Experimental Spectroscopic and Computational Studies on A New Synthesized Sulfisoxazole Derivative; Molecular Docking, Drug-likeness, ADME, Toxicity Predictions and Carbonic Anhydrase II Activity Investigations

Abstract

In this paper, 5-Dimethylamino-2-hydroxy-3-methoxy benzaldehyde sulfisoxazole (5DHMS) and Cu(5DHMS)2 compounds have been synthesized. The molecular structure characterizations were performed using experimental and computational methods. In the experimental part of the study, CHNS, FT-IR, NMR, TGA, and LC-MS analysis techniques were used. Density Functional Theory (DFT) was selected for the calculation level in the theoretical part. Firstly, optimized structures were obtained from the predicted 3D structures. Vibrational modes were calculated using the optimized structures of the compounds. The vibrational modes of each compound were analyzed in detail using potential energy distribution (PED). Molecular electrostatic potential and HOMO-LUMO maps were drawn. Global chemical reactivity descriptors of compounds were determined. Moreover, the effects of solvent media on chemical reactivity descriptors were revealed in detail. Protein-ligand interactions with the target receptor carbonic anhydrase II enzyme were performed. In addition, some essential biological activity parameters such as drug-likeness, toxicity, and ADME predictions were examined in silico.

Keywords

• Sulfisoxazole derivatives
• Quantum chemical calculations
• Vibrational spectroscopy
• Molecular docking
• In silico predictions

References

1. [1] Parasca, O. M., Gheaţă, F., Pânzariu, A., Geangalău, I., Profire, L. “Importance of sulfonamide moiety in current and future therapy”, Revista medico-chirurgicala a Societatii De Medici Si Naturalisti, April-June, 117: 558-564, (2013).
2. [2] Dai, T., Huang, Y. Y., Sharma, S. K., Hashmi, J. T., Kurup, D. B., Hamblin, M. R., “Topical antimicrobials for burn wound infections”, Recent Patents on Anti-Infective Drug Discovery, 5: 124-51, (2010).
3. [3] Blondeau, J. M., and Fitch, S. D. “In vitro killing of canine urinary tract infection pathogens by ampicillin, cephalexin, marbofloxacin, pradofloxacin, and trimethoprim/sulfamethoxazole”, Microorganisms, 9(11): 2279, (2021).
4. [4] Mushtaq, S., Sarkar, R., “Sulfasalazine in dermatology: A lesser explored drug with broad therapeutic potential”, International Journal of Women's Dermatology, 13: 191-198, (2020).
5. [5] Edgar, Selvaag., “In Vitro Phototoxicity Due to Sulfonamide-Derived Oral Antidiabetic and Diuretic Drugs”, Journal of Toxicology: Cutaneous and Ocular Toxicology, 16: 77-84, (1997).
6. [6] Renzi, A. A., Chart, J. J., Gaunt, R. R., “Sulfonamide compounds with high diuretic activity”, Toxicology and Applied Pharmacology, 1(4): 406-416, (1959).
7. [7] Tang, C., Dong, X., He, W., Cheng, S., Chen, Y., Huang, Y., Yin, B., Sheng, Y., Zhou, J., Wu, X., Zeng, F., Li, Z., Liang, F., “Cerebral mechanism of celecoxib for treating knee pain: study protocol for a randomized controlled parallel trial”, Trials, 20: 58, (2019).
8. [8] Petkar, P. A., Jagtap, J. R., “A Review on Antimicrobial Potential of Sulfonamide Scaffold”, International Journal of Pharmaceutical Sciences Review and Research, 2: 2535-2547, (2020).

9. [9] Mondal, S., Malakar, S., “Synthesis of sulfonamide and their synthetic and therapeutic applications: Recent advances”, Tetrahedron, 76(48): 131662, (2020).
10. [10] Wan, Y., Fang, G., Chen, H., Deng, X., Tang, Z., “Sulfonamide derivatives as potential anti-cancer agents and their SARs elucidation”, European Journal of Medicinal Chemistry, 226: 113837, (2021).
11. [11] Ovung, A., Bhattacharyya, J., “Sulfonamide drugs: Structure, antibacterial property, toxicity, and biophysical interactions”, Biophysical Reviews, 13(2): 259-272, (2021).
12. [12] Venkatesan, M., Fruci, M., Verellen, L. A., Skarina, T., Mesa, N., Flick, R., Savchenko, A., “Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics”, Nature Communications, 14(1): 4031, (2023).
13. [13] Dege, N., Gökçe, H., Doğan, O. E., Alpaslan, G., Ağar, T., Muthu, S. Sert, Y., “Quantum computational, spectroscopic investigations on N-(2-((2-chloro-4,5-dicyanophenyl)amino) ethyl)-4-methylbenzenesulfonamide by DFT/TD-DFT with different solvents, molecular docking and drug-likeness researches”, Colloid Surface A, 638: 128311, (2022).
14. [14] Bilkan, M. T., Alyar, S., Alyar, H., “Experimental Spectroscopic and Theoretical Studies of New Synthesized Sulfonamide Derivatives”, Russian Journal of Physical Chemistry A, 94: 143-151, (2020).
15. [15] Alyar, S., Bilkan, M. T., Karataş, M. F., Bilkan, Ç., Alyar, H., “Experimental and Theoretical Studies on A New Sulfonamide Derivative and Its Copper Complex: Synthesis, FT-IR, NMR, DFT, Molecular Docking and In Silico Investigations”, Journal of Molecular Structure, 137531, (2024).
16. [16] Dennington, R. D., Keith, T. A., Millam, J. M., GaussView 5, Gaussian, Inc., (2008).
17. [17] Frisch, M. J., et al., Gaussian 09, Revision B.01, Gaussian Inc., C.T. Wallingford, (2009).
18. [18] Jamróz, M. H., Vibrational Energy Distribution Analysis. VEDA 4, Warsaw, (2004).
19. [19] Parr, R. G., Szentpa´ly, L.V., Liu, S., “Computational Analysis of Theacrine, a Purported Nootropic and Energy-Enhancing Nutritional Supplement”, Journal of the American Chemical Society, 121: 1922-1924, (1999).
20. [20] Bitencourt-Ferreira, G., and de Azevedo, W. F., “Molegro virtual docker for docking”, Docking Screens for Drug Discovery, 149-167, (2019).
21. [21] PreADMET, https://preadmet.qsarhub.com/, (2022).
22. [22] ProTox-II- Prediction of Toxicity of Chemicals, (2022).
23. [23] Ji, Y., Yang, X., Ji, Z., Zhu, L., Ma, N., Chen, D., Jia, X., Tang, J., and Cao, Y., “DFT-calculated IR spectrum amide I, II, and III band contributions of N-methylacetamide fine components”, ACS Omega, 5(15): 8572-8578, (2020).
24. [24] Franke, P. R., Stanton, J. F., and Douberly, G. E., “How to VPT2: Accurate and intuitive simulations of CH stretching infrared spectra using VPT2+ K with large effective Hamiltonian resonance treatments”, The Journal of Physical Chemistry A, 125(6): 1301-1324, (2021).
25. [25] Anderson, R. J., Bendell, D. J., Groundwater, P. W., “Organic spectroscopic analysis”, Royal Society of Chemistry, (2004).
26. [26] Gunawan, R., Nandiyanto, A. B. D., “How to read and interpret 1H-NMR and 13C-NMR spectrums”, Indonesian Journal of Science and Technology, 6(2): 267-298, (2021).
27. [27] Bilkan, M. T., Yurdakul, Ş., Demircioğlu, Z., Büyükgüngör, O., “Crystal structure, FT-IR, FT-Raman and DFT studies on a novel compound [C10H9N3]4.AgNO3”, Journal of Organometallic Chemistry, 805: 108-116, (2016).
28. [28] Bilkan, M. T., “Quantum chemical studies on solvent effects, ligand–water complexes and dimer structure of 2,2ʹ-dipyridylamine”, Physics and Chemistry of Liquids, 57: 100-116, (2019).
29. [29] Lee, M. S., Kerns, E. H., “LC/MS applications in drug development”, Mass Spectrometry Reviews, 18(3‐4): 187-279, (1999).
30. [30] Supuran, C. T., “Carbonic anhydrases-an overview”, Current Pharmaceutical Design, 14(7): 603-614, (2008).
31. [31] Supuran, C. T., Scozzafava, A., “Carbonic anhydrases as targets for medicinal chemistry”, Bioorganic & Medicinal Chemistry, 1: 4336-50, (2007).
32. [32] Supuran, C. T., “Carbonic anhydrases--an overview”, Current Pharmaceutical Design, 14: 603-614, (2008).
33. [33] Butina, D., Segall, M. D., Frankcombe, K., “Predicting ADME properties in silico: methods and models”, Drug Discovery Today, 7: 83-88, (2002).
34. [34] Ma, X. L., Chen, C., Yang, J., “Predictive model of blood-brain barrier penetration of organic compounds”, Acta Pharmacologica Sinica, 26: 500-512, (2005).
35. [35] Lea, T., Caco-2 Cell Line, “The Impact of Food Bioactives on Health in Vitro and Ex Vivo Models”, Springer, Cham, Chapter 10, (2015).
36. [36] Yamashita, S., Furubayashi, T., Kataoka, M., Sakane, T., Sezaki, H., Tokuda, H., “Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells”, European Journal of Pharmaceutical Sciences, 10(3): 195-204, (2000).
37. [37] Christopher, A. L., “Lead- and drug-like compounds: the rule-of-five revolution”, Drug Discovery Today Technologies, 1: 337-341, (2004).
38. [38] "Absolute lethal dose (LD100)", IUPAC Gold Book. International Union of Pure and Applied Chemistry, Archived from the original on 2019-07-01, Retrieved, (2019).
39. [39] "What is a LD50 and LC50?", OSH Answers Fact Sheets. Canadian Centre for Occupational Health and Safety, 5 October, (2021).
40. [40] Copper Toxicity, “Fundamentals of Toxicologic Pathology (Second Edition)”, (2010).
41. [41] Janssen, J., Saluja, S. S., “How much did you take? Reviewing acetaminophen toxicity”, Canadian Family Physician, 61: 347-356, (2015).