016/j.bmc.2009.09.028 19837595
    [Google Scholar]
  25. Andreani A. Burnelli S. Granaiola M. Leoni A. Locatelli A. Morigi R. Rambaldi M. Varoli L. Cremonini M.A. Placucci G. Cervellati R. Greco E. New isatin derivatives with antioxidant activity. Eur. J. Med. Chem. 2010 45 4 1374 1378 10.1016/j.ejmech.2009.12.035 20060202
    [Google Scholar]
  26. Kumar K. Carrère-Kremer S. Kremer L. Guérardel Y. Biot C. Kumar V. 1 H -1,2,3-triazole-tethered isatin–ferrocene and isatin–ferrocenylchalcone conjugates: Synthesis and in vitro antitubercular evaluation. Organometallics 2013 32 20 5713 5719 10.1021/om301157z
    [Google Scholar]
  27. Jarrahpour A. Khalili D. De Clercq E. Salmi C. Brunel J.M. Synthesis, antibacterial, antifungal and antiviral activity evaluation of some new bis-Schiff bases of isatin and their derivatives. Molecules 2007 12 8 1720 1730 10.3390/12081720 17960083
    [Google Scholar]
  28. Saravanan G. Alagarsamy V. Dineshkumar P. Anticonvulsant activity of novel 1-(morpholinomethyl)-3-substituted isatin derivatives. Bull. Fac. Pharm. Cairo Univ. 2014 52 1 115 124 10.1016/j.bfopcu.2014.02.001
    [Google Scholar]
  29. Thakur R.K. Joshi P. Upadhyaya K. Singh K. Sharma G. Shukla S.K. Tripathi R. Tripathi R.P. Synthesis of isatin based N1-alkylated 3-β-C-glycoconjugated-oxopropylidene oxindoles as potent antiplasmodial agents. Eur. J. Med. Chem. 2019 162 448 454 10.1016/j.ejmech.2018.11.008 30469040
    [Google Scholar]
  30. Kang I.J. Wang L.W. Hsu T.A. Yueh A. Lee C.C. Lee Y.C. Lee C.Y. Chao Y.S. Shih S.R. Chern J.H. Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors. Bioorg. Med. Chem. Lett. 2011 21 7 1948 1952 10.1016/j.bmcl.2011.02.037 21356589
    [Google Scholar]
  31. Gideon D.A. Annadurai P. Nirusimhan V. Parashar A. James J. Dhayabaran V.V. Evaluation of the anticancer activities of isatin-based derivatives. Handbook of Oxidative Stress in Cancer: Therapeutic Aspects Springer Singapore 2022 1 25 10.1007/978‑981‑16‑1247‑3_51‑1
    [Google Scholar]
  32. Ferraz de Paiva R.E. Vieira E.G. Rodrigues da Silva D. Wegermann C.A. Costa Ferreira A.M. Anticancer compounds based on isatin-derivatives: Strategies to ameliorate selectivity and efficiency. Front. Mol. Biosci. 2021 7 627272 10.3389/fmolb.2020.627272 33614708
    [Google Scholar]
  33. Kemel H. Benguedouar L. Boudjerda D. Menadi S. Cacan E. Sifour M. Phytochemical profiling, cytotoxic, anti-migration, and anti-angiogenic potential of phenolic-rich fraction from Peganum harmala: In vitro and in ovo studies. Med. Oncol. 2024 41 6 144 10.1007/s12032‑024‑02396‑4 38717574
    [Google Scholar]
  34. Berkel Ç. Küçük B. Usta M. Yılmaz E. Çaçan E. The effect of Olaparib and Bortezomib combination treatment on ovarian cancer cell lines. Eur. J. Biol. 2020 79 2 115 123 10.26650/EurJBiol.2020.0035
    [Google Scholar]
  35. Abu-Helalah M. Azab B. Mubaidin R. Ali D. Jafar H. Alshraideh H. Drou N. Awidi A. BRCA1 and BRCA2 genes mutations among high risk breast cancer patients in Jordan. Sci. Rep. 2020 10 1 17573 10.1038/s41598‑020‑74250‑2 33067490
    [Google Scholar]
  36. Swain S.M. Shastry M. Hamilton E. Targeting HER2-positive breast cancer: Advances and future directions. Nat. Rev. Drug Discov. 2023 22 2 101 126 10.1038/s41573‑022‑00579‑0 36344672
    [Google Scholar]
  37. Dasgupta A. Wahed A. Tumor markers. Clinical Chemistry, Immunology and Laboratory Quality Control. Elsevier 2021 269 293 10.1016/B978‑0‑12‑815960‑6.00026‑1
    [Google Scholar]
  38. Ribatti D. The discovery of the fundamental role of VEGF in the development of the vascular system. Mech. Dev. 2019 160 103579 10.1016/j.mod.2019.103579 31644946
    [Google Scholar]
  39. Lv D. Pal P. Liu X. Jia Y. Thummuri D. Zhang P. Hu W. Pei J. Zhang Q. Zhou S. Khan S. Zhang X. Hua N. Yang Q. Arango S. Zhang W. Nayak D. Olsen S.K. Weintraub S.T. Hromas R. Konopleva M. Yuan Y. Zheng G. Zhou D. Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity. Nat. Commun. 2021 12 1 6896 10.1038/s41467‑021‑27210‑x 34824248
    [Google Scholar]
  40. Uxa S. Castillo-Binder P. Kohler R. Stangner K. Müller G.A. Engeland K. Ki-67 gene expression. Cell Death Differ. 2021 28 12 3357 3370 10.1038/s41418‑021‑00823‑x 34183782
    [Google Scholar]
  41. Daina A. Michielin O. Zoete V. Swisstargetprediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019 47 W1 W357 W364 10.1093/nar/gkz382 31106366
    [Google Scholar]
  42. Benny F. Oh J.M. Kumar S. Abdelgawad M.A. Ghoneim M.M. Abdel-Bakky M.S. Kukerti N. Jose J. Kim H. Mathew B. Isatin-based benzyloxybenzene derivatives as monoamine oxidase inhibitors with neuroprotective effect targeting neurogenerative disease treatment. RSC Advances 2023 13 50 35240 35250 10.1039/D3RA07035B 38053684
    [Google Scholar]
  43. Ellman G.L. Courtney K.D. Andres V. Jr Featherstone R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961 7 2 88 95 10.1016/0006‑2952(61)90145‑9 13726518
    [Google Scholar]
  44. Kumar S. Bhowmik R. Oh J.M. Abdelgawad M.A. Ghoneim M.M. Al-Serwi R.H. Kim H. Mathew B. Machine learning driven web-based app platform for the discovery of monoamine oxidase B inhibitors. Sci. Rep. 2024 14 1 4868 10.1038/s41598‑024‑55628‑y 38418571
    [Google Scholar]
  45. Berkel C. Cacan E. In silico analysis of DYNLL1 expression in ovarian cancer chemoresistance. Cell Biol. Int. 2020 44 8 1598 1605 10.1002/cbin.11352 32208526
    [Google Scholar]
  46. Cacan E. Ozmen Z.C. Regulation of Fas in response to bortezomib and epirubicin in colorectal cancer cells. J. Chemother. 2020 32 4 193 201 10.1080/1120009X.2020.1740389 32162602
    [Google Scholar]
  47. Al-Janabi A.S.M. Alheety M.A. Al-Samrai O.A.Y. Shaaban S. Kibar B. Cacan E. Anti-cancer and anti-fungal evaluation of novel palladium(II) 1-phenyl-1H-tetrazol-5-thiol complexes. Inorg. Chem. Commun. 2020 121 108193 10.1016/j.inoche.2020.108193
    [Google Scholar]
  48. Cheung J. Gary E.N. Shiomi K. Rosenberry T.L. Structures of human acetylcholinesterase bound to dihydrotanshinone I and territrem B show peripheral site flexibility. ACS Med. Chem. Lett. 2013 4 11 1091 1096 10.1021/ml400304w 24900610
    [Google Scholar]
  49. Nachon F. Carletti E. Ronco C. Trovaslet M. Nicolet Y. Jean L. Renard P.Y. Crystal structures of human cholinesterases in complex with huprine W and tacrine: Elements of specificity for anti-Alzheimer’s drugs targeting acetyl- and butyryl-cholinesterase. Biochem. J. 2013 453 3 393 399 10.1042/BJ20130013 23679855
    [Google Scholar]
  50. Kumar S. Jayan J. Manoharan A. Benny F. Abdelgawad M.A. Ghoneim M.M. El-Sherbiny M. Thazhathuveedu Sudevan S. Aneesh T.P. Mathew B. Discerning of isatin-based monoamine oxidase (MAO) inhibitors for neurodegenerative disorders by exploiting 2D, 3D-QSAR modelling and molecular dynamics simulation. J. Biomol. Struct. Dyn. 2024 42 5 2328 2340 10.1080/07391102.2023.2214216 37261844
    [Google Scholar]
  51. Mathew B. Oh J.M. Abdelgawad M.A. Khames A. Ghoneim M.M. Kumar S. Nath L.R. Sudevan S.T. Parambi D.G.T. Agoni C. Soliman M.E.S. Kim H. Conjugated dienones from differently substituted cinnamaldehyde as highly potent monoamine oxidase-b inhibitors: Synthesis, biochemistry, and computational chemistry. ACS Omega 2022 7 9 8184 8197 10.1021/acsomega.2c00397 35284720
    [Google Scholar]
  52. Thomas R.R. Trisciuzzi D. Sudevan S.T. Gambacorta N. Catto M. Kumar S. Abdelgawad M.A. El-Ghorab A.H. Selim S. Ghoneim M.M. Zachariah S.M. Nicolotti O. Mathew B. Isatin derived morpholine and piperazine derivatives as acetylcholinesterase inhibitors. J. Mol. Struct. 2025 1322 140503 10.1016/j.molstruc.2024.140503
    [Google Scholar]
  53. Sridhar G.R. Acetylcholinesterase inhibitors (galantamine, rivastigmine, and donepezil). NeuroPsychopharmacotherapy. Cham Springer International Publishing 2022 2709 2721 10.1007/978‑3‑030‑62059‑2_418
    [Google Scholar]
  54. Aydın G. Ercan A. Gene expression levels of apoptotic proteins and multidrug resistance genes in HEPG2 cells. Hacettepe Univ. J. Fac. Pharm. 2012 2 119 132
    [Google Scholar]
/content/journals/cad/10.2174/0115734099359621250320073543
Loading
Cholinesterase Inhibition and Anticancer Properties of [4-(Benzyloxy)phenyl]{Methylidene}hydrazinylidene]-1,3-dihydro-2H-Indol-2-ones Using Swiss Target-guided Prediction
Bentham Science Publishers ; https://doi.org/10.2174/0115734099359621250320073543
/content/journals/cad/10.2174/0115734099359621250320073543
/content/journals/cad/10.2174/0115734099359621250320073543
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: molecular dynamics ; acetylcholinesterase ; hydrazone ; butylcholinestrase ; MTT assay ; Isatin

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test