Cover
Vol. 4 No. 1 (2026)

Published: June 1, 2026

Pages: 245-258

Research Article

Design, Molecular Docking, and Pharmacokinetic Evaluation of 4-Aminoantipyrine Derivatives as Potential Anticancer Compounds Targeting Histone Deacetylase-2 (HDAC-2)

Doaa Abdullah 1 Mohammed Jasim Hamzah 1 Ameer H. Alwash 2
1 Al-Nahrain University college of pharmacy
2 Al-Bayan University
History
  • Received: March 28, 2026
  • Revised: May 3, 2026
  • Accepted: May 16, 2026
  • Available Online: June 1, 2026

Abstract

Objective: Histone deacetylase-2 (HDAC-2) has emerged as an important molecular target in cancer therapy because of its role in gene silencing, regulation of the cell cycle, and resistance to apoptosis in several cancer types. In the present study, a series of novel 4-aminoantipyrine-based derivatives incorporating semicarbazide, thiosemicarbazide, and hydroxylamine pharmacophoric groups were rationally designed and evaluated for their potential HDAC-2 inhibitory activity using in silico approaches. Methods:. The binding affinity of the newly designed compounds toward the HDAC-2 enzyme and their interactions within the catalytic pocket were investigated using molecular docking analysis. The three-dimensional structure of HDAC-2 (PDB ID: 4LXZ) was obtained from the RCSB Protein Data Bank and prepared for docking studies.   Results: Docking indicated that ligand stability within the enzyme active site was mainly achieved through coordination with the catalytic zinc ion, in addition to hydrogen bonding and hydrophobic interactions with essential amino acid residues located in the HDAC-2 catalytic domain. The reference inhibitor vorinostat (SAHA) was used as a standard compound and produced a docking score of −5.445 kcal/mol. Among the designed compounds, Compound Ia exhibited the most favorable binding energy with a calculated ΔG of −9.711 kcal/mol. In addition, Compound IIe and Compound Ib demonstrated promising docking scores of −8.285 and −8.147 kcal/mol, respectively.   Conclusions: Pharmacokinetic properties were predicted using the QikProp module, revealing that most designed compounds exhibited acceptable drug-likeness according to Lipinski’s Rule of Five. These computational findings suggest that the designed derivatives may represent promising candidates as HDAC-2 inhibitors with potential anticancer activity.

Keywords

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. https://doi.org/10.3322/caac.21834
  2. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. https://doi.org/10.1158/2159-8290.CD-21-1059
  3. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357(6348):eaal2380. https://doi.org/10.1126/science.aal2380
  4. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713. https://doi.org/10.1101/cshperspect.a018713
  5. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18(7):1414. https://doi.org/10.3390/ijms18071414
  6. Niegisch G, Grassner L, Bernardo E, Hrouda D. HDAC inhibition in cancer: an updated review on class I HDACs. Molecules. 2020;25(4):832. https://doi.org/10.3390/molecules25040832
  7. Bhagat R, Panchal S, Bhatt V, Thakor P. Zinc-based inhibition of HDAC enzymes: structural and mechanistic perspectives. Biometals. 2021;34(4):757-774. https://doi.org/10.1007/s10534-021-00307-4
  8. Negmeldin AT, Knoff JR, Pflum MKH. The structural requirements of histone deacetylase inhibitors: C4-modified SAHA analogs display dual HDAC6/HDAC8 selectivity. Eur J Med Chem. 2018;143:1399-1412. https://doi.org/10.1016/j.ejmech.2017.10.029
  9. Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13(9):673-691. https://doi.org/10.1038/nrd4360
  10. Lauffer BE, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, Doberstein SK. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J Biol Chem. 2013;288(37):26926-26943. https://doi.org/10.1074/jbc.M113.490706
  11. Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 insight and hindsight. J Med Chem. 2020;63(21):12460-12484. https://doi.org/10.1021/acs.jmedchem.0c00830
  12. El-Gohary NS, Shaaban MI. Synthesis and antimicrobial evaluation of new 4-aminoantipyrine-based heterocyclic scaffolds. Arch Pharm. 2020;353(3):e1900293. https://doi.org/10.1002/ardp.201900293
  13. Verma G, Marella A, Shaquiquzzaman M, Akhtar M, Ali MR, Alam MM. A review exploring biological activities of hydrazones. J Pharm Bioallied Sci. 2014;6(2):69-80. https://doi.org/10.4103/0975-7406.129170
  14. Nasr MNA, Abdelgawad NM, Bondock S, Youssef M. Design, synthesis and anticancer evaluation of novel 4-aminoantipyrine derivatives. Future Med Chem. 2021;13(14):1213-1227. https://doi.org/10.4155/fmc-2020-0225
  15. Pinzi L, Rastelli G. Molecular docking: shifting paradigms in drug discovery. Int J Mol Sci. 2019;20(18):4331. https://doi.org/10.3390/ijms20184331
  16. Walters WP, Murcko MA. Prediction of drug-likeness. Adv Drug Deliv Rev. 2002;54(3):255-271. https://doi.org/10.1016/S0169-409X(02)00003-0
  17. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Bourne PE. The Protein Data Bank. Nucleic Acids Res. 2000;28(1):235-242. https://doi.org/10.1093/nar/28.1.235
  18. Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Deliv Rev. 2002;54(3):355-366. https://doi.org/10.1016/S0169-409X(02)00008-X
  19. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26. https://doi.org/10.1016/S0169-409X(00)00129-0
  20. Iwaloye O, Elekofehinti OO, Momoh AI, Babatomiwa K, Ariyo EO. In silico molecular studies of natural compounds as possible anti-Alzheimer's agents: ligand-based design. Network Model Anal Health Inform Bioinform. 2020;9:1-14. https://doi.org/10.1007/s13721-020-00261-6
  21. Iwaloye O, Elekofehinti OO, Oluwarotimi EA, Kikiowo BI, Fadipe TM. Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies. In Silico Pharmacol. 2020;8:1-13. https://doi.org/10.1007/s40203-020-00054-x
  22. Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, Wang L, Lupyan D, Dahlgren MK, Knight JL. OPLS3: A force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput. 2016;12(1):281-296. https://doi.org/10.1021/acs.jctc.5b00864
  23. Schrödinger LLC. LigPrep, version 4.5. New York, NY: Schrödinger, LLC; 2021. https://www.schrodinger.com/products/ligprep