Structural Parameters, NLO, HOMO, LUMO, MEP, Chemical Reactivity Descriptors, Mulliken-NPA, Thermodynamic Functions, Hirshfeld Surface Analysis and Molecular Docking of 1,3-Bis(4-methylphenyl)triazine

Öz

In the current study, the molecular geometry, electronic characteristics, nonlinear optical (NLO) properties, and potential biological activity of 1,3-bis(4-methylphenyl)triazene (I) were investigated by a combination of experimental crystallographic data and density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level. The optimized molecular geometry was in very good agreement with experimental X-ray data, with a low root-mean-square deviation (RMSD) of 0.106 Å, verifying the computational model. The molecule demonstrated high NLO activity, possessing a first-order hyperpolarizability roughly seven times larger than that of urea, and potential application in optoelectronic and photonic devices. Frontier molecular orbital (FMO) calculation demonstrated HOMO–LUMO energy gap of 5.6015 eV in the gas-phase indicating kinetic stability, and solvent-phase calculation indicated higher reactivity and polarity at high-dielectric conditions. Global reactivity descriptors and molecular electrostatic potential (MEP) mapping identified key electrophilic and nucleophilic sites, with implications for the charge distribution of the molecule and probable modes of interaction. Mulliken and natural population analyses (NPA) also revealed electronic behavior, NPA providing more chemically meaningful charge partitioning. Thermodynamic properties -entropy, enthalpy, and heat capacity- exhibited smooth temperature dependence, which established the thermal stability of the compound. Hirshfeld surface and 2D fingerprint plots of the crystal structure highlighted the dominant role played by van der Waals interactions in crystal packing. Molecular docking studies with the HER2 receptor (PDB ID: 3PP0) showed good binding affinity (-9.8 k cal mol⁻¹) with the aid of supporting hydrogen bonding and hydrophobic interactions with prominent amino acid residues, which reflected potential anticancer activity. Combined, the findings emphasize the exciting multifunctionality of I, whose potential uses range from materials science to being a lead scaffold in drug design, particularly for HER2-targeted anticancer drugs.

Anahtar Kelimeler

• Quantum mechanical calculations
• Hirshfeld surface analysis
• Molecular docking

Kaynakça

1. P. de M. S. Figueirêdo et al., “Assessment of the biological potential of diaryltriazene-derived triazene compounds,” Sci. Rep., vol. 11, p. 2541, 2021.
2. F. Marchesi, M. Turriziani, G. Tortorelli, G. Avvisati, F. Torino, ve L. De Vecchis, “Triazene compounds: Mechanism of action and related DNA repair systems,” Pharmacol. Res., vol. 56, no. 4, pp. 275-287, 2007.
3. N. Iqbal ve N. Iqbal, “Human epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications,” Mol. Biol. Int., vol. 2014, p. 852748, 2014.
4. S. Lamichhane, R. P. Rai, A. Khatri, R. Adhikari, B. G. Shrestha, ve S. K. Shrestha, “Screening of phytochemicals as potential anti-breast cancer agents targeting HER2: An in-silico approach,” J. Biomol. Struct. Dyn., vol. 41, no. 3, pp. 897-911, 2023.
5. R. B. O. Ouma, S. M. Ngari, ve J. K. Kibet, “A review of the current trends in computational approaches in drug design and metabolism,” Discov. Public Health, vol. 21, p. 108, 2024.
6. P. C. Agu et al., “Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management,” Sci. Rep., vol. 13, no. 1, p. 13398, 2023. doi: 10.1038/s41598-023-40160-2
7. M. J. Frisch et al., Gaussian 03, Revision C.02, Gaussian, Inc., 2004.
8. C. Lee, W. Yang, ve R. G. Parr, “Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density,” Phys. Rev. B, vol. 37, no. 2, pp. 785-789, 1988. doi: 10.1103/PhysRevB.37.785

9. A. D. Becke, “Density-functional thermochemistry. III. The role of exact exchange,” J. Chem. Phys., vol. 98, no. 7, pp. 5648-5652, 1993. doi: 10.1063/1.464913
10. R. Dennington, T. Keith, ve J. Millam, GaussView, Version 5.0 [Computer software], Semichem Inc., 2009.
11. R. G. Parr, L. V. Szentpály, ve S. Liu, “Electrophilicity index,” J. Am. Chem. Soc., vol. 121, no. 9, pp. 1922-1924, 1999. doi: 10.1021/ja983494x
12. J. Tomasi, B. Mennucci, ve R. Cammi, “Quantum mechanical continuum solvation models,” Chem. Rev., vol. 105, no. 8, pp. 2999-3094, 2005. doi: 10.1021/cr9904009
13. M. J. Turner et al., CrystalExplorer17 (Version 17.5) [Computer software], University of Western Australia, 2017.
14. J. J. McKinnon, D. Jayatilaka, ve M. A. Spackman, “Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces,” Chem. Commun., no. 37, pp. 3814-3816, 2007. doi: 10.1039/B704980C
15. M. A. Spackman ve D. Jayatilaka, “Hirshfeld surface analysis,” CrystEngComm, vol. 11, no. 1, pp. 19-32, 2009. doi: 10.1039/B818330A
16. F. L. Hirshfeld, “Bonded-atom fragments for describing molecular charge densities,” Theor. Chim. Acta, vol. 44, no. 2, pp. 129-138, 1977. doi: 10.1007/BF00549096
17. K. Aertgeerts et al., “Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein,” J. Biol. Chem., vol. 286, no. 21, pp. 18756-18765, 2011. doi: 10.1074/jbc.M110.206193
18. O. Trott ve A. J. Olson, “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading,” J. Comput. Chem., vol. 31, no. 2, pp. 455-461, 2010.
19. D. Biovia et al., Discovery Studio Visualizer (Version 17.2) [Computer software], Dassault Systèmes, 2016.
20. N. Karadayı, Ş. Çakmak, M. Odabaşoğlu, ve O. Büyükgüngör, “1,3-Bis(4-methylphenyl)triazene, 1-(4-chlorophenyl)-3-(4-fluorophenyl)triazene and 1-(4-fluorophenyl)-3-(4-methylphenyl)triazene,” Acta Crystallogr. Sect. E Struct. Rep. Online, vol. 61, no. 5, pp. o303-o305, 2005. doi: 10.1107/S0108270105004373
21. R. G. Parr ve W. Yang, Density-functional theory of atoms and molecules. Oxford University Press, 1989.
22. W. Koch ve M. C. Holthausen, A chemist’s guide to density functional theory, 2nd ed. Wiley-VCH, 2001.
23. Y. Zhao ve D. G. Truhlar, “Density functional theory for highly excited states: The role of exact exchange,” J. Chem. Phys., vol. 128, no. 18, p. 184103, 2008. doi: 10.1063/1.2928720
24. Y. Zhao, Y. Xie, ve H. F. Schaefer, “Benchmark studies of dipole moments and first hyperpolarizabilities of push-pull π-conjugated systems,” Theor. Chem. Acc., vol. 116, no. 1, pp. 131-137, 2006. doi: 10.1007/s00214-005-0023-6
25. W. Kohn ve L. J. Sham, “Self-consistent equations including exchange and correlation effects,” Phys. Rev., vol. 140, no. 4A, pp. A1133-A1138, 1965. doi: 10.1103/PhysRev.140.A1133
26. P. Politzer ve J. S. Murray, “The fundamental nature and role of the electrostatic potential in atoms and molecules,” Theor. Chem. Acc., vol. 108, no. 3, pp. 134-142, 2002. doi: 10.1007/s00214-002-0363-9
27. W. Yang ve R. G. Parr, “Hardness, softness, and the Fukui function in the electronic theory of metals and catalysis,” Proc. Natl. Acad. Sci. U.S.A., vol. 82, no. 20, pp. 6723-6726, 1985. doi: 10.1073/pnas.82.20.6723
28. P. Geerlings, F. De Proft, ve W. Langenaeker, “Conceptual density functional theory,” Chem. Rev., vol. 103, no. 5, pp. 1793-1874, 2003. doi: 10.1021/cr990029p
29. R. G. Parr ve R. G. Pearson, “Absolute hardness: companion parameter to absolute electronegativity,” J. Am. Chem. Soc., vol. 105, no. 26, pp. 7512-7516, 1983. doi: 10.1021/ja00364a005
30. C. J. Cramer ve D. G. Truhlar, “Implicit solvation models: Equilibria, structure, spectra, and dynamics,” Chem. Rev., vol. 99, no. 8, pp. 2161-2200, 1999. doi: 10.1021/cr960149m
31. D. A. McQuarrie ve J. D. Simon, Physical chemistry: A molecular approach. University Science Books, 1999.
32. P. Atkins ve J. de Paula, Atkins’ physical chemistry, 10th ed. Oxford University Press, 2014.
33. K. S. Pitzer, E. R. Lippincott ve R. F. Curl, “The Thermodynamic Properties of Organic Compounds,” J. Am. Chem. Soc., vol. 67, no. 8, pp. 1341-1350, 1945. doi: 10.1021/ja01224a002
34. L. A. Curtiss, K. Raghavachari, P. C. Redfern ve J. A. Pople, “Assessment of Gaussian-2 and density functional theories for the computation of enthalpies of formation,” J. Chem. Phys., vol. 106, no. 3, pp. 1063-1079, 1997. doi: 10.1063/1.473182
35. A. N. Khalilov et al., “Crystal structure and Hirshfeld surface analysis of (2E)-1-phenyl-3-(4-fluorophenyl)prop-2-en-1-one,” Acta Crystallogr. Sect. E: Crystallogr. Commun., vol. 78, no. 2, pp. 525-529, 2022. doi: 10.1107/S2056989022000343
36. C. Jelsch ve Y. B. M. Bisseyoub, “Deciphering the driving forces in crystal packing by analysis of intermolecular interactions in aromatic hydrocarbons,” IUCrJ, vol. 10, no. 5, pp. 557-567, 2023. doi: 10.1107/S2056989023005043
37. C. Bissantz, B. Kuhn ve M. Stahl, “A medicinal chemist’s guide to molecular interactions,” J. Med. Chem., vol. 53, no. 14, pp. 5061-5084, 2010. doi: 10.1021/jm100112j
38. S. Başak ve C. C. Ersanlı, “Structure elucidation of Schiff base-containing compound by quantum chemical methods,” Int. Sci. Vocat. Stud. J., vol. 8, no. 2, pp. 129-136, 2024. doi: 10.47897/bilmes.1553500
39. C. C. Ersanlı ve S. Başak, “Quantum Mechanical Calculations and Molecular Docking Simulation Studies of N-(5-chloro-2-oxobenzyl)-2-hydroxy-5-methylanilinium Compound,” Int. Sci. Vocat. Stud. J., vol. 8, no. 2, pp. 162-177, 2024. doi: 10.47897/bilmes.1573560
40. S. Öztürk, T. Aycan, Z. Demircioğlu ve C. C. Ersanlı, “Quantum Mechanical Calculations, Hirshfeld Surface Analysis, Molecular Docking, ADME and Toxicology Studies of the Ethyl 4-chloro-2-[(4-nitrophenyl)hydrazono]-3-oxobutrate Compound,” Int. Sci. Vocat. Stud. J., vol. 7, no. 2, pp. 109-121, 2023. doi: 10.47897/bilmes.1385170
41. D. B. Kitchen, H. Decornez, J. R. Furr ve J. Bajorath, “Docking and scoring in virtual screening for drug discovery: methods and applications,” Nat. Rev. Drug Discov., vol. 3, no. 11, pp. 935-949, 2004. doi: 10.1038/nrd1549
42. D. E. V. Wilman, “Triazenes as antitumor agents,” Med. Res. Rev., vol. 8, no. 1, pp. 1-20, 1988. doi: 10.1002/med.2610080102
43. C. N. Cavasotto ve A. J. W. Orry, “Ligand docking and structure-based virtual screening in drug discovery,” Curr. Top. Med. Chem., vol. 7, no. 10, pp. 1006-1014, 2007. doi: 10.2174/156802607780906468