Abstract

In this study, the quinolone derivatives (RS)-1-ethyl-5,6,8-trichloro-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (ECMPQC) and (RS)-1-ethyl-5,6,8-trifluoro-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (EFMPQC) were theoretically investigated using density functional theory (DFT) at the B3LYP/6-31G(d,p) level to determine their structural and spectroscopic properties. Time-dependent density functional theory (TD-DFT) was employed to analyse the frontier molecular orbitals (FMOs) and simulate the UV-Vis spectra of the quinolone derivatives in the gas phase. Natural bond orbital (NBO) and molecular electrostatic potential (MEP) analyses were carried out to elucidate intra- and intermolecular interactions as well as charge distribution characteristics. Topological analysis indicated the presence of both localized and delocalized electronic regions within the molecular frameworks. Furthermore, molecular docking studies were conducted to assess the potential biological interactions of these derivatives with viral proteins that play crucial roles in viral replication, disease progression, host mortality, and overall health outcomes.

Keywords

Quinolone, DFT, Topological, Molecular docking, Mortality,

Downloads

Download data is not yet available.

References

  1. D. Benedetto Tiz, L. Bagnoli, O. Rosati, F. Marini, L. Sancineto, C. Santi, New halogen-containing drugs approved by FDA in 2021: An overview on their syntheses and pharmaceutical use. Molecules, 27(5), (2022) 1643. https://doi.org/10.3390/molecules27051643v
  2. Z. Xu, Z. Yang, Y. Liu, Y. Lu, K. Chen, W. Zhu, Halogen bond: its role beyond drug–target binding affinity for drug discovery and development. Journal of Chemical Information and Modeling, 54(1), (2014) 69-78. https://doi.org/10.1021/ci400539q
  3. M.Z. Hernandes, S.M.T. Cavalcanti, D.R.M. Moreira, W.F. de Azevedo Junior, A.C.L. Leite, Halogen atoms in the modern medicinal chemistry: hints for the drug design. Current Drug Targets, 11(3), (2010) 303-314. http://dx.doi.org/10.2174/138945010790711996
  4. H. Mei, J. Han, S. Fustero, M. Medio‐Simon, D.M. Sedgwick, C. Santi, R. Ruzziconi, V.A. Soloshonok, Fluorine‐containing drugs approved by the FDA in 2018. Chemistry–A European Journal, 25(51), (2019) 11797-11819. https://doi.org/10.1002/chem.201985161
  5. K.L. Kirk, Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules. Journal of Fluorine Chemistry, 127(8), (2006) 1013-1029. https://doi.org/10.1016/j.jfluchem.2006.06.007
  6. C. Isanbor, D. O’Hagan, Fluorine in medicinal chemistry: A review of anti-cancer agents. Journal of Fluorine Chemistry, 127(3), (2006) 303-319. https://doi.org/10.1016/j.jfluchem.2006.01.011
  7. N. Sheikhi, M. Bahraminejad, M. Saeedi, S.S. Mirfazli, A review: FDA-approved fluorine-containing small molecules from 2015 to 2022. European Journal of Medicinal Chemistry, 260, (2023)115758. https://doi.org/10.1016/j.ejmech.2023.115758
  8. W.Y. Fang, L. Ravindar, K.P. Rakesh, H.M. Manukumar, C.S. Shantharam, N.S. Alharbi, H.L. Qin, Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: A critical review. European Journal of Medicinal Chemistry, 173, (2019)117-153. https://doi.org/10.1016/j.ejmech.2019.03.063
  9. J.G. Topliss, Utilization of operational schemes for analog synthesis in drug design. Journal of Medicinal Chemistry, 15(10), (1972) 1006-1011. https://doi.org/10.1021/jm00280a002
  10. J.G. Topliss, A manual method for applying the Hansch approach to drug design. Journal of Medicinal Chemistry, 20(4), (1977) 463-469. https://doi.org/10.1021/jm00214a001
  11. D. Chiodi, Y. Ishihara, “Magic chloro”: profound effects of the chlorine atom in drug discovery. Journal of Medicinal Chemistry, 66(8) (2023) 5305-5331, https://doi.org/10.1021/acs.jmedchem.2c02015
  12. D.G. Brown, M.M. Gagnon, J. Bostrom, Understanding our love affair with p-chlorophenyl: present day implications from historical biases of reagent selection. Journal of Medicinal Chemistry, 58(5) (2015) 2390-2405, https://doi.org/10.1021/jm501894t
  13. S. Joshi, R. Srivastava, Effect of “Magic Chlorine” in drug discovery: an in silico approach. RSC Advances, 13(49) (2023) 34922-34934, https://doi.org/10.1039/D3RA06638J.
  14. I. Vicenti, M. Zazzi, F. Saladini, SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19. Expert Opinion on Therapeutic Patents, 31(4) (2021) 325-337, https://doi.org/10.1080/13543776.2021.1880568
  15. S. Ullrich, C. Nitsche, The SARS-CoV-2 main protease as drug target. Bioorganic & Medicinal Chemistry Letters, 30(17) (2020) 127377, https://doi.org/10.1016/j.bmcl.2020.127377
  16. R.S. Keri, S.A. Patil, Quinoline: A promising antitubercular target. Biomedicine & Pharmacotherapy, 68(8) (2014) 1161-1175, https://doi.org/10.1016/j.biopha.2014.10.007
  17. A. Dorababu, Quinoline: A promising scaffold in recent antiprotozoal drug discovery. Chemistry Select, 6(9) (2021) 2164-2177, https://doi.org/10.1002/slct.202100115
  18. R. Musiol, J. Jampilek, V. Buchta, L. Silva, H. Niedbala, B. Podeszwa, A. Palka, K. Majerz-Maniecka, B. Oleksyn, J. Polanski, Antifungal properties of new series of quinoline derivatives. Bioorganic & Medicinal Chemistry, 14(10) (2006) 3592-3598. https://doi.org/10.1016/j.bmc.2006.01.016
  19. M.Y. Wang, R. Zhao, L.J. Gao, X.F. Gao, D.P. Wang, J.M. Cao, SARS-CoV-2: structure, biology, and structure-based therapeutics development. Frontiers in Cellular and Infection Microbiology, 10 (2020) 587269, https://doi.org/10.3389/fcimb.2020.587269
  20. V. Arjunan, P. Ravindran, T. Rani, S. Mohan, FTIR, FT-Raman, FT-NMR, ab initio and DFT electronic structure investigation on 8-chloroquinoline and 8-nitroquinoline. Journal of Molecular Structure, 988(1-3) (2011) 91-101, https://doi.org/10.1016/j.molstruc.2010.12.032
  21. A. Komasa, M. Szafran, A. Katrusiak, K. Roszak, Z. Dega-Szafran, Crystal and molecular structure of 8-hydroxyquinoline betaine monohydrate studied by X-ray, FTIR, NMR and DFT. Journal of Molecular Structure, 1248 (2022) 131421, https://doi.org/10.1016/j.molstruc.2021.131421
  22. M. Kumru, A. Altun, M. Kocademir, V. Kucuk, T. Bardakçı, I. Sasmaz, Combined experimental and quantum chemical studies on spectroscopic (FT-IR, FT-Raman, UV–Vis, and NMR) and structural characteristics of quinoline-5-carboxaldehyde. Journal of Molecular Structure, 1125 (2016) 302-309, https://doi.org/10.1016/j.molstruc.2016.06.066
  23. M. Kumru, V.E.S.I.L.E. Kucuk, M. Kocademir, H.M. Alfanda, A. Altun, L. Sarı, Experimental and theoretical studies on IR, Raman, and UV–Vis spectra of quinoline-7-carboxaldehyde. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 134 (2015) 81-89, https://doi.org/10.1016/j.saa.2014.06.094
  24. R. Thirumurugan, K. Raju, K. Moovendaran S. Raju, E. Shobhana, Exploring Second-Order Nonlinear Optical Performance in Oxyquinolinium 3-Carboxypropanoate: A Combined Experimental and DFT Study. International Research Journal of Multidisciplinary Technovation, 7(6) (2025) 191-211. https://doi.org/10.54392/irjmt25612
  25. S. Kavi Karunya, K. Jagathy, K. Anandaraj, C. Pavithra, R. Manjula, Exploration of Solvent Effects, Structural and Spectroscopic Properties, Chemical Shifts, Bonding Nature, Reactive Sites and Molecular Docking Studies on 3-Chloro-2,6-Difluoropyridin-4-Amine As a Potent Antimicrobial Agent. International Research Journal of Multidisciplinary Technovation, 6 (1) (2024) 109-27, https://doi.org/10.54392/irjmt2419
  26. M.J. Frisch, et al., Gaussian 09, Gaussian Inc, Wallingford CT, 2009, https://doi.org/10.1016/j.molstruc.2024.140062
  27. A.D. Becke, Density functional thermo chemistry – I: The effect of the exchange only gradient correlation, Journal of Chemical Physics, 98 (1993) 5648-5652, https://doi.org/10.1063/1.462066
  28. C. Lee, W. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density, Physical Review B, 37 (1988) 785-789.
  29. B. Miehlich, A. Savin, H. Stoll, H. Preuss, Results obtained with the correlation energy density functional of Becke and Lee, Yang and Parr, Chemical Physics Letters. 157 (3) (1989) 200-206.
  30. W. Kohn, L.J. Sham, Self-consistent equations including exchange and correlation effects, Physical Reiew, 140 (1965) A1133-A1138, https://doi.org/10.1103/PhysRev.140.A1133
  31. R. G. Parr and W. Yang, Density-functional theory of atoms and molecules (Oxford Univ. Press, Oxford, 1989).
  32. P. Hohenberg and W. Kohn, “Inhomogeneous Electron Gas,” Physical Reiew,136 (1964) B864-B71. DOI: https://doi.org/10.1103/PhysRev.136.B864
  33. R. Dennington, T.A. Keith, J.M. Millam GaussView 6.0. Semichem Inc., Shawnee Mission, KS, USA (2016).
  34. M. Petersilka, U.J. Gossman, E.K.U. Gross, Excitation energies from timedependent density-functional theory, Physical Reiew Letters, 76 (1996) 1212-1215, https://doi.org/10.1103/PhysRevLett.76.1212
  35. E. Runge, E.K.U. Gross, Density functional theory for time-dependent systems, Physical Reiew Letters, 52 (1984) 997, https://doi.org/10.1103/PhysRevLett.52.997
  36. R. Bauernschmitt, R. Ahlrichs, Treatment of electronic excitations within the adiabatic approximation of time-dependent density functional theory, Chemical Physics Letters. 256 (1996) 454-464. https://doi.org/10.1016/0009-2614(96)00440-X
  37. N.M. O'Boyle, A.L. Tenderholt, K.M. Langner. Journal of Computational Chemistry, 2008, 29, 839-845.
  38. E.D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO Version 3.1, TCI, University of Wisconsin, Madison, 1998.
  39. G.A. Zhurko and D.A. Zhurko, Chemcraft Program Version 1.6 (Build 315), (2009) http://www.chemcraftprog.com
  40. T. Lu, F. Chen, Multiwfn: a multifunctional wavefunction analyzer, Journal of Computational Chemistry, 33 2012 580-592. https://doi.org/10.1002/jcc.22885
  41. G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, A.J. Olson, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, Journal of Computational Chemistry, 30 (2009) 2785-2791, https://doi.org/10.1002/jcc.21256
  42. W.L. DeLano, Pymol: an open-source molecular graphics tool. CCP4 Newsletter on protein Crystallography, 40(1) (2002) 82–92, http://www.pymol.org.
  43. A.C. Wallace, R.A. Laskowski, J.M. Thornton, LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions, Protein Engineering, 8 (1995) 127–134, https://doi.org/10.1093/protein/8.2.127
  44. S. Badoglu, S. Yurdakul, FT-IR spectroscopic and dft computational study on solvent effects on 8-hydroxy-2-quinolinecarboxylic acid. Optics and Spectroscopy, 118 (2015) 364-388, https://doi.org/10.1134/S0030400X15030066
  45. R. Kanimozhi, V. Arjunan, S. Mohan, Conformations, structure, vibrations, chemical shift and reactivity properties of isoquinoline–1–carboxylic acid and isoquinoline–3–carboxylic acid–Comparative investigations by experimental and theoretical techniques. Journal of Molecular Structure, 1207 (2020) 127841, https://doi.org/10.1016/j.molstruc.2020.127841
  46. R.T. Ulahannan, C.Y. Panicker, H.T. Varghese, C. Van Alsenoy, R. Musiol, J. Jampilek, P.L. Anto, Spectroscopic (FT-IR, FT-Raman) investigations and quantum chemical calculations of 4-hydroxy-2-oxo-1, 2-dihydroquinoline-7-carboxylic acid. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 121, (2014) 404-414, https://doi.org/10.1016/j.saa.2013.10.114.
  47. V. Vijayalakshmi, N. Kanagathara, J. Jan, M.K. Marchewka, A. Mohammad, K. Senthilkumar, Structural, spectroscopic and second harmonic generation evaluation of 1, 2, 4-triazolinium tartrate-tartaric acid as a promising nonlinear optical material, Optical Materials, 147 (2024) 11469. https://doi.org/10.1016/j.optmat.2023.114694
  48. C.C. Sangeetha, R. Madivanane, V. Pouchaname, The vibrational spectroscopic (FT-IR & FTR) study and HOMO & LUMO analysis of 6-methyl quinoline using DFT studies. Archives of Physics Research, 4(3) (2013) 67-77.
  49. N. Sundaraganesan, E. Kavitha, S. Sebastian, J.P. Cornard, M. Martel, Experimental FTIR, FT-IR (gas phase), FT-Raman and NMR spectra, hyperpolarizability studies and DFT calculations of 3, 5-dimethylpyrazole. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 74(3) (2009) 788-797, https://doi.org/10.1016/j.saa.2009.08.019
  50. A. Ram Kumar, S. Selvaraj, A.S. Vickram, J. Jenifer, R.K. Raja, Experimental and theoretical investigations on antiproliferative compound nootkatone’s vibrational characteristics, solvent effects of electronic properties, topological insights, Hirshfeld surface, donor-acceptor insights, ADME, and molecular docking against SMAD proteins. Journal of Molecular Structure, 1346 (2025) 143156, https://doi.org/10.1016/j.molstruc.2025.143156
  51. V. Udayakumar, S. Periandy, M. Karabacak, S. Ramalingam, Experimental (FT-IR, FT-Raman) and theoretical (HF and DFT) investigation and HOMO and LUMO analysis on the structure of p-fluoronitrobenzene. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 83(1) (2011) 575-586. https://doi.org/10.1016/j.saa.2011.09.008
  52. M. Karabacak, D. Karagoz, M. Kurt, Experimental (FT-IR and FT-Raman spectra) and theoretical (ab initio HF, DFT) study of 2-chloro-5-methylaniline. Journal of Molecular Structure, 892(1-3) (2008) 25-31, https://doi.org/10.1016/j.molstruc.2008.04.054
  53. N. Sundaraganesan, B. Anand, C. Meganathan, B.D. Joshua, FT-IR, FT-Raman spectra and ab initio HF, DFT vibrational analysis of 2, 3-difluoro phenol. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 68(3) (2007) 561-566, https://doi.org/10.1016/j.saa.2006.12.028
  54. P. Divya, V.J. Reeda, S. Selvaraj, B. Jothy, Theoretical spectroscopic electronic elucidation with polar and nonpolar solvents (IEFPCM model), molecular docking and molecular dynamic studies on bendiocarb-antiallergic drug agent. Journal of Molecular Liquids, 404 (2024) 124895, https://doi.org/10.1016/j.molliq.2024.124895
  55. P. Divya, V.J. Reeda, S. Renuga, C.D. Annapoorani, V.B. Jothy, Vibrational analysis, DFT computations of spectroscopic, non-covalent analysis with molecular docking and dynamic simulation of 2-amino-4, 6-dimethyl pyrimidine benzoic acid, Journal of Molecular Structure, 1318 (2024) 139160, https://doi.org/10.1016/j.molstruc.2024.139160
  56. A, Mani, R. Elaiyaraja, Taurolidine, a Sulfonic Amino Acid Derivative, Induces Apoptosis and Cytotoxicity Against Cervical Cell Carcinoma an In Silico and in Vitro Approach, International Research Journal of Multidisciplinary Technovation, 7 (4) (2025) 70-81. https://doi.org/10.54392/irjmt2546
  57. E. Mohanapriya, S. Elangovan, N. Kanagathara, M.K. Marchewka, J. Janczak, P. Revathi, P, Density functional theory calculations, structural and spectroscopic characterization, and solvent-dependent HOMO-LUMO studies of 2-nitro-4-methylanilinium benzenesulfonate. Journal of Molecular Structure, 1317 (2024) 139147, https://doi.org/10.1016/j.molstruc.2024.139147
  58. S. Akshay Kalyan, N. Kanagathara, M.K. Marchewka, J. Janczak, K. Senthilkumar, Structure, Spectroscopy, and Theoretical insights on Co-crystals of 2, 4-Diamino-6-Methyl-1, 3, 5-Triazine Bis (4-Aminobenzoic acid) Monohydrate as a promising anti-cancer agent. Physica B: Condensed Matter, 679 (2024) 415807, https://doi.org/10.1016/j.physb.2024.415807
  59. K.A. Peele, C.P. Durthi, T. Srihansa, S. Krupanidhi, V.S. Ayyagari, D.J. Babu, M. Indira, A.R. Reddy, T.C. Venkateswarulu, Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study. Informatics in Medicine Unlocked, 19 (2020) 100345, https://doi.org/10.1016/j.imu.2020.100345
  60. W.S. Qayed, R.S. Ferreira, J.R.A. Silva, In silico study towards repositioning of FDA-approved drug candidates for anticoronaviral therapy: Molecular docking, molecular dynamics and binding free energy calculations. Molecules, 27(18) (2002) 5988, https://doi.org/10.3390/molecules27185988