Synthesis, Antimicrobial Activity, Molecular Docking and DFT Studies of Some New 2,5-Disubstituted Benzoxazole Derivatives

Abstract

In this study, 6 original 2,5-disubstituted benzoxazole derivatives were synthesized and their structures were elucidated by 1H-NMR, 13C-NMR spectroscopy, and HRMS.Their antimicrobial activities against various Gram (+), Gram (-) bacteria, fungi, and their isolates were investigated by microdilution technique. Although antimicrobial activities of tested benzoxazole derivatives were generally weaker than reference drugs; C1, C5 and C6 derivatives showed the best activity against C. albicans isolate with MIC: 16 µg/mL. Molecular docking study of the compounds was carried out and 2D/3D protein-ligand interactions of C5 (the lowest docking score), one of the most effective compounds against C. albicans isolate, were demonstrated. In addition, HOMO-LUMO energies of all compounds and electronic parameters such as ionization potential (IP), electron affinity (EA), electronegativity (X), chemical hardness (η), chemical softness (S), chemical potential (μ) and electrophilic index (ω) obtained from these energies were calculated. The HOMO-LUMO diagram, molecular electrostatic potential analysis, and optimized molecular structures of C1, C5, and C6 were also presented visually.

Keywords

• Benzoxazole
• Synthesis
• Antimicrobial activity
• DFT
• Molecular docking.

Bazı Yeni 2,5-Disübstitüe Benzoksazol Türevlerinin Sentezi, Antimikrobiyal Aktivite, Moleküler Doking ve DFT Çalışmaları

Abstract

Bu çalışmada 6 adet orijinal 2,5-disübstitüe benzoksazol türevi sentezlendi ve yapıları 1H-NMR, 13C-NMR spektrokopisi ve HRMS ile aydınlatıldı. Sentezlenen bileşiklerin mikrodilüsyon tekniği ile çeşitli Gram (+), Gram (-) bakteri, mantar ve bunların izolatlarına karşı antimikrobiyal aktiviteleri incelendi. Test edilen benzoksazol türevlerinin antimikrobiyal aktiviteleri genel olarak referans ilaçlara göre daha zayıf olmakla birlikte; en iyi aktiviteyi C. albicans izolatına karşı MİK: 16 µg/mL ile C1, C5 ve C6 türevleri gösterdi. Bileşiklerin moleküler doking çalışması gerçekleştirildi ve C. albicans izotına karşı en etkili bileşiklerden biri olan C5'in (doking skoru en düşük olan) 2D/3D protein-ligand etkileşimleri gösterildi. Ayrıca tüm bileşiklerin HOMO-LUMO enerjileri ve bu enerjilerden elde edilen iyonlaşma potansiyeli (İP), elektron afinitesi (EA), elektronegatiflik (X), kimyasal sertlik (η), kimyasal yumuşaklık (S), kimyasal potansiyel (μ ) ve elektrofilik indeks (ω) gibi diğer elektronik parametreleri hesaplandı. C1, C5 ve C6’nın HOMO-LUMO diyagramı, moleküler elektrostatik potansiyel analizi ve optimize edilmiş moleküler yapıları da görsel olarak sunuldu.

Keywords

• Benzoksazol
• Sentez
• Antimikrobiyal aktivite
• DFT
• Moleküler doking.

References

1. Abushaheen, M. A., Fatani, A. J., Alosaimi, M., Mansy, W., George, M., Acharya, S., Rathod, S., Divakar, D. D., Jhugroo, C., & Vellappally, S. (2020). Antimicrobial resistance, mechanisms and its clinical significance. Disease-a-Month, 66(6):100971.
2. Alqahtani, S. (2017). In silico ADME-Tox modeling: progress and prospects. Expert opinion on drug metabolism & toxicology, 13(11):1147-1158.
3. Arisoy, M., Temiz-Arpaci, O., Yildiz, I., Kaynak-Onurdag, F., Aki, E., Yalcin, I., & Abbasoglu, U. (2008). Synthesis, antimicrobial activity and QSAR studies of 2,5-disubstituted benzoxazoles. SAR and QSAR in Environmental Research, 19(5-6):589-612.
4. Arisoy, M., Temiz-Arpaci, O., Kaynak-Onurdag, F., & Ozgen, S. (2014). Synthesis and Antimicrobial Evaluation of 2-(p-Substituted Phenyl)-5-[(4-substituted piperazin-1-yl) acetamido]-benzoxazoles. Zeitschrift für Naturforschung C, 69(9-10):368-374.
5. Aslam, B., Wang, W., Arshad, M. I., Khurshid, M., Muzammil, S., Rasool, M. H., Nisar, M. A., Alvi, R. F., Aslam, M. A., & Qamar, M. U. (2018). Antibiotic resistance: a rundown of a global crisis. Infection and Drug Resistance, 11:1645-1648.
6. Benazzouz, A., Boraud, T., Dubédat, P., Boireau, A., Stutzmann, J.-M., & Gross, C. (1995). Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study. European Journal of Pharmacology, 284(3):299-307.
7. Celik, I., Erol, M., Puskullu, M. O., Uzunhisarcikli, E., Ince, U., Kuyucuklu, G., & Suzen, S. (2020). In Vitro and In Silico Studies of Quinoline-2-Carbaldehyde Hydrazone Derivatives as Potent Antimicrobial Agents. Polycyclic Aromatic Compounds, 1-17.
8. Cheminformatics, M. (2018). Calculation of molecular properties and bioactivity score. Computer software]. Retrieved from http://www. molinspiration. com/cgi-bin/properties.

9. Christaki, E., Marcou, M., & Tofarides, A. (2020). Antimicrobial resistance in bacteria: mechanisms, evolution, and persistence. Journal of Molecular Evolution, 88(1):26-40.
10. CLSI, W. P. (2008). Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard—third edition CLSI document M27-A3.
11. CLSI, C. (2018). Performance Standards for Antimicrobial Susceptibility Testing: Approved Twenty-: Document M100-S28. Wayne, PA, USA: CLSI, 2018.
12. De Oliveira, D. M., Forde, B. M., Kidd, T. J., Harris, P. N., Schembri, M. A., Beatson, S. A., Paterson, D. L., & Walker, M. J. (2020). Antimicrobial resistance in ESKAPE pathogens. Clinical Microbiology Reviews, 33(3): e00181-19.
13. Erol, M., Celik, I., Temiz-Arpaci, O., Kaynak-Onurdag, F., & Okten, S. (2020). Design, synthesis, molecular docking, density functional theory and antimicrobial studies of some novel benzoxazole derivatives as structural bioisosteres of nucleotides. Journal of Biomolecular Structure and Dynamics, 39(9):3080-3091.
14. French, G. (2010). The continuing crisis in antibiotic resistance. International journal of antimicrobial agents, 36(S3-S7.
15. Frisch, M. (2019). Gaussian09. http://www. gaussian. com/.
16. GaussView, V. (2016). 6, Roy Dennington, Todd A. Keith, and John M. Millam, Semichem Inc., Shawnee Mission, KS.
17. Kashid, B. B., Ghanwat, A. A., Khedkar, V. M., Dongare, B. B., Shaikh, M. H., Deshpande, P. P., & Wakchaure, Y. B. (2019). Design, Synthesis, In Vitro Antimicrobial, Antioxidant Evaluation, and Molecular Docking Study of Novel Benzimidazole and Benzoxazole Derivatives. Journal of Heterocyclic Chemistry, 56(3):895-908.
18. Kilic-Kurt, Z., Bakar-Ates, F., & Bahat, M. (2019). N, N′-diaryl urea derivatives: Molecular docking, molecular properties prediction and anticancer evaluation. Journal of Molecular Structure, 1193:239-246.
19. Kontoyiannis, D. P., & Lewis, R. E. (2002). Antifungal drug resistance of pathogenic fungi. The Lancet, 359(9312):1135-1144.
20. Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies, 1(4):337-341.
21. Mary, Y. S., Yalcin, G., Mary, Y. S., Resmi, K., Thomas, R., Önkol, T., Kasap, E. N., & Yildiz, I. (2020). Spectroscopic, quantum mechanical studies, ligand protein interactions and photovoltaic efficiency modeling of some bioactive benzothiazolinone acetamide analogs. Chemical Papers, 74(6):1957-1964.
22. Erol M., Çelik, İ., Kuyucuklu, G., & Uzunhisarcıklı, E. (2021). Synthesis of Some New Benzoxazole Derivatives and Antimicrobial and Cytotoxic Activity Studies. Avrupa Bilim ve Teknoloji Dergisi, 21:455-462.
23. Oehlers, L., Mazzitelli, C. L., Brodbelt, J. S., Rodriguez, M., & Kerwin, S. (2004). Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry. Journal of the American Society for Mass Spectrometry, 15(11):1593-1603.
24. Osmaniye, D., Çelikateş, B. K., Sağlık, B. N., Levent, S., Çevik, U. A., Çavuşoğlu, B. K., Ilgın, S., Özkay, Y., & Kaplancıklı, Z. A. (2021). Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities. European Journal of Medicinal Chemistry, 210:112979.
25. Song, M. X., Huang, Y., Wang, S., Wang, Z. T., & Deng, X. Q. (2019). Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1, 2, 4‐triazolone moiety. Archiv der Pharmazie, 352(8):1800313.
26. Taşcı, M., Temiz-Arpaci, O., Kaynak-Onurdag, F., & Okten, S. (2018). Synthesis and antimicrobial evaluation of novel 5-substituted-2-(p-tert-butylphenyl) benzoxazoles. Indian Journal of Chemistry -Section B, 57B(3):385-389.
27. Temiz‐Arpacı, Ö., Oezdemir, A., Yalçın, İ., Yıldız, İ., Akı‐Şener, E., & Altanlar, N. (2005). Synthesis and Antimicrobial Activity of Some 5‐[2‐(Morpholin‐4‐yl) acetamido] and/or 5‐[2‐(4‐Substituted piperazin‐1‐yl) acetamido]‐2‐(p‐substituted phenyl) benzoxazoles. Archiv der Pharmazie: An International Journal Pharmaceutical and Medicinal Chemistry, 338(2‐3):105-111.
28. Temiz-Arpaci, O., Arisoy, M., Sac, D., Doganc, F., Tasci, M., Senol, F. S., & Orhan, I. E. (2016). Biological evaluation and docking studies of some benzoxazole derivatives as inhibitors of acetylcholinesterase and butyrylcholinesterase. Zeitschrift Fur Naturforschung Section C-a Journal of Biosciences, 71(11-12):409-413.
29. Ventola, C. L. (2015). The antibiotic resistance crisis: part 1: causes and threats. P T, 40(4):277-283.
30. Wu, Z., Bao, X.-L., Zhu, W.-B., Wang, Y.-H., Phuong Anh, N. T., Wu, X.-F., Yan, Y.-J., & Chen, Z.-L. (2018). Design, synthesis, and biological evaluation of 6-benzoxazole benzimidazole derivatives with antihypertension activities. ACS Medicinal Chemistry Letters, 10(1):40-43.