The Relationship Between AChE and BChE Enzymes and Alzheimer’s Disease: ADME, Molecular Docking, and DFT Studies of Schiff Base-Substituted Phenylpyrimidine

Year 2025, Volume: 21 Issue: 4, 1 - 15, 29.12.2025

Kenan Gören , Mehmet Bağlan , Veysel Tahiroğlu , Ümit Yıldıko

https://doi.org/10.18466/cbayarfbe.1538029

Abstract

The theoretical molecular structure of Ethyl 2-(2-benzylidenehydrazinyl)-4-methyl-6-phenylpyrimidine-5-carboxylate (DHPM), a pyrimidine derivative containing the Schiff base structure, was investigated using the Gaussian 09 software program. The chemical structure and chemical reactivity of the compound were calculated using Density Functional Theory (DFT). Quantum chemical calculations were performed using DFT(B3LYP/6-311G(d,p)) and DFT(B3PW91/LANL2DZ) methods and basis sets. Using these two methods and basis sets, molecular electrostatic potential (MEP) maps of the DHPM compound were drawn. Charge transfer properties of DHPM compound were analyzed using HOMO and LUMO level energy analysis. The stability of molecules as a consequence of charge delocalization and hyperconjugative interaction was studied using NBO analysis. In this study, the relationship between Alzheimer's disease and Acetylcholinesterase (AChE) (PDB:6WUY) and Butyrylcholinesterase (BChE) (PDB: 6SAM) enzymes was evaluated by molecular docking. The molecular docking scores of in molecular docking analysis were found to be -7.76 (PDB ID: 6WUY) and -7.98 (PDB ID: 6SAM) kcal. Finally in the study, ADME analysis was performed to evaluate DHPM compound as a drug according to Lipinski's rules. As a result of the ADME analysis, we think that DHPM compound will be evaluated as a drug candidate since it complies with Lipinski's rules.

Keywords

DFT , Molecular Docking , ADME , NBO , Alzheimer , 2-(2-benzylidenehydrazinyl)-4-methyl-6-phenylpyrimidine-5-carboxylate.

References

• [1]. Raczuk, E, Dmochowska, B, Samaszko-Fiertek, J, Madaj, J. 2022. Different Schiff Bases—Structure, Importance and Classification. Molecules, 27(3): 787.
• [2]. Berhanu, AL, Gaurav, Mohiuddin, I, Malik, AK, Aulakh, JS, Kumar, V, Kim, K-H. 2019. A review of the applications of Schiff bases as optical chemical sensors. TrAC Trends in Analytical Chemistry, 116(74-91. https://doi.org/10.1016/j.trac.2019.04.025.
• [3]. Hodnett, EM, Dunn, WJ. 1970. Structure-antitumor activity correlation of some Schiff bases. Journal of Medicinal Chemistry, 13(4): 768-770. 10.1021/jm00298a054.
• [4]. Cordes, EH, Jencks, WP. 1962. On the Mechanism of Schiff Base Formation and Hydrolysis. Journal of the American Chemical Society, 84(5): 832-837. 10.1021/ja00864a031.
• [5]. Metzler, CM, Cahill, A, Metzler, DE. 1980. Equilibriums and absorption spectra of Schiff bases. Journal of the American Chemical Society, 102(19): 6075-6082. 10.1021/ja00539a017.
• [6]. Gupta, KC, Sutar, AK. 2008. Catalytic activities of Schiff base transition metal complexes. Coordination Chemistry Reviews, 252(12): 1420-1450. https://doi.org/10.1016/j.ccr.2007.09.005.
• [7]. Sinn, E, Harris, CM. 1969. Schiff base metal complexes as ligands1. Coordination Chemistry Reviews, 4(4): 391-422. https://doi.org/10.1016/S0010-8545(00)80080-6.
• [8]. Tian, X, Song, Z, Wang, B, Zhou, G. 2020. A Theoretical Calculation Method of Influence Radius of Settlement Based on the Slices Method in Tunnel Construction. Mathematical Problems in Engineering, 2020: 5804823. 10.1155/2020/5804823.
• [9]. Bağlan, M, Gören, K, Çakmak, İ. 2022. Theoretical Investigation of 1H and 13C NMR Spectra of Diethanol Amine Dithiocarbamate RAFT Agent. Journal of the Institute of Science and Technology, 12(3): 1677-1689. 10.21597/jist.1103750.
• [10]. Parlak, C, Bilge, M, Kalaycı, T, Bardakçı, B. 2011. DFT, FT-Raman and FT-IR investigations of 5-o-tolyl-2-pentene. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 79(5): 1077-1083. https://doi.org/10.1016/j.saa.2011.04.022.
• [11]. Kartal, B, Tanriverdi, AA, Yildiko, U, Tekes, AT, Çakmak, I. 2024. Polyimide synthesis and characterizations: DFT-assisted computational studies on structural units. Iranian Polymer Journal, 10.1007/s13726-024-01414-6.
• [12]. Yildiko, U, Tanriverdi, AA. 2021. Synthesis and characterization of pyromellitic dianhydride based sulfonated polyimide: Survey of structure properties with DFT and QTAIM. Journal of Polymer Research, 29(1): 19. 10.1007/s10965-021-02872-9.
• [13]. Becke, AD. 1988. Density-functional exchange-energy approximation with correct asymptotic behavior. Physical review A, 38(6): 3098.
• [14]. Lee, C, Yang, W, Parr, RG. 1988. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical review B, 37(2): 785.
• [15]. Perdew, JP. 1986. Density-functional approximation for the correlation energy of the inhomogeneous electron gas. Physical review B, 33(12): 8822.
• [16]. Demir, Z, Türkan, F. 2022. Asetilkolinesteraz ve Bütirilkolinesteraz Enzimlerinin Alzheimer Hastalığı ile İlişkisi. Journal of the Institute of Science and Technology, 12(4): 2386-2395. 10.21597/jist.1161271.
• [17]. Lane, CA, Hardy, J, Schott, JM. 2018. Alzheimer's disease. European Journal of Neurology, 25(1): 59-70. https://doi.org/10.1111/ene.13439.
• [18]. Darvesh, S. 2016. Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer’s Disease. Current Alzheimer Research, 13(10): 1173-1177.
• [19]. Yildiko, Ü, Türkan, F, Tanriverdi, AA, Ata, AC, Atalar, MN, Cakmak, İ. 2021. Synthesis, enzymes inhibitory properties and characterization of 2- (bis (4-aminophenyl) methyl) butan-1-ol compound: Quantum simulations, and in-silico molecular docking studies. Journal of the Indian Chemical Society, 98(11): 100206. https://doi.org/10.1016/j.jics.2021.100206.
• [20]. Liu, M, Sun, X, Zhang, J. 2017. Synthesis and characterization of a series of novel 2-Schiff base-substituted phenylpyrimidine. Arabian Journal of Chemistry, 10(2): 167-171. https://doi.org/10.1016/j.arabjc.2014.11.053.
• [21]. Nayak, SG, Poojary, B. 2019. Synthesis of novel Schiff bases containing arylpyrimidines as promising antibacterial agents. Heliyon, 5(e02318. 10.1016/j.heliyon.2019.e02318.
• [22]. Liu, M, Sun, X, Zhang, J. Synthesis and characterization of a series of novel 2-Schiff base-substituted phenylpyrimidine. Arabian Journal of Chemistry, 10(10.1016/j.arabjc.2014.11.053.
• [23]. G. W. T. M.J. Frisch, HBS, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, Ö. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian 09. 2009.
• [24]. Release, S, 1: Maestro, Schrodinger, LLC, New York. 2019.
• [25]. Burley, SK, Berman, HM, Bhikadiya, C, Bi, C, Chen, L, Di Costanzo, L, Christie, C, Dalenberg, K, Duarte, JM, Dutta, S. 2019. RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic acids research, 47(D1): D464-D474.
• [26]. ADMETlab 2.0. [cited 2024].
• [27]. Bağlan, M, Gören, K, Yıldıko, Ü. 2023. HOMO–LUMO, NBO, NLO, MEP analysis and molecular docking using DFT calculations in DFPA molecule. International Journal of Chemistry and Technology, 7(1): 38-47. 10.32571/ijct.1135173
• [28]. Tahiroğlu, V, Gören, K, Yıldıko, Ü, Bağlan, M. 2024. IInvestigation, Structural Characterization and Evaluation of the Biological Potency by Molecular Docking of Amoxicillin Analogue of a Schiff Base Molecule. International Journal of Chemistry and Technology, 8(2): 190-199. 10.32571/ijct.1410570.
• [29]. Gören, K, Bağlan, M, Tahiroğlu, V, Yıldıko, Ü. 2024. Theoretical Calculations and Molecular Docking Analysis of 4-(2-(4-Bromophenyl)Hydrazineylidene)-3,5-Diphenyl-4H-Pyrazole Molecule. Journal of Advanced Research in Natural and Applied Sciences, 10(4): 786-802. 10.28979/jarnas.1516154.
• [30]. Zhang, G, Musgrave, CB. 2007. Comparison of DFT Methods for Molecular Orbital Eigenvalue Calculations. The Journal of Physical Chemistry A, 111(8): 1554-1561. 10.1021/jp061633o.
• [31]. Tsipis, CA. 2005. DFT study of “all-metal” aromatic compounds. Coordination Chemistry Reviews, 249(24): 2740-2762. https://doi.org/10.1016/j.ccr.2005.01.031.
• [32]. Ersanlı, CC, Başak, S. 2024. Structure Elucidation of Schiff Base-Containing Compound by Quantum Chemical Methods. International Scientific and Vocational Studies Journal, 8(2): 129-136. 10.47897/bilmes.1553500.
• [33]. Uluçam, G, Yentürk, B. 2019. (1E,1;E)-N,N;-(hekzan-1,6-diil)bis(1-(tiyofen-2-il)metanimin) ve (1E,1;E)-N,N;-(oktan-1,8-diil)bis(1-(tiyofen-2-il)metanimin) Schiff Baz Ligantlarının Deneysel ve Teorik Karakterizasyonu. Journal of the Institute of Science and Technology, 9(3): 1431-1442. 10.21597/jist.500254.
• [34]. Gören, K, Bağlan, M, Yıldıko, Ü. 2025. Analysis By DFT, Adme And Docking Studies Of N'-(4-Hydroxy-3-Methoxybenzylidene)Naphtho[2,3-B]Furan-2-Carbohydrazide. Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi B-Teorik Bilimler, 13(1): 7-23. 10.20290/estubtdb.1501639.
• [35]. Bağlan, M, Yıldıko, Ü, Gören, K. 2022. Computational Investigation of 5.5'',7''-trihydroxy-3,7-dimethoxy-4'-4'''-O-biflavone from Flavonoids Using DFT Calculations and Molecular Docking. Adıyaman University Journal of Science, 12(2): 283-298. 10.37094/adyujsci.1121018.
• [36]. Gören, K, Bağlan, M, Yıldıko, Ü. 2024. Antimicrobial, and Antitubercular Evaluation with ADME and Molecular Docking Studies and DFT Calculatıons of (Z)-3-((1-(5-amino-1,3,4-thiadiazol-2-yl)-2-Phenylethyl)imino)-5-nitroindolin-2-one Schiff Base. Karadeniz Fen Bilimleri Dergisi, 14(4): 1694-1708. 10.31466/kfbd.1423367.
• [37]. Tahiroğlu, V, Gören, K, Çimen, E, Yıldıko, Ü. 2024. Moleculer Docking and Theoretical Analysis of the (E)-5-((Z)-4-methylbenzylidene)-2-(((E)-4-methylbenzylidene)hydrazineylidene)-3-phenylthiazolidin-4-one Molecule. Bitlis Eren Üniversitesi Fen Bilimleri Dergisi, 13(3): 659-672. 10.17798/bitlisfen.1471235.
• [38]. Hratchian, HP, Parandekar, PV, Raghavachari, K, Frisch, MJ, Vreven, T. 2008. QM:QM electronic embedding using Mulliken atomic charges: Energies and analytic gradients in an ONIOM framework. The Journal of Chemical Physics, 128(3): 10.1063/1.2814164.
• [39]. Kalaycı, T, Kınaytürk, NK, Tunalı, B. 2021. Experimental and theoretical investigations (FTIR, UV-VIS spectroscopy, HOMO-LUMO, NLO and MEP analysis) of aminothiophenol isomers. Bulletin of the Chemical Society of Ethiopia, 35(3): 601-614.
• [40]. Yildiko, U, Tanriverdi, AA. 2022. A novel sulfonated aromatic polyimide synthesis and characterization: Energy calculations, QTAIM simulation study of the hydrated structure of one unit. Bulletin of the Korean Chemical Society, 43(6): 822-835. https://doi.org/10.1002/bkcs.12521.
• [41]. Gören, K, Bağlan, M, Yıldıko, Ü. 2024. Melanoma Cancer Evaluation with ADME and Molecular Docking Analysis, DFT Calculations of (E)-methyl 3-(1-(4-methoxybenzyl)-2,3-dioxoindolin-5-yl)-acrylate Molecule. Journal of the Institute of Science and Technology, 14(3): 1186-1199. 10.21597/jist.1467666.
• [42]. Gören, K, Yıldıko, Ü. 2024. Aldose Reductase Evaluation against Diabetic Complications Using ADME and Molecular Docking Studies and DFT Calculations of Spiroindoline Derivative Molecule. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 28(2): 281-292. 10.19113/sdufenbed.1474689.
• [43]. Bağlan, M, Yildiko, Ü, Gören, K. 2023. DFT Calculatıons cnd Molecular Docking Study In 6-(2”-Pyrrolıdınone-5”-Yl)-(-) Epıcatechın Molecule from Flavonoıds. Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi B - Teorik Bilimler, 11(1): 43-55. 10.20290/estubtdb.1126604.
• [44]. Muthu, S, Uma Maheswari, J. 2012. Quantum mechanical study and spectroscopic (FT-IR, FT-Raman, 13C, 1H, UV) study, first order hyperpolarizability, NBO analysis, HOMO and LUMO analysis of 4-[(4-aminobenzene) sulfonyl] aniline by ab initio HF and density functional method. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 92(154-163. https://doi.org/10.1016/j.saa.2012.02.056.
• [45]. Karabacak, M, Bilgili, S, Atac, A. 2015. Molecular structure, spectroscopic characterization, HOMO and LUMO analysis of 3,3′-diaminobenzidine with DFT quantum chemical calculations. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 150(83-93. https://doi.org/10.1016/j.saa.2015.05.013.
• [46]. Bağlan, M, Gören, K, Yildiko, Ü. 2023. DFT Computations and Molecular Docking Studies of 3-(6-(3-aminophenyl)thiazolo[1,2,4]triazol-2-yl)-2H-chromen-2-one(ATTC) Molecule. Hittite Journal of Science and Engineering, 10(1): 11-19. 10.17350/HJSE19030000286.
• [47]. Aydoğdu, Ö, Öztürkkan, FE, Hökelek, T, Uğurlu, G, Necefoğlu, H. 2025. Syntheses, crystal structures, and DFT calculations of N'-(Pyridin-2-ylmethylene)nicotinohydrazide dihydrate and its copper complex. Journal of the Iranian Chemical Society, 22(4): 683-697. 10.1007/s13738-025-03177-0.
• [48]. Aydoğdu, Ö, Uğurlu, G, Necefoğlu, H, Öztürkkan, FE, Hökelek, T. 2024. Syntheses, Crystal Structure and Theoretical Properties of Schiff Bases Obtained from Isoniazid and Pyridine‐2‐, 3‐, 4‐Carboxaldehyde and Their Zinc (II) Complexes. ChemistrySelect, 9(14): e202304861.
• [49]. Abdel Aziz, AA, Elantabli, FM, Moustafa, H, El-Medani, SM. 2017. Spectroscopic, DNA binding ability, biological activity, DFT calculations and non linear optical properties (NLO) of novel Co(II), Cu(II), Zn(II), Cd(II) and Hg(II) complexes with ONS Schiff base. Journal of Molecular Structure, 1141(563-576. https://doi.org/10.1016/j.molstruc.2017.03.081.
• [50]. Mahmood, A, Khan, SU-D, Rana, UA, Janjua, MRSA, Tahir, MH, Nazar, MF, Song, Y. 2015. Effect of thiophene rings on UV/visible spectra and non-linear optical (NLO) properties of triphenylamine based dyes: a quantum chemical perspective. Journal of Physical Organic Chemistry, 28(6): 418-422. https://doi.org/10.1002/poc.3427.
• [51]. Glendening, ED, Landis, CR, Weinhold, F. 2013. NBO 6.0: Natural bond orbital analysis program. Journal of Computational Chemistry, 34(16): 1429-1437. https://doi.org/10.1002/jcc.23266.
• [52]. Kurt, M, Babu, PC, Sundaraganesan, N, Cinar, M, Karabacak, M. 2011. Molecular structure, vibrational, UV and NBO analysis of 4-chloro-7-nitrobenzofurazan by DFT calculations. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 79(5): 1162-1170. https://doi.org/10.1016/j.saa.2011.04.037.
• [53]. Govindarajan, M, Karabacak, M. 2012. Spectroscopic properties, NLO, HOMO–LUMO and NBO analysis of 2,5-Lutidine. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 96: 421-435. https://doi.org/10.1016/j.saa.2012.05.067.
• [54]. Gören, K, Bağlan, M, Yıldıko, Ü, Tahiroğlu, V. Molecular Docking and DFT Analysis of Thiazolidinone-Bis Schiff Base for anti-Cancer and anti-Urease Activity. Journal of the Institute of Science and Technology, 14(2): 822-834. [55]. Vijesh, AM, Isloor, AM, Telkar, S, Arulmoli, T, Fun, H-K. 2013. Molecular docking studies of some new imidazole derivatives for antimicrobial properties. Arabian Journal of Chemistry, 6(2): 197-204. https://doi.org/10.1016/j.arabjc.2011.10.007.
• [56]. Yuriev, E, Ramsland, PA. 2013. Latest developments in molecular docking: 2010–2011 in review. Journal of Molecular Recognition, 26(5): 215-239. https://doi.org/10.1002/jmr.2266.
• [57]. Abdullah, Tanriverdi, AA, Khan, AA, Lee, S-J, Park, JB, Kim, YS, Yildiko, U, Min, K, Alam, M. 2024. Selenium-substituted conjugated small molecule: Synthesis, spectroscopic, computational studies, antioxidant activity, and molecular docking. Journal of Molecular Structure, 1304: 137694. https://doi.org/10.1016/j.molstruc.2024.137694.
• [58]. Luedtke, S, Bojo, C, Li, Y, Luna, E, Pomar, B, Radić, Z. 2021. Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition. Crystals, 11(11): 1270.
• [59]. Miličević, A, Šinko, G. 2022. Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors. Molecules, 27(20): 6894.
• [60]. Arendt, T, Brückner, MK, Lange, M, Bigl, V. 1992. Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development—A study of molecular forms. Neurochemistry International, 21(3): 381-396. https://doi.org/10.1016/0197-0186(92)90189-X.
• [61]. Ali, B, M.S. Jamal, Q, Shams, S, A. Al-Wabel, N, U. Siddiqui, M, A. Alzohairy, M, A. Al Karaawi, M, Kumar Kesari, K, Mushtaq, G, A. Kamal, M. 2016. In Silico Analysis of Green Tea Polyphenols as Inhibitors of AChE and BChE Enzymes in Alzheimer’s Disease Treatment. CNS & Neurological Disorders - Drug Targets-CNS & Neurological Disorders), 15(5): 624-628.
• [62]. Greig, NH, Lahiri, DK, Sambamurti, K. 2002. Butyrylcholinesterase: An Important New Target in Alzheimer's Disease Therapy. International Psychogeriatrics, 14(S1): 77-91. 10.1017/S1041610203008676.
• [63]. Greig, NH, Utsuki, T, Yu, Q-s, Zhu, X, Holloway, HW, Perry, T, Lee, B, Ingram, DK, Lahiri, DK. 2001. A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase. Current medical research and opinion, 17(3): 159-165.
• [64]. Carmona, P, Toledano Gasca, A, Álvarez-Vicente, MI, Fuiz, S, Molina, M, Calero Lara, M, Martínez-Martín, P, Bermejo Pareja, F. 2011. Infrared spectroscopic analysis of blood as a diagnostic tool in Alzheimer disease.
• [65]. Kassel, DB. 2004. Applications of high-throughput ADME in drug discovery. Current Opinion in Chemical Biology, 8(3): 339-345. https://doi.org/10.1016/j.cbpa.2004.04.015.
• [66]. Shou, WZ. 2020. Current status and future directions of high-throughput ADME screening in drug discovery. Journal of Pharmaceutical Analysis, 10(3): 201-208. https://doi.org/10.1016/j.jpha.2020.05.004