Computational Investigation of 2,3-Dihydroquinazolin-4(1H)-one Derivatives as Multitarget Anti-Alzheimer Agents

DFT and Molecular Docking Studies against AChE, BChE, and BACE1

Authors

  • Abosede Adejoke Badeji
    Department of Chemical Sciences, Tai Solarin Federal University of Education, Ijagun, Ogun State, Nigeria
  • Olalekan Samuel
    Department of Physiology, Olabisi Onabanjo University, Sagamu Campus, Sagamu, Ogun State, Nigeria
  • Segun D. Oladipo
    Department of Chemical Sciences, Olabisi Onabanjo University, PMB 2002, Ago-Iwoye, Nigeria
  • Adejoke D. Osinubi
    Department of Chemical Sciences, Tai Solarin Federal University of Education, Ijagun, Ogun State, Nigeria
  • Adetoro A. Osanyinbi
    Department of Chemical Sciences, Tai Solarin Federal University of Education, Ijagun, Ogun State, Nigeria
  • Isaac Adebayo Akinbulu
    Department of Chemistry, University of Lagos, Akoka-Yaba 101245, Lagos State, Nigeria

Keywords:

Alzheimer's disease , 2,3-Dihydroquinazolin-4(1H)-one , , Molecular docking , Density functional theory , Multitarget inhibitors

Abstract

Alzheimer's disease (AD) remains one of the greatest unmet medical needs worldwide and requires a multitarget therapeutic approach as a result of its multifactorial pathogenesis. The 2,3-dihydroquinazolin-4(1H)-one scaffold is a pharmacologically privileged drug known to possess neuroprotective, antioxidant, and enzyme-inhibitory activities that are relevant to AD. Six structurally diverse derivatives (3a, 3k, 3m, 3n, 3r, and 3u) were computationally investigated against three important enzymes associated with AD (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase 1 (BACE1)). Molecular electrostatic potential maps, quantum chemical reactivity descriptors, and frontier molecular orbital analysis were calculated via the density functional theory (DFT) method at the M062X/def2TZVP level. The molecular docking was done using the Glide program of Maestro against co-crystallized protein structures (PDB: 7E3H, 7AIY, 5HU1) with Rivastigmine and Verubecestat as reference drugs. DFT analysis showed that compound 3n is the most chemically reactive compound with a HOMO–LUMO gap of 6.51 eV, and compound 3r is the most electrophilic with ω = 2.40 eV. The molecular docking revealed that 3k showed the highest binding affinity towards all three targets (AChE: −11.22 kcal/mol, BChE: −8.17 kcal/mol, BACE1: −7.78 kcal/mol) as compared to Rivastigmine (AChE: −6.66 kcal/mol, BChE: −5.21 kcal/mol). Analysis of interactions indicated that aromatic π–π stacking and hydrogen bonding are the predominant types of interactions involved in the binding of AChE, hydrophobic interactions are predominant in the binding of BChE, and polar interactions are predominant in the binding of BACE1. These results identify 3k as a potential multitarget agent that requires further experimental studies

Dimensions

[1] Ghoneim, M. M., Abdelgawad, M. A., Elkanzi, N. A. A., Parambi, D. G. T., Alsalahat, I., Farouk, A., & Bakr, R. B. (2024). A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives. Archiv Der Pharmazie, 357(8), 2400057. https://doi.org/10.1002/ardp.202400057

[2] Kalakwade, A., Kavalapure, R. S., Gharge, S., Alegaon, S. G., Ranade, S. D., Wong, L. S., & Ramu, R. (2026). Heterocyclic compounds with diverse biological activities: A review of quinazoline and quinazolinone derivatives. Results in Chemistry, 19, 102932. https://doi.org/10.1016/j.rechem.2025.102932

[3] Tokalı, F. S. (2025). Recent advances in quinazolinone derivatives: Structure, design and therapeutic potential. Future Medicinal Chemistry, 17(9), 1071–1091. https://doi.org/10.1080/17568919.2025.2504327

[4] Haneen, D. S. A., Abdalha, A. A., Alkhatib, M. M., Kamal, M., Youssef, A. S. A., Abou-Elmagd, W. S. I., & Samir, S. S. (2025). Synthesis, comprehensive in silico studies, and cytotoxicity evaluation of novel quinazolinone derivatives as potential anticancer agents. Scientific Reports, 15(1), 23697. https://doi.org/10.1038/s41598-025-08062-7

[5] Tokalı, F. S., Taslimi, P., Tuzun, B., Karakuş, A., Sadeghian, N., & Gulçin, İ. (2023). Novel Quinazolinone Derivatives: Potential Synthetic Analogs for the Treatment of Glaucoma, Alzheimer’s Disease and Diabetes Mellitus. Chemistry & Biodiversity, 20(10), e202301134. https://doi.org/10.1002/cbdv.202301134

[6] Liu, J., Yang, B., & Zhang, X. (2024). Theories of Alzheimer’s disease: Amyloid hypothesis, blood-brain barrier hypothesis and cholinergic hypothesis. 553, 05036.

[7] Aarsland, D., Sunde, A. L., Tovar-Rios, D. A., Leuzy, A., Fladby, T., Zetterberg, H., Blennow, K., Tan, K., De Santis, G., & Yakoub, Y. (2026). Prevalence of Alzheimer’s disease pathology in the community. Nature, 650(8100), 182–186. https://www.nature.com/articles/s41586-025-09841-y

[8] Fronza, M. G., Alves, D., Praticò, D., & Savegnago, L. (2023). The neurobiology and therapeutic potential of multi-targeting β-secretase, glycogen synthase kinase 3β and acetylcholinesterase in Alzheimer’s disease. Ageing Research Reviews, 90, 102033. https://www.sciencedirect.com/science/article/pii/S1568163723001927

[9] Liu, J., Yang, B., & Zhang, X. (2024). Theories of Alzheimer’s disease: Amyloid hypothesis, blood-brain barrier hypothesis and cholinergic hypothesis. E3S Web of Conferences, 553, 05036. https://www.e3s-conferences.org/articles/e3sconf/abs/2024/83/e3sconf_epec2024_05036/e3sconf_epec2024_05036.html

[10] Adeowo, F. Y., Elrashedy, A. A., Ejalonibu, M. A., Lawal, I. A., Lawal, M. M., & Kumalo, H. M. (2022). Pharmacophore mapping of the crucial mediators of acetylcholinesterase and butyrylcholinesterase dual inhibition in Alzheimer’s disease. Molecular Diversity, 26(5), 2761–2774. https://doi.org/10.1007/s11030-022-10377-w

[11] Al-Karmalawy, A. A., Mohamed, A. F., Shalaby, H. N., Elmaaty, A. A., El-Shiekh, R. A., Zeidan, M. A., Alnajjar, R., Alzahrani, A. Y. A., Al Mughram, M. H., Shaldam, M. A., & Tawfik, H. O. (2025). Donepezil-based rational design of N -substituted quinazolinthioacetamide candidates as potential acetylcholine esterase inhibitors for the treatment of Alzheimer’s disease: In vitro and in vivo studies. RSC Medicinal Chemistry, 16(5), 2078–2097. https://doi.org/10.1039/D4MD00778F

[12] Arya, R., Jain, S., Paliwal, S., Madan, K., Sharma, S., Mishra, A., Tiwari, P., & Kadiri, S. K. (2024). BACE1 inhibitors: A promising therapeutic approach for the management of Alzheimer’s disease. Asian Pacific Journal of Tropical Biomedicine, 14(9), 369–381. https://journals.lww.com/aptb/fulltext/2024/14090/bace1_inhibitors__a_promising_therapeutic_approach.1.aspx

[13] Abualassal, Q., Abudayeh, Z., Sirhan, A., & Mkia, A. (2025). Exploring quinazoline as a scaffold for developing novel therapeutics in Alzheimer’s disease. Molecules, 30(3), 555.

[14] Verma, A., Waiker, D. K., Singh, N., Roy, A., Singh, N., Saraf, P., Bhardwaj, B., Krishnamurthy, S., Trigun, S. K., & Shrivastava, S. K. (2024). Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer’s Disease Therapy. ACS Chemical Neuroscience, 15(4), 745–771. https://doi.org/10.1021/acschemneuro.3c00653

[15] Chandran, R., Dileep, K. V., Gorantla, S. C., Jeelan Basha, S., Mothukuru, S., Siva Kumar, I., Vamsi, K., Kumar, S., Reddy, A. B. M., & Subramanyam, R. (2024). Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer’s Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses. ACS Chemical Neuroscience, 15(18), 3401–3420. https://europepmc.org/article/med/39235838

[16] Azmal, M., Paul, J. K., Shohan, Md. N. H., Haque, A. N. M. S. N. B., Mrinmoy, M., Talukder, O. F., & Ghosh, A. (2025). Evaluating computational and experimental approaches in early-stage Alzheimer’s drug discovery: A systematic review. Journal of Computer-Aided Molecular Design, 39(1), 27. https://doi.org/10.1007/s10822-025-00610-7

[17] Mihai, D. P., & Nitulescu, G. M. (2025). Computer-aided drug design and drug discovery. Pharmaceuticals, 18(3), 436.

[18] Ferreira, L., Dos Santos, R., Oliva, G., & Andricopulo, A. (2015). Molecular Docking and Structure-Based Drug Design Strategies. Molecules, 20(7), 13384–13421. https://doi.org/10.3390/molecules200713384

[19] Pinzi, L., & Rastelli, G. (2019). Molecular docking: Shifting paradigms in drug discovery. International Journal of Molecular Sciences, 20(18), 4331.

[20] Gürer, E. S., Kaya, S., Berisha, A., & Morales-Bayuelo, A. (2025). On the effect of conceptual density functional theoretical descriptors in the inhibition of acetylcholinesterase enzyme: Gallic acid derivatives. Journal of the Indian Chemical Society, 102(8), 101831.

[21] Hasan, A. H., Abdulrahman, F. A., Obaidullah, A. J., Alotaibi, H. F., Alanazi, M. M., Noamaan, M. A., Murugesan, S., Amran, S. I., Bhat, A. R., & Jamalis, J. (2023). Discovery of Novel Coumarin-Schiff Base Hybrids as Potential Acetylcholinesterase Inhibitors: Design, Synthesis, Enzyme Inhibition, and Computational Studies. Pharmaceuticals, 16(7), 971. https://doi.org/10.3390/ph16070971

[22] Abdullah, N., Hussain, F., Ullah, N., Fatima, H., Tahir, M. A., Rashid, U., & Hassan, A. (2025). Synthesis, Pharmacological Evaluation, and Molecular Modeling of Phthalimide Derivatives as Monoamine Oxidase and Cholinesterase Dual Inhibitors. ACS Omega, 10(10), 10385–10400.

[23] Morales-Bayuelo, A., Baldiris, R., & Vivas-Reyes, R. (2013). Scale alpha and beta of quantitative convergence and chemical reactivity analysis in dual cholinesterase/monoamine oxidase inhibitors for the Alzheimer disease treatment using density functional theory (DFT). Journal of Theoretical Chemistry, 2013(1), 768185.

[24] Chandrashekharappa, S., Mogali, N. M., Sagar, T. K., Guliani, G., Barick, S., Behera, B. K., Khan, A., & Tiwari, P. (2025). Aqueous ammonia mediated catalyst-free green synthesis of 2, 3-dihydroquinazolin-4 (1H)-one derivatives. Tetrahedron, 134997. https://www.sciencedirect.com/science/article/pii/S0040402025005538

[25] Banerjee, P., Kemmler, E., Dunkel, M., & Preissner, R. (2024). ProTox 3.0: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Research, 52(W1), W513–W520.

[26] Frisch, M., Trucks, G., Schlegel, H., Scuseria, G., Robb, M., Cheeseman, J., Scalmani, G., Barone, V., Petersson, G., & Nakatsuji, H. (2016). Gaussian 16 Revision C. 01, 2016. Gaussian Inc. Wallingford CT, 1, 572.

[27] Hohenstein, E. G., Chill, S. T., & Sherrill, C. D. (2008). Assessment of the performance of the M05− 2X and M06− 2X exchange-correlation functionals for noncovalent interactions in biomolecules. Journal of Chemical Theory and Computation, 4(12), 1996–2000.

[28] Badeji, A. (2025). Benzotrithiophene Derivative as a Corrosion Inhibitor: Insights from Density Functional Theory and Monte Carlo Simulation Studies. Journal of Science and Information Technology, 19(1), 10–22.

[29] Gadre, S. R., Suresh, C. H., & Mohan, N. (2021). Electrostatic Potential Topology for Probing Molecular Structure, Bonding and Reactivity. Molecules, 26(11), 3289. https://doi.org/10.3390/molecules26113289

[30] Liu, L., Miao, L., Li, L., Li, F., Lu, Y., Shang, Z., & Chen, J. (2018). Molecular Electrostatic Potential: A New Tool to Predict the Lithiation Process of Organic Battery Materials. The Journal of Physical Chemistry Letters, 9(13), 3573–3579. https://doi.org/10.1021/acs.jpclett.8b01123

[31] Bradley, J. D., & Gerrans, G. C. (1973). Frontier molecular orbitals. A link between kinetics and bonding theory. Journal of Chemical Education, 50(7), 463. https://doi.org/10.1021/ed050p463

[32] Huang, Y., Rong, C., Zhang, R., & Liu, S. (2017). Evaluating frontier orbital energy and HOMO/LUMO gap with descriptors from density functional reactivity theory. Journal of Molecular Modeling, 23(1), 3. https://doi.org/10.1007/s00894-016-3175-x

[33] Kateris, N., Xu, R., & Wang, H. (2023). HOMO-LUMO energy gaps of complexes of transition metals with single and multi-ring aromatics. Combustion and Flame, 257, 112513.

[34] Oladipo, S. D., Luckay, R. C., Badeji, A. A., Zamisa, S. Z., Olalekan, S. O., & Oladoye, P. O. (2025). Structural studies, DFT computational analysis and inhibitory potential of (E)-N’-(2-bromophenyl)-N-(2,6-diisopropylphenyl)formamidine against CDK1 and CDK2. Journal of Molecular Structure, 1320, 139734. https://doi.org/10.1016/j.molstruc.2024.139734

[35] Huang, Y., Rong, C., Zhang, R., & Liu, S. (2017). Evaluating frontier orbital energy and HOMO/LUMO gap with descriptors from density functional reactivity theory. Journal of Molecular Modeling, 23(1), 3. https://doi.org/10.1007/s00894-016-3175-x

[36] Saidj, M., Djafri, A., Rahmani, R., Belkafouf, N. E. H., Boukabcha, N., Djafri, A., & Chouaih, A. (2023). Molecular Structure, Experimental and Theoretical Vibrational Spectroscopy, (HOMO-LUMO, NBO) Investigation, (RDG, AIM) Analysis, (MEP, NLO) Study and Molecular Docking of Ethyl-2-{[4-Ethyl-5-(Quinolin-8-yloxyMethyl)-4H-1,2,4-Triazol-3-yl] Sulfanyl} Acetate. Polycyclic Aromatic Compounds, 43(3), 2152–2176. https://doi.org/10.1080/10406638.2022.2039238

[37] Islam, N., & Ghosh, D. C. (2011). The electronegativity and the global hardness are periodic properties of atoms. Journal of Quantum Information Science, 1(3), 135–141.

[38] Morad, R., Akbari, M., & Maaza, M. (2023). Theoretical study of chemical reactivity descriptors of some repurposed drugs for COVID-19. MRS Advances, 8(11), 656–660. https://doi.org/10.1557/s43580-023-00590-6

[39] Olalekan, S. O., Obakachi, V. A., Badeji, A. A., Akinsipo, O. B., Familoni, O., Asekun, O. T., Oladipo, S. D., & Osinubi, A. D. (2024). Exploring the therapeutic potential of prolinamides as multi-targeted agents for Alzheimer’s disease treatment: Molecular docking and molecular dynamic simulation studies. In Silico Pharmacology, 12(2), 80. https://doi.org/10.1007/s40203-024-00250-z

[40] Dennington, R., Keith, T., & Millam, J. (2023). GaussView, Version 6.0. 1.6, Semichem Inc., Shawnee Mission, KS, 2016. There Is No Corresponding Record for This Reference.

[41] Andrienko, G. (2010). Chemcraft-graphical software for visualization of quantum chemistry computations. See Https://Www. Chemcraftprog. Com.

[42] Awas, E. O., Midiwo, J. O., Omosa, L. K., Derese, S., Kiganda, I., Omole, R. A., Akala, H. M., Ochora, D. O., Obakachi, V. A., Olalekan, S., Govender, K. K., & Nchiozem-Ngnitedem, V.-A. (2025). In vitro, ex vivo, and in silico studies of phytochemicals from the stem bark of Bischofia javanica. Natural Product Research, 1–7. https://doi.org/10.1080/14786419.2025.2521380

[43] Oladipo, S., Adeleke, A. A., Badeji, A. A., Babalola, K. I., Labulo, A. H., Hassan, I., Yussuf, S. T., & Olalekan, S. O. (2024). Computational investigation and biological activity of selected Schiff bases. Journal of the Nigerian Society of Physical Sciences, 2103–2103. https://doi.org/10.46481/jnsps.2024.2103

[44] Dileep, K. V., Ihara, K., Mishima-Tsumagari, C., Kukimoto-Niino, M., Yonemochi, M., Hanada, K., Shirouzu, M., & Zhang, K. Y. J. (2022). Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery. International Journal of Biological Macromolecules, 210, 172–181. https://doi.org/10.1016/j.ijbiomac.2022.05.009

[45] Viayna, E., Coquelle, N., Cieslikiewicz-Bouet, M., Cisternas, P., Oliva, C. A., Sánchez-López, E., Ettcheto, M., Bartolini, M., De Simone, A., Ricchini, M., Rendina, M., Pons, M., Firuzi, O., Pérez, B., Saso, L., Andrisano, V., Nachon, F., Brazzolotto, X., García, M. L., … Muñoz-Torrero, D. (2021). Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice. Journal of Medicinal Chemistry, 64(1), 812–839. https://doi.org/10.1021/acs.jmedchem.0c01775

[46] Scott, J. D., Li, S. W., Brunskill, A. P. J., Chen, X., Cox, K., Cumming, J. N., Forman, M., Gilbert, E. J., Hodgson, R. A., Hyde, L. A., Jiang, Q., Iserloh, U., Kazakevich, I., Kuvelkar, R., Mei, H., Meredith, J., Misiaszek, J., Orth, P., Rossiter, L. M., … Stamford, A. W. (2016). Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease. Journal of Medicinal Chemistry, 59(23), 10435–10450. https://doi.org/10.1021/acs.jmedchem.6b00307

[47] Shelley, J. C., Cholleti, A., Frye, L. L., Greenwood, J. R., Timlin, M. R., & Uchimaya, M. (2007). Epik: A software program for pK a prediction and protonation state generation for drug-like molecules. Journal of Computer-Aided Molecular Design, 21(12), 681–691. https://doi.org/10.1007/s10822-007-9133-z

[48] Jacobson, M. P., Pincus, D. L., Rapp, C. S., Day, T. J. F., Honig, B., Shaw, D. E., & Friesner, R. A. (2004). A hierarchical approach to all‐atom protein loop prediction. Proteins: Structure, Function, and Bioinformatics, 55(2), 351–367. https://doi.org/10.1002/prot.10613

[49] Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., Shaw, D. E., Francis, P., & Shenkin, P. S. (2004). Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. Journal of Medicinal Chemistry, 47(7), 1739–1749. https://doi.org/10.1021/jm0306430

cover

Published

2026-06-29

How to Cite

Computational Investigation of 2,3-Dihydroquinazolin-4(1H)-one Derivatives as Multitarget Anti-Alzheimer Agents: DFT and Molecular Docking Studies against AChE, BChE, and BACE1. (2026). Lafia Journal of Scientific and Industrial Research, 4(2), 42-59. https://doi.org/10.62050/ljsir2026.v4n2.876

Issue

Volume 4, Issue 2 (October, 2026), Lafia Journal of Scientific and Industrial Research (LJSIR) [IN PROGRESS]

Section

Physical Sciences
Copyright & Licensing

Copyright (c) 2026 Abosede Adejoke Badeji, Olalekan Samuel, Segun D. Oladipo, Adejoke D. Osinubi, Adetoro A. Osanyinbi, Isaac Adebayo Akinbulu (Author)

Creative Commons License

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

How to Cite

Computational Investigation of 2,3-Dihydroquinazolin-4(1H)-one Derivatives as Multitarget Anti-Alzheimer Agents: DFT and Molecular Docking Studies against AChE, BChE, and BACE1. (2026). Lafia Journal of Scientific and Industrial Research, 4(2), 42-59. https://doi.org/10.62050/ljsir2026.v4n2.876

Similar Articles

1-10 of 45

You may also start an advanced similarity search for this article.