Conformational Analysis and DFT Investigations of 1-(4-Fluorophenyl)Piperazine by ELF and LOL, Inhibitory activity against Alzheimer’s Disease, and ADME Prediction

Abstract

This study reports 1-(4-Fluorophenyl)Piperazine molecule structural and electronic properties calculated at the DFT/B3LYP level. A potential energy surface scan along the rotational bonds discovered the most stable minimum energy conformer of the title compound. Frontier molecular orbital (FMO) analyses, density of state (DOS), molecular electrostatic potential (MEP), and global and chemical reactivity descriptors were also used to investigate the reactivity of the pFPP molecule. In addition, ELF and LOL analysis were performed. In silico biological studies such as drug-likeness, ADME, and toxicity properties were also performed. Molecular docking studies are performed to predict the anti-Alzheimer agent enzyme (AChE) active site of the pFPP. The docking predicts the possibility of a potential drug to improve Alzheimer's disease (AD) treatment.

Keywords

• 1-(4-Fluorophenyl)Piperazine
• DFT
• ADME
• ELF
• LOL
• Molecular Docking

References

1. [1] D. Y. Peng, Q. Sun, X. L. Zhu, H. Y. Lin, Q. Chen, N. X. Yu, W. C. Yang, G. F. Yang, “Design, synthesis, and bioevaluation of benzamides: Novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase,’’ Bioorganic Medicinal Chemistry, vol. 20, pp. 6739-6750, 2012.
2. [2] Q. Sun, D. Y. Peng, S. G. Yang, X. L. Zhu, W. C. Yang, G. F. Yang, “Syntheses of coumarin–tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase,” Bioorganic Medicinal Chemistry, vol. 22, pp. 4784-4791, 2014.
3. [3] K. S. T. Diasa, C. Viegas, “Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the treatment of Alzheimer’s Disease,” Current Neuropharmacology, vol. 12, pp. 239-255, 2014.
4. [4] E. M. H. Brewton, E. M. Hersh, G. Brewton, D. Abrams, J. Bartlett, J. Galpin, P. Gill, R. Gorter, M. Gottlieb, J. J. Jonikas, S. Landesman, A. Levine, A. Marcel, E. A. Petersen, M.Whiteside, J. Zahradnik, C. Negron, F. Boutitie, J. Caraux, J.-M. Dupuy, L. R. Salmi, “Dithiocarbsodium(diethyldithiocarbamate) therapy in patients with symptomatic HIV-infection. Aids a randomized, double-blind, placebo-controlled multicenter study, ” American Medical Association, vol. 265, pp. 1538–1544, 1991.
5. [5] C. B. Mishra, A. Manral, S. Kumari, V. Saini, M. Tiwari, “Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-bamyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease,’’ Bioorganic Medicinal Chemistry, vol. 24, pp. 3829–384, 2016.
6. [6] H. S. N. Prasada, A.P. Ananda, T.N. Lohithd, P. Prabhuprasad, H.S. Jayanth, N.B. Krishnamurthy, M.A. Sridhar, L. Mallesha, P. Mallu, “Design, synthesis, molecular docking and DFT computational insight on the structure of Piperazine sulfynol derivatives as a new antibacterial contender against superbugs MRSA,’’ Journal of Molecular Structure, vol. 1247, 131333, 2022.
7. [7] S. B. Ozdemir, N. Demirbas, A. Demirbas, N. Colak, F.A. Ayaz, “Design, Microwave-Assisted and Conventional Synthesis of New Hybrid Compounds Derived From 1-(4-Fluorophenyl) piperazine and Screening for Their Biological Activities,’’ ChemistrySelect 3, pp. 2144 – 2151, 2018.
8. [8] A. Alzheimer, “Alzheimer's disease facts and figures,’’ Alzheimer's & dementia: The Journal of the Alzheimer's Association, vol. 11, pp. 332-384, 2015.

9. [9] D. Scherman, M. Hamon, H. Gozlan, J .P. Henry, A. Lesage, M. Masson, “Molecular pharmacology of niaprazine,’’ Progress in Neuropsychopharmacolgy and Biological. Psychiatry, vol. 12, pp. 989–1001, 1988
10. [10] R. A. Glennon, M.Y. Yousif, A.M. Ismaiel, M.B. el-Ashmawy, J.L. Herndon, J.B. Fischer, A.C Server, K.J.B.Howier, “Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands,’’ Journal of Medicinal Chemistry, vol. 34, pp. 3360–3365, 1991.
11. [11] W. N . Wu, L. A. McKown, G.H. Kuo, “Hepatic metabolism of two α-1A-adrenergic receptor antagonists, phthalimide-phenylpiperazine analogs (RWJ-69205 and RWJ-69471), in the rat, dog and human,’’ European Journal of Drug Metabolism and Pharmacokinetics, vol. 31, pp. 271–276, 2006.
12. [12] B. G. Mockett, D. Guévremont, M. Wutte, S. R. Hulme, J .M. Williams, W. C. Abraham, “Calcium/Calmodulin-dependent protein kinase II mediates group I metabotropic glutamate receptor-dependent protein synthesis and long-term depression in rat hippocampus,’’ Journal of Neuroscience, vol. 31, pp. 7380–7391, 2011.
13. [13] F. M. D. Ismail, “Important fluorinated drugs in experimental and clinical use,’’ Journal Fluorine Chemistry, vol. 118, pp. 27–33. 25, 2002.
14. [14] A. A. Gakh, M.N. Burnett, “Extreme modulation properties of aromatic fluorine,’' Journal Fluorine Chemistry, 132, pp. 88–93, 2011.
15. [15] 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, J. M. 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, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox.,“Gaussian Inc,’’Wallingford CT,2009.
16. [16] R. Dennington, T. Keith, J. Millam, “GaussView Version 5,’’ Semichem Inc., Shawnee Mission KS., 2009
17. [17] T. Lu, F. Chen, “Multiwfn: a Multifunctional Wavefunction Analyzer,’’ Journal of Computaional Chemistry, vol. 33, pp. 580–592, 2012.
18. [18] G. M. Morris, D. S. Goodwill, R. S. Halliday, R. Huey, W. Hart, R. K. Belew, A. J. Olson, “Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function,’’ Journal of Computaional Chemistry, vol. 19, pp. 1639-1662, 1998.
19. [19] W. L. D. Pymol, “An open-source molecular graphics tool, CCP4 Newsletter on protein,’’ Crystallography, vol. 40, pp. 82, 2002.
20. [20] Dassault Systemes BIOVIA, Discovery Studio Visualizer v17.2.0.16349, 2016. San Diego
21. [21] PreADMET Citation Statistics, (2022, May. 31). Available: www.preadmet.com
22. [22] Swiss Institute of Bioinformatics, (2022, May. 31). Available: www.swissadme.ch/index.php
23. [23] ProTox-II- Prediction of Toxicity of Chemicals, (2022, May. 31). Available: http://tox.charite.de/protox_II/
24. [24] T. Chaudharya, M. K. Chaudharya, B. D. Joshi, M. S. A. de Santana, A.P. Ayala, “Spectroscopic (FT-IR, Raman) analysis and computational study on conformational geometry, AIM and biological activity of cephalexin from DFT and molecular docking approach,’’ Journal of Molecular Structure, vol. 1240, 130594, 2021.
25. [25] M. N. Ahmed, K. A. Yasin, K. Ayub, T. Mahmood, M. N. Tahir, B. A. Khan, M. Hafeez, M. Ahmed, I. ul-Haq, “Click one pot synthesis, spectral analyses, crystal structures, DFT studies and brine shrimp cytotoxicity assay of two newly synthesized 1,4,5-trisubstituted 1,2,3-triazoles,’’ Journal of Molecular Structure, vol. 1106, pp. 430-439, 2016.
26. [26] M. Arshad, A. Bibi, T. Mahmood, A. Asiri, K. Ayub, “Synthesis, crystal structures and spectroscopic properties of triazine-based hydrazone derivatives; a comparative experimental-theoretical study, “ Molecules, vol. 20, pp. 5851-5874, 2015.
27. [27] M. Noreen, N. Rasool, Y. Gull, M. Zubair, T. Mahmood, K. Ayub, F.-H. Nasim, A. Yaqoob, M. Zia-Ul-Haq, V. Feo , “Synthesis, density functional theory (DFT), urease inhibition and antimicrobial activities of 5-aryl thiophenes bearing sulphonylacetamide moieties,’’ Molecules, vol. 20, pp. 19914-19928, 2015.
28. [28] M. Evecen, “Structural, Conformational and Spectroscopic Properties of C16H16BrNO3 SchiffBase Molecule: A Theoretical Investigation,” Sakarya Üniversitesi Fen Bilimleri Enstitüsü Dergisi, vol. 22, pp. 1591-1600, 2018.
29. [29] M. Hagar, H. A. Ahmed, G. Aljohani, O.A. Alhaddad, “Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations,’’ International Journalo of Molecular Sciences, vol. 21, pp. 3922, 2020.
30. [30] S. J. Basha, S. P. V. Chamundeeswari, S. Muthu, B. R. Raajaraman, “Quantum computational, spectroscopic investigations on 6- aminobenzimidazole by DFT/TD-DFT with different solvents and molecular docking studies,’’ Journal of Molecular Liquids, vol. 296, pp. 11178, 2019.
31. [31] R. Mathammal, N. R. Monisha, S. Yasaswini, V. Krishnakumar, “Molecular structure, vibrational analysis (FT-IR, FT-Raman), NMR, UV, NBO and HOMO–LUMO analysis of N,N-Diphenyl Formamide based on DFT calculations,’’ Spectrochimica Acta A, vol. 139, pp. 521-532, 2015.
32. [32] T. Chaudharya, M. K. Chaudharya , B. D. Joshi, M. S. A. de Santana, A. P. Ayala, “Spectroscopic (FT-IR, Raman) analysis and computational study on conformational geometry, AIM and biological activity of cephalexin from DFT and molecular docking approach,’’ Journal of Molecular Structure, vol. 1240, pp. 130594, 2021.
33. [33] H. P. Gümüş, Ö. Tamer, Y. Atalay, “4-(Metoksimetil)-1,6-dimetil-2-okso-1,2-dihidropiridin-3-karbonitril molekülünün teorik olarak incelenmesi,” Sakarya Üniversitesi Fen Bilimleri Enstitüsü Dergisi, vol. 19 no 3, pp. 303-311, 2015.
34. [34] B. Silvi, A. Savin, “Classification of chemical bonds based on topological analysis of electron localization functions,’’ Nature, 371, pp. 683-686, 1994.
35. [35] B. F. Rizwana, J. C. Prasana, S. Muthu, C. S. Abrahama, “Molecular docking studies, charge transfer excitation and wave function analyses (ESP, ELF, LOL) on valacyclovir : a potential antiviral drug,’’ Computational Biological Chemistry, vol. 78, pp. 9-17, 2019.
36. [36] C. B. Mishra, A. Manral, S. Kumari, V. Saini, M. Tiwari, “Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-bamyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease,’’ Bioorganic Medicinal Chemistry, vol. 24, pp. 3829–3841, 2016.
37. [37] M.D. Arbo, R. Silva, D.J. Barbosa, D.D. da Silva, L.G. Rossato, M.L. Bastos, H. Carmo, “Piperazine designer drugs induce toxicity in cardiomyoblast h9c2 cells through mitochondrial impairment,’’ Toxicology Letters, vol.229, pp. 178-189, 2014.
38. [38] A. Christopher, “Lipinski, Lead- and drug-like compounds: the rule-of-five revolution,’’ Drug Discovery Today Technologies vol. 1 no 4,pp. 337-341, 2004.