Synthesis, Molecular Docking, DFT and Antimicrobial Activity Studies of 2-(p-Fluorophenyl)-5-(2-(4- acetylpiperazin-1-yl)acetamido)benzoxazole

Year 2021, , 2122 - 2132, 01.09.2021

Meryem Erol , İsmail Çelik , Gülcan Kuyucuklu

https://doi.org/10.21597/jist.861067

Abstract

In this study, the new compound 2-(p-Fluorophenyl)-5-(2-(4-acetylpiperazine-1-yl) acetamido)benzoxazole was synthesized in three steps and its structure was clarified by 1H-NMR and 13C-NMR spectroscopy. Its antimicrobial activity was studied on Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii NTCC 13304, Klebsiella pneumoniae ATCC 700603, Candida albicans ATCC 1023, and their isolates. When the antimicrobial activity results were examined, although the reference drugs showed better antimicrobial activity in general, the synthesized compound showed quite promising activity on E. faecalis isolates and E. coli isolates compared to ampicillin with MIC: 32 µg mL-1. Molecular docking study was carried out on the DNA gyrase subunit B structure. Theoretical ADME (absorption, distribution, metabolism, elimination) properties were calculated. In addition, HOMO-LUMO energies, molecular electrostatic potential analysis, and optimized geometric structure were determined using the DFT/B3LYP method and the 6-311G (d,p) basis set, and the results were displayed.

Keywords

Benzoxazole, antimicrobial activity, DFT, molecular docking

2-(p-Florofenil)-5-(2-(4-asetilpiperazin-1-il)asetamido)benzoksazol’ün Sentezi, Moleküler Doking, DFT ve Antimikrobiyal Aktivite Çalışmaları

Abstract

Bu çalışmada, yeni 2-(p-Florofenil)-5-(2-(4-asetilpiperazin-1-il)asetamido)benzoksazol bileşiği üç aşamada sentezlenmiş ve yapısı 1H-NMR ve 13C-NMR spektroskopisi ile aydınlatılmıştır. Antimikrobiyal aktivite çalışmaları, Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii NTCC 13304, Klebsiella pneumoniae ATCC 700603, Candida albicans ATCC 10231 ve bunların izolatları izolatları üzerinde gerçekleştirildi. Antimikrobiyal aktivite sonuçlarına göre, referans ilaçlar genel olarak daha iyi antimikrobiyal aktivite göstermesine rağmen sentezlenen bileşik, MİK: 32 µg mL-1 ile ampisilin ile karşılaştırıldığında E. faecalis izolatları ve E. coli izolatları üzerinde oldukça umut verici aktivite gösterdi. Moleküler doking çalışması DNA giraz subunit B yapısı üzerinde gerçekleştirildi. Teorik ADME (absorbsiyon, dağılım, metabolizma, eliminasyon) özellikleri hesaplandı. Ayrıca DFT/B3LYP yöntemi ve 6-311G (d,p) temel seti kullanılarak HOMO-LUMO enerjileri, moleküler elektrostatik potansiyel analizi ve optimize edilmiş geometrik yapısı belirlendi ve sonuçlar görüntülendi.

Keywords

Benzoksazol, antimikrobiyal aktivite, DFT, moleküler doking

References

• Arandjelovic P, Doerflinger M, Pellegrini M, 2019. Current and emerging therapies to combat persistent intracellular pathogens. Current opinion in pharmacology, 48: 33-39.
• 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.
• Arısoy M, Temiz-Arpaci O, Kaynak-Onurdag F, Ozgen S, 2012. Synthesis and antimicrobial activity of novel benzoxazoles. Zeitschrift fur Naturforschung. C, Journal of biosciences, 67(9-10): 466-472. Biovia DS, 2017. Discovery studio visualizer. San Diego, CA, USA.
• Celik I, Erol M, Temiz Arpaci O, Sezer Senol F, Erdogan Orhan I, 2020. Evaluation of Activity of Some 2,5-Disubstituted Benzoxazole Derivatives against Acetylcholinesterase, Butyrylcholinesterase and Tyrosinase: ADME Prediction, DFT and Comparative Molecular Docking Studies. Polycyclic Aromatic Compounds, 1-12.
• Cheminformatics M, 2018. Calculation of molecular properties and bioactivity score. Computer software. Retrieved from http://www. molinspiration. com/cgi-bin/properties.
• CLSI, 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard third edition CLSI document M27-A3.
• CLSI, 2018. Performance Standards for Antimicrobial Susceptibility Testing: Approved Twenty-: Document M100-S28. Wayne, PA, USA.
• El‐Helby AGA, Sakr H, Eissa IH, Abulkhair H, Al‐Karmalawy AA, El‐Adl K, 2019. Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors. Archiv der Pharmazie, 352(10): 1-19.
• Erol M, Celik I, Uzunhisarcikli E, Kuyucuklu G, 2020. Synthesis, Molecular Docking, and DFT Studies of Some New 2, 5-Disubstituted Benzoxazoles as Potential Antimicrobial and Cytotoxic Agents. Polycyclic Aromatic Compounds, 1-18.
• French G, 2010. The continuing crisis in antibiotic resistance. International journal of antimicrobial agents, 36: S3-S7.
• Frisch M, 2019. Gaussian09. http://www. gaussian. com. (Erişim Tarihi:05.01 2021).
• GaussView V, 2016. Roy Dennington, Todd A. Keith, and John M. Millam, Semichem Inc., Shawnee Mission, KS.
• Huey R, Morris GM, 2008. Using AutoDock 4 with AutoDocktools: a tutorial. The Scripps Research Institute, USA, 54-56.
• Kaur A, Pathak DP, Sharma V, Wakode S, 2018. Synthesis, biological evaluation and docking study of a new series of di-substituted benzoxazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Bioorganic & medicinal chemistry, 26(4): 891-902.
• Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA, Goossens H, Laxminarayan R, 2018. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proceedings of the National Academy of Sciences, 115(15): E3463-E3470.
• Klimešová V, Kočí J, Waisser K, Kaustová J, Möllmann U, 2009. Preparation and in vitro evaluation of benzylsulfanyl benzoxazole derivatives as potential antituberculosis agents. European Journal of Medicinal Chemistry, 44(5): 2286-2293.
• Lipinski CA, 2004. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol, 1(4): 337-341.
• Mary YS, Yalcin G, Mary YS, Resmi K, Thomas R, Önkol T, Kasap EN, Yildiz I, 2020. Spectroscopic, quantum mechanical studies, ligand protein interactions and photovoltaic efficiency modeling of some bioactive benzothiazolinone acetamide analogs. Chemical Papers, 1-8.
• Molsoft L. (2004). Retrieved from https://www.molsoft.com/.
• Oehlers L, Mazzitelli CL, Brodbelt JS, Rodriguez M, Kerwin S, 2004. Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry. J Am Soc Mass Spectrom, 15(11): 1593-1603.
• Pacios O, Blasco L, Bleriot I, Fernandez-Garcia L, González Bardanca M, Ambroa A, López M, Bou G, Tomás M, 2020. Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases. Antibiotics, 9(2): 1-20.
• Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE, 2004. UCSF Chimera—a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13): 1605-1612.
• Sheena Mary Y, Ertan-Bolelli T, Thomas R, Krishnan AR, Bolelli K, Kasap EN, Onkol T, Yildiz I, 2019. Quantum Mechanical Studies of Three Aromatic Halogen-Substituted Bioactive Sulfonamidobenzoxazole Compounds with Potential Light Harvesting Properties. Polycyclic Aromatic Compounds, 1-17.
• Song MX, Huang Y, Wang S, Wang ZT, Deng XQ, 2019. Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1, 2, 4‐triazolone moiety. Archiv der Pharmazie, 352(8): 1-8.
• Temiz‐Arpacı Ö, Ozdemir 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.
• Trott O, Olson AJ, 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry, 31(2): 455-461.
• Ventola CL, 2015. The antibiotic resistance crisis: part 1: causes and threats. Pharmacy and Therapeutics, 40(4): 277-283.
• Yoneyama H, Katsumata R, 2006. Antibiotic resistance in bacteria and its future for novel antibiotic development. Bioscience, Biotechnology, and Biochemistry, 70(5): 1060-1075.