A Study on the Synthesis, Crystallographic Structure, DFT Calculations, Hirshfeld Surface Analysis, Drug-likeness and Molecular Docking of the Julolidene-Based Schiff Base Containing Compound

Year 2025, Volume: 10 Issue: 1, 165 - 187, 29.06.2025

Seher Meral , Cem Cüneyt Ersanlı , Zeynep Keleşoğlu , Ayşen Alaman Ağar

https://doi.org/10.33484/sinopfbd.1664284

Abstract

This study gives an in-depth investigation of the molecular structure of a julolidene-based molecule, (C36H50N4O2). The investigation comprises the X-ray diffraction, density functional theory calculations, Hirshfeld surface analysis, drug similarity evaluation, and molecular docking simulations. The compound’s structure was initially derived from X-ray coordinates and then optimized using the B3LYP density functional theory method with the 6-31G(d,p) and 6-311G(d,p) basis sets. In the present paper, the detailed molecular interactions and X-ray crystal structure of this molecule are discussed. The space group is P1 ̅ and has the following unit cell parameters: a = 6.8512 (9) Å, b = 9.9748 (14) Å, c = 13.892(3) Å, α = 74.679 (13)o, β = 86.608 (13)o, γ = 75.049 (11)o, V = 884.6 (2) Å3, Z = 1. The julolidene-based compound is crystallized with only half of the molecule in the asymmetric unit, which has reverse symmetry. A complex network comprised of O–H···N and C–H···O hydrogen bonds, and C–H···π interactions stabilizes the crystal structure, forming supramolecular architectures. The synthesized compound’s theoretical parameters were compared with experimental findings. The optimized structure was analyzed at the same theoretical level, encompassing frontier molecular orbital analysis, molecular electrostatic potential, and chemical reactivity indices. Hirshfeld surface assessment was employed to anticipate molecular interactions. In addition, a drug similarity study was performed on the synthesized compound. Finally, an analysis of molecular docking for the compound under investigation was conducted.

Keywords

Julolidene , X-ray , DFT studies , drug-likeness , Hirshfeld surface analysis , molecular docking analysis

Ethical Statement

Ethics Committee Approval and Permissions: The study does not require ethics committee permission or any special permission.

Supporting Institution

Funding/Financial Disclosure: The authors received no financial support for the research, writing or publication of this study.

Project Number

Acknowledgements: This study was supported by Sinop University Scientific Research Coordination Unit. Project Number: BMYO-1901-21-001, 2023

Thanks

-

Juloliden Bazlı Schiff Bazı İçeren Bileşiğin Sentezi, Kristalografik Yapısı, DFT Hesaplamaları, Hirshfeld Yüzey Analizi, İlaç Benzerliği ve Moleküler Yerleştirme Üzerine Bir Çalışma

Abstract

Bu çalışma, juloliden bazlı bir molekülün (C36H50N4O2) moleküler yapısının derinlemesine bir incelemesini sunmaktadır. Araştırma X-ışını kırınımı, yoğunluk fonksiyonel teorisi hesaplamaları, Hirshfeld yüzey analizi, ilaç benzerliği değerlendirmesi ve moleküler yerleştirme simülasyonlarını içermektedir. Bileşiğin yapısı ilk olarak X-ışını koordinatlarından türetilmiş ve daha sonra 6-31G(d,p) ve 6-311G(d,p) temel setleri ile B3LYP yoğunluk fonksiyonel teorisi yöntemi kullanılarak optimize edilmiştir. Bu makalede, bu molekülün ayrıntılı moleküler etkileşimleri ve X-ışını kristal yapısı tartışılmaktadır. Uzay grubu P1 ̅ ve aşağıdaki birim hücre parametrelerine sahiptir: a = 6.8512 (9) Å, b = 9.9748 (14) Å, c = 13.892(3) Å, α = 74.679 (13)o, β = 86.608 (13)o, γ = 75.049 (11)o, V = 884.6 (2) Å3, Z = 1. Juloliden bazlı bileşik, ters simetriye sahip asimetrik birimdeki molekülün sadece yarısı ile kristalize edilmiştir. O–H···N ve C–H···O hidrojen bağları ve C–H···π etkileşimlerinden oluşan karmaşık bir ağ, kristal yapıyı stabilize ederek supramoleküler mimariler oluşturur. Sentezlenen bileşiğin teorik parametreleri deneysel bulgularla karşılaştırılmıştır. Optimize edilmiş yapı, sınır moleküler orbital analizi, moleküler elektrostatik potansiyel ve kimyasal reaktivite indekslerini kapsayan aynı teorik düzeyde analiz edilmiştir. Moleküler etkileşimleri tahmin etmek için Hirshfeld yüzey değerlendirmesi kullanılmıştır. Buna ek olarak, ilaç benzerliği çalışması şema üzerinde gerçekleştirilmiştir.

Keywords

Juloliden , X-ışını , DFT çalışmaları , ilaç-benzerliği , Hirshfeld yüzey analizi , moleküler kenetlenme analizi

Project Number

Acknowledgements: This study was supported by Sinop University Scientific Research Coordination Unit. Project Number: BMYO-1901-21-001, 2023

References

• Katritzky, A. R., Rachwal, B., Rachwal, S., & Abboud, K. A. (1996). Convenient synthesis of julolidines using benzotriazole methodology. The Journal of Organic Chemistry, 61(9), 3117-3126. https://doi.org/10.1021/jo9519118
• Martini, G., Martinelli, E., Ruggeri, G., Galli, G., & Pucci, A. (2015). Julolidine fluorescent molecular rotors as vapour sensing probes in polystyrene films. Dyes Pigments, 113, 47-54. https://doi.org/10.1016/j.dyepig.2014.07.025
• Wu, W. H., Wang, Y., Zhou, Y. X., Shao, Y., Zhang, L. H., & Li, H. (2015). Selective fluorescence lighting-up recognition of DNA abasic site environment possessing guanine context. Sensors and Actuators B: Chemical, 206, 449-455. http://dx.doi.org/10.1016/j.snb.2014.09.090
• Avhad, K., Jadhav, M., Patil, D., Chowdhury, T. H., Islam, A., Bedja, I., & Sekar, N. (2019). Rhodanine- 3-acetic acid containing D-π-A push-pull chromophores: effect of methoxy group on the performance of dye-sensitized solar cells. Organic Electronics, 65, 386-393. https://doi.org/10.1016/j.orgel.2018.11.041
• Halter, O., & Plenio, H. (2018). Fluorescent dyes in organometallic chemistry: Coumarin-tagged NHC-metal complexes. European Journal of Inorganic Chemistry, 2018(25), 2935-2943. https://doi.org/10.1002/ejic.201800395
• Lichlyter, D. J., & Haidekker, M. A. (2009). Immobilization techniques for molecular rotors-Towards a solid-state viscosity sensor platform. Sensors and Actuators B: Chemical, 139(2), 648-656. https://doi.org/10.1016/j.snb.2009.03.073
• Royal, J. S., & Torkelson, J. M. (1992). Molecular-scale asymmetry and memory behavior in poly (vinyl acetate) monitored with mobility-sensitive fluorescent molecules. Macromolecules, 25(6), 1705-1710.
• Boldt, P., Eisenträger, T., Glania, C., Göldenitz, J., Krämer, P., Matschiner, R., Rase, J., Schwesinger, R., Wichern, J., & Wortmann, R. (1996). Guanidyl and phosphoraniminyl substituents: New electron donors in second‐order nonlinear optical chromophores. Advanced Materials, 8(8), 672-675. https://doi.org/10.1002/adma.19960080817
• Chavan, N. D., & Vijayakumar, V., (2024). Synthesis, DFT studies on a series of tunable quinoline derivatives. The Royal Society of Chemistry Advances, 14(29), 21089-21101. https://doi.org/10.1039/D4RA03961K
• Khalid, M., Akbar, A., Jawaria, R., Asghar, M. A., Asim, S., Khan, M. U., Hussain, R., Rehman, M. F., Ennis, C. J., & Akram, M. S. (2020). First principles study of electronic and nonlinear optical properties of A-D-π-A and D-A-D-π-a configured compounds containing novel quinoline-carbazole derivatives, The Royal Society of Chemistry Advances, 10, 22273-22283. https://doi.org/10.1039/D0RA02857F
• Jamal, A., Ferjani, H., Faizi, M. S. H., Alzahrani, A. Y. A. (2024). DFT calculation and molecular docking studies of designing quinoline-derived anti-Alzheimer agents with NLO response. Journal of the Indian Chemical Society, 101(8), 101181. https://doi.org/10.1016/j.jics.2024.101181
• Ahamed, A. A., Alharbi, S. A., & Venkatesan, G. (2024). A julolidine aldehyde dansyl hydrazine Schiff Base as fluorescence chemosensor for Zn2+ ions recognition and its application. Journal of Fluorescence, 1-11. https://doi.org/10.1007/s10895-024-03842-2
• Waizenegger, I. C., Baum, A., Steurer, S., Stadtmüller, H., Bader, G., Schaaf, O., Garin-Chesa, P., Schlattl, A., Schweifer, N., Haslinger, C., Colbatzky, F., Mousa, S., Kalkuhl, A., Kraut, N., & Adolf, G. R. (2016). A novel RAF kinase inhibitor with DFG-out-binding mode: High efficacy in BRAF-mutant tumor xenograft models in the absence of normal tissue hyperproliferation. Molecular Cancer Therapeutics, 15(3), 354-365. https://doi.org/10.1158/1535-7163.MCT-15-0654
• Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). Autodock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785-2791. https://doi.org/10.1002/jcc.21256
• Kemmish, H., Fasnacht, M., & Yan, L. (2017). Fully automated antibody structure prediction using BIOVIA tools: Validation study. PLoS One, 12(5), e0177923. https://doi.org/10.1371/journal.pone.0177923
• Meral, S., Agar, A. A. (2024). Synthesis, characterization and effects to cholesteric lyotropic liquid crystal media of -ONNO- type Schiff Bases and metal complexes. Bulgarian Chemical Communations, 56(3), 274-281.
• Stoe, C. (2002). X-area (version 1.18) and Xred32 (version 1.04), Stoe & Cie, Darmstadt, Germany.
• Sheldrick, G. M. (2015). SHELXT-Integrated space-group and crystal-structure determination. Acta Crystallographica Section A: Foundations and Advances, 71(1), 3-8. https://doi.org/10.1107/S2053273314026370
• Sheldrick, G. M. (2018). SHELXL-2018 Program for crystal structure refinement. University of Göttingen, Göttingen.
• Farrugia, L. J. (1999). WinGX suite for smallmolecule single-crystal crystallography. Journal of Applied Crystallography, 32(4), 837-838. http://dx.doi.org/10.1107/S0021889899006020
• Farrugia, L. J. (1997). It ORTEP-3 for Windows-A version of it ORTEP-III with a graphical user interface (GUI). Journal of Applied Crystallography, 30, 565. https://doi.org/10.1107/S0021889897003117
• Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M., & Streek, J. V. D. (2006). Mercury: Visualization and analysis of crystal structures. Journal of Applied Crystallography, 39, 453-457. http://dx.doi.org/10.1107/S002188980600731X
• Nardelli, M. (1995). PARST95-An update to PARST: A system of Fortran routines for calculating molecular structure parameters from the results of crystal structure analyses. Journal of Applied Crystallography, 28, 659. http://dx.doi.org/10.1107/S0021889895007138
• Spek, A. L. (2005). PLATON-a multipurpose crystallographic tool, Utrecht University, Utrecht.
• Frisch, MJ, Trucks, GW, Schlegel, HB, Scuseria, GE, Robb, MA, Cheeseman, JR, Scalmani, G, Barone, V, Mennucci, B, Petersson, GA, Nakatsuji, H, Caricato, M, Li, X, Hratchian, HP, Izmaylov, AF, Bloino, J, Zheng, G, Sonnenberg, J., Hada, M, Ehara, M, Toyota, K, Fukuda, R, Hasegawa, J, Ishida, M, Nakajima, T, Honda, Y, Kitao, O, Nakai, H, Vreven, T, Montgomery Jr, JA, Peralta, JE, Ogliaro, F, Bearpark, M, Heyd, JJ, Brothers, E, Kudin, KN, Staroverov, VN, Kobayashi, R, Normand, J, Raghavachari, K, Rendell, A, Burant, JC, Iyengar, SS, Tomasi, J, Cossi, M, Rega, N, Millam, JM, Klene, M, Knox, JE, Cross, JB, Bakken, V, Adamo, C, Jaramillo, J, Gomperts, R, Stratmann, RE, Yazyev, O, Austin, AJ, Cammi, R, Pomelli, C, Ochterski, JW, Martin, RL, Morokuma, K, Zakrzewski, VG, Voth, GA, Salvador, P, Dannenberg, JJ, Dapprich, S, Daniels, AD, Farkas, O, Foresman, JB, Ortiz, JV, Cioslowski, J, & Fox, DJ. (2009). Gaussian 09, revision E.01, Gaussian, Inc., Wallingford CT.
• Dennington, R., Keith, T., & Millam, J. (2007) Gauss View, Version 4.1.2. Semichem Inc., Shawnee Mission.
• Becke, A. D. (1993). Density‐functional thermochemistry. III. The role of exact exchange, Journal of Chemical Physics, 98, 5648-5652. https://doi.org/10.1063/1.464913
• Lee, C, Yang, W, & Parr, R. G. (1998). Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density, Physical Review B, 37, 785-789. https://doi.org/10.1103/PhysRevB.37.785
• Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D., & Spackman, M. A. (2017). CrystalExplorer17, University of Western Australia, Perth.
• McKinnon, J. J., Jayatilaka, D., & Spackman, M. A. (2007). Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chemical Communications, 37, 3814-3816. http://dx.doi.org/10.1039/b704980c
• Spackman, M. A., & Jayatilaka, D. (2009). Hirshfeld surface analysis. Crystal Engineering Communication, Royal Society of Chemistry, 11(1), 19-32. http://dx.doi.org/10.1039/B818330A
• Daina, A., Michielin, O., & Zoete, V. (2014). iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach, Journal of Chemical Information and Modeling, 54(12), 3284-3301. https://doi.org/10.1021/ci500467k
• Daina, A., Michielin, O., & Zoete, V. (2017) SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 42717. https://doi.org/10.1038/srep42717
• Evecen, M., Ersanlı, C. C., Doğan, O. E., Bozkurt, İ., & Ağar, E. (2025). Synthesis and analysis thermodynamic electronic NLO, FMO, NBO, MEP, IR, UV, NMR properties Hirshfeld surface analysis and molecular docking of the new Schiff base molecule (Z)-4-bromo-2-(((2,4-dimethoxypheny)limino)methyl)-5-fluorophenol. Journal of Molecular Structure, 1329, 1-14. https://doi.org/10.1016/j.molstruc.2025.141454
• Keleşoğlu, Z., Albayrak Kaştaş, Ç., Kaştaş, G., & Ersanlı, C. C. (2021). Synthesis, crystal structure, computational chemistry studies and Hirshfeld surface analysis of two Schiff Bases, (E)-2-[(4-bromo-2-methylphenylimino)methyl]-4-methylphenol and (E)-2-[(4-bromo-2-methylphenylimino) methyl]-6-methylphenol. Molecular Crystals and Liquid Crystals, 723, 45-61. https://doi.org/10.1080/15421406.2020.1871178
• Koşar Kırca, B., Albayrak Kaştaş, Ç., & Ersanlı, C. C. (2021). Molecular and electronic structures of two new Schiff Base compounds (E)-2-Bromo-6-[(2-bromo-4-methylphenylimino) methyl]-4-chlorophenol and (E)-2-Bromo-6-[(4-bromo-3-methylphenylimino)methyl]-4-chlorophenol. Journal of Molecular Structure, 1241(130643), 1-12. https://dx.doi.org/10.1016/j.molstruc.2021.130643
• Kaştaş, G., Albayrak Kaştaş, Ç., Ersanlı, C. C., & Koşar Kırca, B. (2020). Investigation of the molecular structure of (E)-2-Bromo-6-[(4-bromo-2-methylphenylimino)methyl]-4-chlorophenol. Crystallography Reports, 65(3), 463-467. https://dx.doi.org/10.1134/S1063774520030153
• Kaştaş, G., Albayrak Kaştaş, Ç., Koşar Kırca, B., & Ersanlı, C. C. (2020). The effect of the change in substituents positions on the formation of supramolecular networks and the solvent type substituent dependence of prototropic behavior in three new o-hydroxy Schiff Bases. Journal of Molecular Structure, 1200, 1-13. https://dx.doi.org/10.1016/j.molstruc.2019.127109
• İnaç, H. (2023). Crystal Structure of Zwitterionic (E)-9-(((3-hydroxyphenyl)iminio)methyl)-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-8-olate. International Scientific and Vocational Studies Journal, 7(2), 72-78. https://doi.org/10.47897/bilmes.1316337
• Kantar, E. N., Köysal, Y., Akdemir, N., Ağar, A. A., & Soylu, M. S. (2013). 8-{(E)-[(4-chloro-phen-yl)imino]-meth-yl}-1,1,7,7-tetra-methyl-1,2,3,5,6,7-hexa-hydro-pyrido[3,2,1-ij]quinolin-9-ol. Acta Crystallographica Section E, 69(6), o883. https://doi.org/10.1107/S1600536813012579
• Pearson, R. G. (1986) Absolute electronegativity and hardness correlated with molecular orbital theory. Proceedings of the National Academy of Sciences of the United States of America, 83, 8440-8441. http://dx.doi.org/10.1073/pnas.83.22.8440
• Guidara, S., Feki, H., & Abid, Y. (2015). Structural, vibrational, NLO, MEP, NBO analysis and DFT calculation of bis 2,5-dimethylanilinium sulfate. Journal of Molecular Structure, 1080, 176-187. http://dx.doi.org/10.1016/j.molstruc.2014.09.084
• Saravanan, R., Seshadri, S., Günasekaran, S, Mendoza-Meroño, R., & García‐Granda, S. (2015). Conformational analysis, x-ray crystallographic, FT-IR, FT-Raman, DFT, MEP and molecular docking studies on 1-(1-(3-methoxyphenyl) ethylidene) thiosemicarbazide. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 139, 321-328. http://dx.doi.org/doi:10.1016/j.saa.2014.12.026
• Tan, S. L., Jotani, M. M., & Tiekink, E. R. T. (2019). Utilizing Hirshfeld surface calculations, non-covalent inter­action (NCI) plots and the calculation of inter­action energies in the analysis of molecular packing. Acta Crystallographica Section E, 75, 308-318. https://doi.org/10.1107/S2056989019001129
• Spackman, P. R., Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Jayatilaka, D., & Spackman, M. A. (2021). CrystalExplorer: a program for Hirshfeld surface analysis, visualization and qu­antitative analysis of molecular crystals. Journal of Applied Crystallography, 54(3), 1006-1011. https://doi.org/10.1107/S1600576721002910
• Abdel-Aal, S. K.; & Ouasri, A. (2022). Crystal structure, Hirshfeld surfaces and vibrational studies of tetrachlorocobaltate hybrid perovskite salts NH3(CH2)nNH3CoCl4 (n=4, 9). Journal of Molecular Structure, 1251, 131997. https://doi.org/10.1016/j.molstruc.2021.131997
• Başak, S. (2023). Investigation of some schiff base molecules with antitumor and anticarsinogenic effects by molecular docking method. (Tez no. 815683) [Master Thesis, Sinop University]
• Shoichet, B. K., Leach, A. R., & Kuntz, I. D. (1999). Ligand solvation in molecular docking. Proteins, 34(1), 4-16. https://doi.org/10.1002/(sici)1097-0134(19990101)34:1<4::aid-prot2>3.0.co;2-6
• Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., & Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28(1), 235-242. https://doi.org/10.1093/nar/28.1.235
• The UniProt Consortium. (2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Research, 51(D1), D523-D531. https://doi.org/10.1093/nar/gkac1052
• Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., & Hassabis, D. (2021). Highly accurate protein structure prediction with AlphaFold. Nature, 596(7873), 583-589. https://doi.org/10.1038/s41586-021-03819-2
• Başak, S., & Ersanlı, C. C. (2024). Investigation of Hirshfeld surface analysis and anticarcinogenic properties of Schiff Base containing compounds by molecular docking method. Hüsniye Sağlıker, (Ed), Original Research and Reviews in Science and Mathematics, (pp. 77-92).