Molecular Modelling of Cyclodextrin Inclusion Complexes of 2-((Morpholinoimino)Methyl)Benzoic Acid and its Heterocyclic Derivative
DOI:
https://doi.org/10.18321/ectj1674Keywords:
N-aminomorpholine hydrazone, Phthalimidine, β-cyclodextrin, Complexation, 1H and 13C NMR spectra, Molecular modellingAbstract
This study investigates the formation and characteristics of inclusion complexes between β-cyclodextrin and two compounds: N-aminomorpholine hydrazone and its phthalimidine derivative. Structural features of the encapsulated forms of these new N-aminomorpholine derivatives were characterized using 1H and 13C NMR spectroscopy, as well as two-dimensional 1H─1H (COSY) and 1H─13C (HMBC, HSQC) NMR experiments. Using molecular modeling methods, the influence of structural factors and the principle of geometric complementarity on the complexation processes between the host and guest molecules were assessed. A conformational study of the guest molecules was carried out using the semiempirical GFN2-xTB method in combination with the GOAT algorithm. Employing density functional theory (DFT), the inclusion complexes were optimized at the ωB97X-D/6-311G(d,p) level, including aqueous solvation effects as described by the CPCM model. The thermodynamic parameters of complex formation were estimated. NMR analysis confirmed 1:1 stoichiometry and showed significant chemical shift perturbations for cavity protons, while DFT calculations revealed spontaneous complexation (ΔG°298 = −2.54 to −3.45 kcal/mol) driven by exothermic enthalpies and hydrophobic/van der Waals interactions, with an enantioselective preference for the R-phthalimidine enantiomer. These findings demonstrate β-CD's potential to enhance the solubility, stability, and bioavailability of these promising antiviral and antibacterial agents for pharmaceutical applications.
References
(1) A.E. Khamitova, D.A. Berillo, Overview of Piperidine and Morpholine Derivatives as Promising Sources of Biologically Active Compounds (Review), Drug development & Registration 12 (2023) 44–54. Crossref
(2) B.G. DelaTorre, F. Albericio, The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules, Molecules 27 (2022) 1075. Crossref
(3) A. Kourounakis, D. Xanthopoulos, A. Tzara, Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules, Med. Res. Rev. 40 (2020) 709–752. Crossref
(4) P. Dhiman, M. Bhatia, Pharmaceutical applications of cyclodextrins and their derivatives, J. Incl. Phenom. Macrocycl. Chem. 98 (2020) 171–186. Crossref
(5) C. Muankaew, T. Loftsson, Cyclodextrin-Based Formulations: A Non-Invasive Platform for Targeted Drug Delivery, Basic Clin. Pharmacol. Toxicol. 122 (2018) 46–55. Crossref
(6) T.M. Seilkhanov, A.Yu. Ten, Kh.S. Tassibekov, et al., Supramolecular cyclodextrin complexes of biologically active nitrogen heterocycles, Chem. Bull. Kaz. Nat. Univ. 3 (2024) 22–33. Crossref
(7) Zh.S. Nurmaganbetov, S.D. Fazylov, O.A. Nurkenov, et al., Combined Computational and Experimental Study of Inclusion Complexes of Lupinine and its 1,2,3-triazole Derivative with β-cyclodextrin, Eurasian Chem.-Technol. J. 27 (2025) 127–138. Crossref
(8) O.A. Nurkenov, S.D. Fazylov, Z.T. Shulgau, et al., Synthesis, Structure and Antiradical Activity of Functionally Substituted Hydrazides of Isonicotinic Acid, Eurasian Chem.-Technol. J. 25 (2023) 121–128. Crossref
(9) O.A. Nurkenov, S.B. Zhautikova, A.I. Khlebnikov, et al., Synthesis and Biological Activity of New Hydrazones Based on N‐Aminomorpholine, Molecules 29 (2024) 3606. Crossref
(10) Zh. Xu, Ch. Liu, Sh. Zhao, et al., Molecular Sensors for NMR-Based Detection, Chem. Rev. 119 (2019) 195–230. Crossref
(11) Y. Inoue, NMR Studies of the Structure and Properties of Cyclodextrins and Their Inclusion Complexes, Annu. Rep. NMR Spectrosc. 27 (1993) 59–101. Crossref
(12) H.J. Schneider, F. Hacket, V. Rudiger, H. Ikeda, NMR Studies of Cyclodextrins and Cyclodextrin Complexes, Chem. Rev. 98 (1998) 1755–1785. Crossref
(13) Mansi, P. Khanna, Sh. Yadav, et al., Inclusion complexes of novel formyl chromone Schiff bases with β-Cyclodextrin: Synthesis, characterization, DNA binding studies and in-vitro release study, Carbohydr. Polym. 347 (2025) 122667. Crossref
(14) E.M. Del Valle, Cyclodextrins and their uses: a review, Process Biochem. 39 (2004) 1033–1046. Crossref
(15) M.V. Rekharsky, Y. Inoue, Complexation Thermodynamics of Cyclodextrins, Chem. Rev. 98 (1998) 1875–1918. Crossref
(16) R. Ferrero, S. Pantaleone, M. Delle Piane, et al., On the Interactions of Melatonin/β-Cyclodextrin Inclusion Complex: A Novel Approach Combining Efficient Semiempirical Extended Tight-Binding (xTB) Results with Ab Initio Methods, Molecules 26 (2021) 5881. Crossref
(17) Chai Jeng-Da, M. Head‐Gordon, Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections, Phys. Chem. Chem. Phys. 10 (2008) 6615–6620. Crossref
(18) K.V. Alantev, D.V. Babailova, M.V. Kaplun, et al., Basis Set Superposition Error: Effects of the Boys‒Bernardi Correction on the DFT Modeling of Hydrogen Sorption on Low-Dimensional Carbon Nanomaterials, Bull. Russ. Acad. Sci. Phys. 87 (2023) 1667–1674. Crossref
(19) A.H. Mazurek, Ł. Szeleszczuk, Current Status of Quantum Chemical Studies of Cyclodextrin Host–Guest Complexes, Molecules 27 (2022) 3874. Crossref
(20) S. Pantaleone, C.I. Gho, R. Ferrero, et al., Exploration of the Conformational Scenario for α-, β-, and γ-Cyclodextrins in Dry and Wet Conditions, from Monomers to Crystal Structures: A Quantum-Mechanical Study, Int. J. Mol. Sci. 24 (2023) 16826. Crossref
(21) W. Khuntawee, M. Karttunend, J. Wong-ekkabut, A molecular dynamics study of conformations of beta-cyclodextrin and its eight derivatives in four different solvents, Phys. Chem. Chem. Phys. 19 (2017) 24219. Crossref
(22) W. Saenger, T. Steiner, Cyclodextrin Inclusion Complexes: Host–Guest Interactions and Hydrogen-Bonding Networks, Acta Cryst. A54 (1998) 798–805. Crossref
(23) C. Bannwarth, S. Ehlert, S. Grimme, GFN2-xTB—An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions, J. Chem. Theory Comput. 15 (2019) 1652–1671. Crossref
(24) B. de Souza, GOAT: A Global Optimization Algorithm for Molecules and Atomic Clusters, Angew. Chem. Int. Ed. 64 (2025) e202500393. Crossref
(25) F. Neese, Software Update: The ORCA Program System—Version 6.0, WIREs Computational Molecular Science 15 (2025) e70019. Crossref
(26) S. Spicher, S. Grimme, Efficient Computation of Free Energy Contributions for Association Reactions of Large Molecules, J. Phys. Chem. Lett. 11 (2020) 6606–6611. Crossref
(27) S. Ehlert, M. Stahn, S. Spicher, S. Grimme, Robust and Efficient Implicit Solvation Model for Fast Semiempirical Methods, J. Chem. Theory Comput. 17 (2021) 4250–4261. Crossref
(28) M.J. Frisch, G.W. Trucks, H.B. Schlegel, 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, N.J. 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. Revision C.01. Gaussian, Inc. (2009).
(29) R.E. Skyner, J.L. McDonagh, C.R. Groom, et al., A review of methods for the calculation of solution free energies and the modelling of systems in solution, Phys. Chem. Chem. Phys. 17 (2015) 6174–6191. Crossref
(30) S. Grimme, Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory, Chem. - Eur. J. 18 (2012) 9955–9964. Crossref
(31) T. Lu, Q. Chen, Shermo: A general code for calculating molecular thermochemistry properties, Comput. Theor. Chem. 1200 (2021) 113249. Crossref
Downloads
Published
How to Cite
Issue
Section
