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

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

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

References

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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.
8. 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

9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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.
17. Stoe, C. (2002). X-area (version 1.18) and Xred32 (version 1.04), Stoe & Cie, Darmstadt, Germany.
18. 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
19. Sheldrick, G. M. (2018). SHELXL-2018 Program for crystal structure refinement. University of Göttingen, Göttingen.
20. 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
21. 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
22. 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
23. 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
24. Spek, A. L. (2005). PLATON-a multipurpose crystallographic tool, Utrecht University, Utrecht.
25. 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.
26. Dennington, R., Keith, T., & Millam, J. (2007) Gauss View, Version 4.1.2. Semichem Inc., Shawnee Mission.
27. 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
28. 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
29. 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.
30. 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
31. 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
32. 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
33. 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
34. 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
35. 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
36. 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
37. 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
38. 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
39. 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
40. 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
41. 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
42. 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
43. 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
44. 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
45. 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
46. 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
47. 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]
48. 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
49. 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
50. 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
51. 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
52. 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).