Synthesis, Antimicrobial Evaluation, and Docking Study of Some New Isoxazoline Derivatives Derived from Chalcones

Abstract

New 2-Isoxazoline derivatives containing furan moieties were synthesized from chalcones as starting materials, followed by antimicrobial activity. Chalcones were synthesized by reacting p-methoxy acetophenone or 3,4-(methylenedioxy)acetophenone with various aldehydes that were synthesized using Claisen-Schmidt condensation. Subsequently, the obtained products underwent cyclization with hydroxylamine hydrochloride to yield the corresponding 2-isoxazoline derivatives. The synthesized isoxazolines have been characterized via 1H-NMR, FTIR, and GC-Mass spectroscopy. The new derivatives were screened for their activity against different bacterial species as well as Candida albicans and exhibited moderate to excellent activity as new antimicrobial agents. A docking study was conducted on most potent derivatives against glucoseamine-6-phosphate synthase (GlcN-6-P), the target enzyme for antimicrobial agents. The study aimed to understand how the discovered derivatives interact with the binding pocket residues of the enzyme.

Keywords

• Synthesis
• Chalcones
• Isoxazoline
• Claisen-Schmidt
• Docking study

References

1. 1. Avan I, Hall CD, Katritzky AR. Peptidomimetics via modifications of amino acids and peptide bonds. Chemical Society Reviews. 2014;43(10):3575–94. Available from: 2. Pozharskii AF, Katritzky AR, Soldatenkov AT. Heterocycles in life and society. Wiley Chichester; 2011. Available from:
2. 3. Michelini LJ, Castro MRC, Custodio JMF, Naves LFN, Vaz WF, Lobón GS, et al. A novel potential anticancer chalcone: Synthesis, crystal structure and cytotoxic assay. Journal of Molecular Structure. 2018;1168:309–15. Available from:
3. 4. Sharma B, Agrawal SC, Gupta KC. Colour reactions of chalcones and their mechanism (a review). Oriental Journal of Chemistry. 2008;24(1):289. Available from:
4. 5. Singh P, Anand A, Kumar V. Recent developments in biological activities of chalcones: A mini review. European Journal of Medicinal Chemistry. 2014;85:758–77. Available from:
5. 6. Sagar P, Vilasrao K, Ramesh B, Sachin SM, Vijay P. Synthesis & Evaluation of isoxazole for their antimicrobial activity. International Journal of Comprehensive and Advanced Pharmacology. 2017;2:19–26.
6. 7. Kaur K, Kumar V, Sharma AK, Gupta GK. Isoxazoline containing natural products as anticancer agents: A review. European Journal of Medicinal Chemistry. 2014;77:121–33. Available from:
7. 8. Kudva NUN, Kotian SY, Basavanna V, Vicas CS, Byrappa SK, Shridevi D, et al. Synthesis, characterization, and evaluation of biological activities of imidazolyl-isoxazoline analogue. Biointerface Research in Applied Chemistry. 2020;10(6): 7187-7197. Available from:
8. 9. Thalassitis A, Hadjipavlou-Litina DJ, Litinas KE, Miltiadou P. Synthesis of modified homo-N-nucleosides from the reactions of mesityl nitrile oxide with 9-allylpurines and their influence on lipid peroxidation and thrombin inhibition. Bioorganic & Medicinal Chemistry Letters. 2009;19(22):6433–6. Available from:

9. 10. Filali I, Bouajila J, Znati M, Bousejra-El Garah F, Ben Jannet H. Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory activities. Journal of Enzyme Inhibition and Medicinal Chemistry. 2015;30(3):371–6. Available from:
10. 11. Al Houari G, Kerbal A, Bennani B, Baba MF, Daoudi M, Hadda T Ben. Drug design of new antitubercular agents: 1, 3-dipolar cycloaddition reaction of para-substituted-benzadoximes and 3-para-methoxy-benzyliden-isochroman-4-ones. Arkivoc. 2008;12:42–50. Available from:
11. 12. Bhardwaj S, Bendi A, Singh L. A Study on Synthesis of Chalcone Derived-5-Membered Isoxazoline and Isoxazole Scaffolds. Current Organic Synthesis. 2022;19(5):643–63. Available from:
12. 13. Zeng Y, Zhang H, Wang B, Zhang L, Xue L, Zhao X. Synthesis and biological evaluation of various new bis-isoxazoline derivatives as potential antioxidant additives. Journal of Chemical Research. 2016;40(9):558–63. Available from:
13. 14. Marri S, Kakkerla R, Murali Krishna MPS, Venkat Rajam M. Synthesis and antimicrobial evaluation of isoxazole-substituted 1, 3, 4-oxadiazoles. Heterocyclic Communications. 2018;24(5):285–92. Available from:
14. 15. Motegaonkar MB. Synthesis and Analysis of Antimicrobial Properties of Isoxazoline. International Journal of Engineering Research & Technology. 2020;9:386–90. Available from:
15. 16. Alawad KM, Mahdi MF, Raauf AMR. Molecular Docking study, and In vitro Evaluation of Antitumor Activity of Some New Isoxazoline and Pyrazoline Derivatives of Nabumetone against breast cancer cell line (MCF-7). Al Mustansiriyah Journal of Pharmaceutical Sciences. 2022;22(3):24–34. Available from:
16. 17. Kumar KA, Jayaroopa P. Isoxazoles: molecules with potential medicinal properties. International Journal of Pharmaceutical and Chemical Sciences. 2013;3:294–304.
17. 18. Kauthale S, Tekale S, Damale M, Sangshetti J, Pawar R. Synthesis, biological evaluation, molecular docking, and ADMET studies of some isoxazole-based amides. Medicinal Chemistry Research. 2018;27:429–41. Available from:
18. 19. Lather A, Sharma S, Khatkar A. Virtual screening of novel glucosamine-6-phosphate synthase inhibitors. Combinatorial Chemistry & High Throughput Screening. 2018;21(3):182–93. Available from:
19. 20. McConnell D. The problem of the carbonate apatites. Journal of the American Chemical Society. 1955;77(8):2344. Available from:
20. 21. Puterová Z, Sterk H, Krutošíková A. Reaction of substituted furan-2-carboxaldehydes and furo [b] pyrrole type aldehydes with hippuric acid. Molecules. 2004;9(1):11–21. Available from:
21. 22. Tomi IHR, Al-Daraji AHR, Abdula AM, Al-Marjani MF. Synthesis, antimicrobial and docking study of three novel 2, 4, 5-triarylimidazole derivatives. Journal of Saudi Chemical Society. 2016;20:S509–16. Available from:
22. 23. Revanasiddappa BC, Kumar MV, Kumar H. Synthesis and Antioxidant Activity of Novel Pyrazoline Derivatives. Hygeia Journal for Drugs and Medicines. 2018;10(1):43-49. Available from:
23. 24. Abdel-Rahman AA-H, Abdel-Megied AE-S, Hawata MAM, Kasem ER, Shabaan MT. Synthesis and antimicrobial evaluation of some chalcones and their derived pyrazoles, pyrazolines, isoxazolines, and 5, 6-Dihydropyrimidine-2-(1 H)-thiones. Monatshefte für Chemie - Chemical Monthly. 2007;138:889–97. Available from:
24. 25. Mohamed MA, Nasr M, Elkhatib WF, Eltayeb WN. In vitro evaluation of antimicrobial activity and cytotoxicity of different nanobiotics targeting multidrug resistant and biofilm forming Staphylococci. BioMed Research International. 2018;2018. Available from:
25. 26. Savin KA. Writing reaction mechanisms in organic chemistry. Academic Press; 2014.
26. 27. Ismail AH, Abdula AM, Tomi IHR, Al-Daraji AHR, Baqi Y. Synthesis, antimicrobial evaluation and docking study of novel 3, 5-disubstituted-2-isoxazoline and 1, 3, 5-trisubstituted-2-pyrazoline derivatives. Medicinal Chemistry. 2021;17(5):462–73. Available from:
27. 28. Fan J, Fu A, Zhang L. Progress in molecular docking. Quant Biol. 2019;7:83–9. Available from:
28. 29. Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules. 2015;20(7):13384–421. Available from:
29. 30. Hussein SAA, Kubba A, Abdula AM. Docking study of some new 2, 5-Disubstituted-1, 3, 4-thiadiazole derivatives against glucosamine-6-phosphate synthase. Journal of Applied Chemistry. 2016;12(1):1–10. Available from: