Synthesis, Spectroscopic Characterization, and In Silico Evaluation of Heteroaromatic Chalcone Derivatives at the Colchicine-Binding Site of α/β-Tubulin

Shireen Nadhem  Saleh; Asmaa Adnan  Abdulnabi; Omeed Muhsin  Hassan

doi:10.51699/cajmns.v7i4.3379

Authors

Shireen Nadhem Saleh Department of Pharmaceutical Chemistry, College of Pharmacy, Tikrit University, Salah Al-Din, Iraq
Asmaa Adnan Abdulnabi Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Nahrain University, Baghdad, Iraq
Omeed Muhsin Hassan Department of Pharmaceutical Chemistry, College of Pharmacy, University of Kirkuk, Kirkuk, Iraq

DOI:

https://doi.org/10.51699/cajmns.v7i4.3379

Keywords:

Chalcone derivatives, Colchicine-binding site, Molecular docking, ProTox 3.0, SwissADME, Tubulin

Abstract

Six heteroaromatic chalcone derivatives (C1–C6) were synthesized by base-catalyzed Claisen–Schmidt condensation and characterized by Fourier-transform infrared (FTIR) and proton nuclear magnetic resonance (¹H NMR) spectroscopy. Physicochemical properties, drug-likeness, absorption, distribution, metabolism, and excretion (ADME), toxicity, and predicted tubulin binding were evaluated using SwissADME, ProTox 3.0, and Molecular Operating Environment (MOE) 2019 docking at the colchicine-binding site of α/β-tubulin (Protein Data Bank ID: 4O2B). The docking protocol was validated by re-docking colchicine. The compounds were obtained in 60–80% yields with melting points of 110–196 °C. All derivatives showed zero Lipinski rule-of-five violations and high predicted gastrointestinal absorption. Predicted oral median lethal dose (LD₅₀) values ranged from 800 to 2652 mg/kg. Docking scores ranged from −7.116 to −5.914 kcal/mol. C3 showed the most favorable score (−7.116 kcal/mol) versus re-docked colchicine (−6.992 kcal/mol), with predicted hydrogen bonds to Asn A101 and Lys B254. C3 also had the highest predicted lipophilicity and poorest aqueous solubility, indicating a structure–property trade-off. Experimental tubulin-focused biochemical and cellular studies are required before biological activity can be inferred.

References

H. Sung, A. M. Filho, M. Laversanne, J. Ferlay, R. L. Siegel, I. Soerjomataram, A. Jemal, and F. Bray, “Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries,” CA Cancer J. Clin., vol. 76, Art. no. e70090, 2026, doi: 10.3322/caac.70090.

H. C. Assunção, P. M. A. Silva, H. Bousbaa, and H. Cidade, “Recent advances in microtubule targeting agents for cancer therapy,” Molecules, vol. 30, Art. no. 3314, 2025, doi: 10.3390/molecules30163314.

E. Pasquier and M. Kavallaris, “Microtubules: A dynamic target in cancer therapy,” IUBMB Life, vol. 60, pp. 165–170, 2008, doi: 10.1002/iub.25.

E. C. McLoughlin and N. M. O'Boyle, “Colchicine-binding site inhibitors from chemistry to clinic: A review,” Pharmaceuticals, vol. 13, Art. no. 8, 2020, doi: 10.3390/ph13010008.

J. Wang, D. D. Miller, and W. Li, “Molecular interactions at the colchicine binding site in tubulin: An X-ray crystallography perspective,” Drug Discov. Today, vol. 27, pp. 759–776, 2022, doi: 10.1016/j.drudis.2021.12.001.

C. Zhuang, W. Zhang, C. Sheng, W. Zhang, C. Xing, and Z. Miao, “Chalcone: A privileged structure in medicinal chemistry,” Chem. Rev., vol. 117, pp. 7762–7810, 2017, doi: 10.1021/acs.chemrev.7b00020.

N. A. A. A. Elkanzi, H. Hrichi, R. A. Alolayan, W. Derafa, F. M. Zahou, and R. B. Bakr, “Synthesis of chalcone derivatives and their biological activities: A review,” ACS Omega, vol. 7, pp. 27769–27786, 2022, doi: 10.1021/acsomega.2c01779.

H. Zhang, J. J. Liu, J. Sun, X. H. Yang, T. T. Zhao, X. Lu, H. B. Gong, and H. L. Zhu, “Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents,” Bioorg. Med. Chem., vol. 20, pp. 3212–3218, 2012, doi: 10.1016/j.bmc.2012.03.055.

R. Romagnoli, P. G. Baraldi, M. D. Carrion, C. Lopez Cara, O. Cruz-Lopez, D. Preti, M. Tolomeo, S. Grimaudo, A. Di Cristina, N. Zonta, J. Balzarini, A. Brancale, T. Sarkar, and E. Hamel, “Design, synthesis, and biological evaluation of thiophene analogues of chalcones,” Bioorg. Med. Chem., vol. 16, pp. 5367–5376, 2008, doi: 10.1016/j.bmc.2008.04.026.

K. Mezgebe, Y. Melaku, and E. Mulugeta, “Synthesis and pharmacological activities of chalcone and its derivatives bearing N-heterocyclic scaffolds: A review,” ACS Omega, vol. 8, pp. 19194–19211, 2023, doi: 10.1021/acsomega.3c01035.

R. M. Mohareb, A. A. Mohamed, and R. A. Ibrahim, “Uses of chalcone acetophenone to synthesis heterocyclic compounds with cytotoxic and c-Met kinase activities,” Bull. Chem. Soc. Ethiop., vol. 36, pp. 149–172, 2022, doi: 10.4314/bcse.v36i1.13.

K. M. Qadir, H. Y. Hussein, M. Y. Aziz, M. M. Ayoob, M. K. Samad, A. J. Hussien, N. G. Ahmed, and F. E. Hawaiz, “Synthesis, molecular docking study and antibacterial activity of new pyrazoline derivatives,” Bull. Chem. Soc. Ethiop., vol. 39, pp. 955–966, 2025, doi: 10.4314/bcse.v39i5.11.

M. A. Shalaby, S. A. Rizk, and A. M. Fahim, “Synthesis, reactions and application of chalcones: A systematic review,” Org. Biomol. Chem., vol. 21, pp. 5317–5346, 2023, doi: 10.1039/D3OB00792H.

A. Daina, O. Michielin, and V. Zoete, “SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules,” Sci. Rep., vol. 7, Art. no. 42717, 2017, doi: 10.1038/srep42717.

P. Banerjee, E. Kemmler, M. Dunkel, and R. Preissner, “ProTox 3.0: A webserver for the prediction of toxicity of chemicals,” Nucleic Acids Res., vol. 52, pp. W513–W520, 2024, doi: 10.1093/nar/gkae303.

RCSB Protein Data Bank, “4O2B: Tubulin-colchicine complex,” RCSB PDB, 2014, doi: 10.2210/pdb4O2B/pdb.

A. E. Prota, F. Danel, F. Bachmann, K. Bargsten, R. M. Buey, J. Pohlmann, S. Reinelt, H. Lane, and M. O. Steinmetz, “The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization,” J. Mol. Biol., vol. 426, pp. 1848–1860, 2014, doi: 10.1016/j.jmb.2014.02.005.

Chemical Computing Group ULC, Molecular Operating Environment (MOE), version 2019.01. Montreal, QC, Canada: Chemical Computing Group ULC, 2019.

T. A. Halgren, “Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94,” J. Comput. Chem., vol. 17, pp. 490–519, 1996, doi: 10.1002/(SICI)1096-987X(199604)17:5/6<490::AID-JCC1>3.0.CO;2-P.

P. Labute, “Protonate3D: Assignment of ionization states and hydrogen coordinates to macromolecular structures,” Proteins, vol. 75, pp. 187–205, 2009, doi: 10.1002/prot.22234.