j. inst. sci. and tech. Journal of the Institute of Science and Technology 2536-4618 Igdir University 10.21597/jist.1561684 Theoretical and Computational Chemistry (Other) Teorik ve Hesaplamalı Kimya (Diğer) 4-(2-(2-İzopropil-5-metilfenoksi) fenoksi) ftalonitril'in Alzheimer ve COVID-19 Enzimleriyle Moleküler Yerleştirme ve DFT Çalışmaları Molecular docking of 4-(2-(2-Isopropyl-5-methylphenoxy) phenoxy) phthalonitrile with Alzheimer's and COVID-19 enzymes and DFT studies https://orcid.org/0000-0001-5811-8253 Tanrıverdi Aslıhan Aycan Kafkas Üniversitesi Fen Edebiyat Fakültesi Kimya Bölümü Fizikokimya Anabilim Dalı https://orcid.org/0000-0001-8627-9038 Yıldıko Ümit KAFKAS ÜNİVERSİTESİ 09 01 2025 15 3 1008 1018 10 05 2024 04 11 2025 Copyright © 2011, Journal of the Institute of Science and Technology 2011 Journal of the Institute of Science and Technology

Ftalonitriller, yüksek performanslı makromoleküllerin sentez ve formülasyonunda önemli bir bileşendir. Moleküler yapılar üzerine sistematik teorik çalışma, yeni terapötik bileşiklerin rasyonel bir şekilde yaratılması için esastır. Bu çalışma, yoğunluk fonksiyonel teorisi (DFT) ve moleküler yerleştirme üzerine sistematik teorik araştırma yürütmek için aromatik nitril tipi 4-(2-(2-İzopropil-5-metilfenoksi)fenoksi)ftalonitril (IMPN) kullanır. IMPN'nin geometri açısından optimize edilmiş yapıları, 6-311G(d,p) baz setiyle DFT/B3LYP ve B3PW91 yöntemleri kullanılarak incelenmiştir. MEP sonuçları, metilfenoksinin elektronik etkisinin siyano gruplarından elektronları çektiğini ve bunun da siyano karbonunu daha fazla açığa çıkardığını ve nükleofilik reaksiyona daha yatkın hale getirdiğini göstermektedir. Temsili farmakolojik olarak aktif bir kısım olan IMPN'nin moleküler yerleştirme analizi ve farmakolojik potansiyeli, asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BChE) Alzheimer ve COVID-19 enzimlerine karşı inhibe edici kapasitesini belirlemek için değerlendirildi. Bir ligand olarak IMPN, enzim kristal yapılarıyla -8.243, -7.920 ve -7.368 kcal/mol'lük etkili yerleştirme puanları gösterdi.

Phthalonitriles are a crucial component in the synthesis and formulation of high-performance macromolecules. Systematic theoretical study on molecular structures is essential for the rational creation of novel therapeutic compounds. This study takes aromatic nitrile type 4-(2-(2-Isopropyl-5-methylphenoxy)phenoxy)phthalonitrile (IMPN) to conduct systematic theoretical research on density functional theory (DFT) and molecular docking. The geometry-optimized structures of IMPN were examined using the DFT/B3LYP and B3PW91 methods with the 6-311G(d,p) basis set. The MEP results show that the electronic effect of methylphenoxy attracts electrons from cyano groups, which makes the cyano carbon more exposed and more prone to nucleophilic reaction. The molecular docking analysis and pharmacological potential of IMPN, as a representative pharmacologically active moiety, were assessed to ascertain its inhibitory capacity against acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) Alzheimer's and COVID-19 enzymes. IMPN, as a ligand, demonstrated effective docking scores of -8.243, -7.920, and -7.368 kcal/mol with the enzyme crystal structures.

 Phthalonytrile DFT calculations Molecular docking Ftalonitril DFT hesaplamaları Moleküler yerleştirme Adiguzel, R., et al. (2021). Synthesis and in silico studies of Novel Ru(II) complexes of Schiff base derivatives of 3-[(4-amino-5-thioxo-1,2,4-triazole-3-yl)methyl]-2(3H)-benzoxazolone compounds as potent Glutathione S-transferase and Cholinesterases Inhibitor. Journal of Molecular Structure, 1231, 129943. Ağırtaş, M.S., et al. (2021). Synthesis, antioxidant, DNA cleavage and antimicrobial properties of phthalocyanine complexes bearing the poly-hydroxyl groups. Chemical Papers, 75(4), 1749-1760. Alghamdi, H.A., et al. (2021). Repurposing the inhibitors of COVID-19 key proteins through molecular docking approach. Process Biochemistry, 110, 216-222. Alshehri, B., et al. (2022). Molecular target prediction and docking of anti-thrombosis compounds and its activation on tissue-plasminogen activator to treat stroke. Journal of King Saud University - Science, 34(1), 101732. Alswaidan, I.A., et al. (2017). 2,4-Ditellurouracil and its 5-fluoro derivative: Theoretical investigations of structural, energetics and ADME parameters. Computational Biology and Chemistry, 68, 56-63. Aras, A., et al. (2021). Biochemical constituent, enzyme inhibitory activity, and molecular docking analysis of an endemic plant species, Thymus migricus. Chemical Papers, 75(3), 1133-1146. Atalar, M.N., et al. (2021). The effects of Daucus carota extract against PC3, PNT1a prostate cells, acetylcholinesterase, glutathione S-transferase, and α-glycosidase; an in vitro–in silico study. Journal of Food Biochemistry, 45(12), e13975. Athar Abbasi, M., et al. (2019). Synthesis of novel N-(1,3-thiazol-2-yl)benzamide clubbed oxadiazole scaffolds: Urease inhibition, Lipinski rule and molecular docking analyses. Bioorganic Chemistry, 83, 63-75. Biovia, D.S., (2017). Discovery studio modeling environment. Release. Cabir, B., et al. (2020). Computational DFT calculations, photovoltaic properties and synthesis of (2R, 3S)-2, 3, 4-trihydroxybutoxy substituted phthalocyanines. Inorganic and Nano-Metal Chemistry, 50(9), 816-827. Cabir, B., Yildiko, U. and Ağirtaş, M. S. (2019). Synthesis, DFT analysis, and electronic properties of new phthalocyanines bearing ETAEO substituents on peripheral position. Journal of Coordination Chemistry, 72(17), 2997-3011. Chagas, C. M., Moss, S. and Alisaraie, L. (2018). Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski’s Rule of Five. International Journal of Pharmaceutics, 549(1), 133-149. Cheng, Z.-Q., et al. (2019). Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors. Bioorganic Chemistry, 83, 277-288. Chtita, S., et al. (2019). QSAR study of anti-Human African Trypanosomiasis activity for 2-phenylimidazopyridines derivatives using DFT and Lipinski's descriptors. Heliyon, 5(3), e01304. Elangovan, N., Thomas, R. and Sowrirajan, S. (2022). Synthesis of Schiff base (E)-4-((2-hydroxy-3,5-diiodobenzylidene)amino)-N-thiazole-2-yl)benzenesulfonamide with antimicrobial potential, structural features, experimental biological screening and quantum mechanical studies. Journal of Molecular Structure, 1250, 131762. Fatriansyah, J. F., et al. (2022). Molecular docking and dynamics studies on propolis sulabiroin-A as a potential inhibitor of SARS-CoV-2. Journal of King Saud University-Science, 34(1), 101707. Franklin, M. C., et al. (2016). Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface. Proteins, 84(9), 1246-56. Frisch, M. J., et al. (2016). GAUSSIAN 09. http://www.gaussian.com/. Gao, M., et al. (2023). Novel liquid phthalonitrile monomers towards high performance resin. European Polymer Journal, 191, 112027. Gao, M., et al. (2024). Rediscovering phthalonitrile resins: a novel liquid monomer towards high-performance resins††Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4py00100a. Polymer Chemistry, 15(21), 2157-2166. Giricheva, N. I., et al. (2015). The difference between gas-phase and crystal structures of ortho-nitromethylbenzenesulfonate. Conformation variety study of free molecules by electron diffraction and quantum chemistry. Journal of Molecular Structure, 1085, 191-197. Hall-Swan, S., et al. (2021). DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins. Computers in Biology and Medicine, 139, 104943. Han, K., et al. (2014). Quantum chemistry study on nonlinear optical properties of hemicyanine dye derivatives with different electron donor groups. Computational and Theoretical Chemistry, 1044, 24-28. He, X., et al. (2023). A theoretical investigation on the chemical environment of pyrazine-2,3-dicarbonitrile and phthalonitrile: Density functional theory (DFT) calculation and experimental verification. Journal of Molecular Structure, 1292, 136117. Kalaimathi, K., et al. (2021). Molecular docking and network pharmacology-based approaches to explore the potential of terpenoids for Mycobacterium tuberculosis. Pharmacological Research - Modern Chinese Medicine, 1, 100002. Keşkek Karabulut, Y., et al. (2024). MAO-A Inhibitor Properties by Molecular Modeling Method, Antimicrobial Activity and Characterization of Silver Nanoparticles Synthesized from Lactifluus Bertillonii Mushroom. Düzce Üniversitesi Bilim ve Teknoloji Dergisi, 4, 2033-2049. Kneller, D. W., et al. (2021). Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease. Journal of medicinal chemistry, 64(23), 17366-17383. Kolesnikova, I. N., et al. (2022). Equilibrium molecular structure of nicotinic acid hydrazide: joint study by means of gas electron diffraction and quantum chemistry. Journal of Molecular Structure, 1253, 132281. Larik, F. A., et al. (2020). Synthesis, inhibition studies against AChE and BChE, drug-like profiling, kinetic analysis and molecular docking studies of N-(4-phenyl-3-aroyl-2(3H)-ylidene) substituted acetamides. Journal of Molecular Structure, 1203, 127459. Maidur, S. R., et al. (2017). Experimental and computational studies on second-and third-order nonlinear optical properties of a novel D-π-A type chalcone derivative: 3-(4-methoxyphenyl)-1-(4-nitrophenyl) prop-2-en-1-one. Optics & Laser Technology, 97, 219-228. Meden, A., et al. (2019). Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease. Chemical communications (Cambridge, England), 55(26), 3765-3768. Mumit, M. A., et al. (2020). DFT studies on vibrational and electronic spectra, HOMO–LUMO, MEP, HOMA, NBO and molecular docking analysis of benzyl-3-N-(2,4,5-trimethoxyphenylmethylene)hydrazinecarbodithioate. Journal of Molecular Structure, 1220, 128715. Priya, M. K., et al. (2019). Molecular Structure, Spectroscopic (FT-IR, FT-Raman, 13C and 1H NMR) Analysis, HOMO-LUMO Energies, Mulliken, MEP and Thermal Properties of New Chalcone Derivative by DFT Calculation. Materials Today: Proceedings, 8, 37-46. Rudrapal, M., et al. (2022). Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies. Saudi Journal of Biological Sciences, 29(4), 2432-2446. Sherin, D. R. and Manojkumar, T. K. (2020). Significance of five membered heterocycles in fine tuning of HOMO-LUMO gap of simple donor-acceptor system as organic solar cell material: A DFT approach. Materials Today: Proceedings, 33, 1229-1233. Shukla, B. K. and Yadava U. (2022). DFT calculations on molecular structure, MEP and HOMO-LUMO study of 3-phenyl-1-(methyl-sulfonyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine. Materials Today: Proceedings, 49(8), 3056-3060. Sudhapriya, N., et al. (2019). Cu-mediated synthesis of differentially substituted diazepines as AChE inhibitors; validation through molecular docking and Lipinski’s filter to develop novel anti-neurodegenerative drugs. Bioorganic & Medicinal Chemistry Letters, 29(11), 1308-1312. Wang, D., et al., (2024). Enhanced mechanical and thermal properties of phenolic-type phthalonitrile nanocomposites with fumed silica nanoparticles. Polymer, 296, 126783. Yang, W., et al. (2024). Aromatic nitrile resins with improved processability and thermal properties prepared by collaborative design of structure and blending strategy. European Polymer Journal, 216, 113247. Yildiko, Ü., et al. (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.