Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies

Author(s): İrem Bozbey, Suat Sari, Emine Şalva, Didem Kart and Arzu Karakurt*

Volume 17, Issue 2, 2020

Page: [169 - 183] Pages: 15

DOI: 10.2174/1570180816666181128112249

Price: $65

Abstract

Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells.

Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions.

Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling.

Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 µM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH.

Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

Keywords: Antimicrobial activity, azoles, CYP51, cytotoxic effects, molecular modeling, oxime ester.

« Previous Next »
Graphical Abstract

[1]
Liu, C.; Shi, C.; Mao, F.; Xu, Y.; Liu, J.; Wei, B.; Zhu, J.; Xiang, M.; Li, J. Discovery of new imidazole derivatives containing the 2,4-dienone motif with broad-spectrum antifungal and antibacterial activity. Molecules, 2014, 19(10), 15653-15672.
[PMID: 25268720]
[2]
Zhang, L.; Peng, X.M.; Damu, G.L.; Geng, R.X.; Zhou, C.H. Comprehensive review in current developments of imidazole-based medicinal chemistry. Med. Res. Rev., 2014, 34(2), 340-437.
[PMID: 23740514]
[3]
Pfaller, M.A.; Messer, S.A.; Moet, G.J.; Jones, R.N.; Castanheira, M. Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008-2009). Int. J. Antimicrob. Agents, 2011, 38(1), 65-69.
[4]
Silva, S.; Negri, M.; Henriques, M.; Oliveira, R.; Williams, D.W.; Azeredo, J. Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, epidemiology, pathogenicity and antifungal resistance. FEMS Microbiol. Rev., 2012, 36(2), 288-305.
[http://dx.doi.org/10.1111/j.1574-6976.2011.00278.x] [PMID: 21569057]
[5]
Wong, S.S.W.; Samaranayake, L.P.; Seneviratne, C.J. In pursuit of the ideal antifungal agent for Candida infections: High-throughput screening of small molecules. Drug Discov. Today, 2014, 19(11), 1721-1730.
[http://dx.doi.org/10.1016/j.drudis.2014.06.009] [PMID: 24952336]
[6]
Sagatova, A.A.; Keniya, M.V.; Wilson, R.K.; Sabherwal, M.; Tyndall, J.D.; Monk, B.C. Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14alpha-demethylase. Scientific. Rep., 2016, 6, 26213.
[http://dx.doi.org/10.1038/srep26213] [PMID: 27188873]
[7]
Hargrove, T.Y.; Friggeri, L.; Wawrzak, Z.; Qi, A.; Hoekstra, W.J.; Schotzinger, R.J.; York, J.D.; Guengerich, F.P.; Lepesheva, G.I. Structural analyses of Candida albicans sterol 14alpha-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis. J. Biol. Chem., 2017, 292(16), 6728-6743.
[PMID: 28258218]
[8]
Nenoff, P.; Koch, D.; Kruger, C.; Drechsel, C.; Mayser, P. New insights on the antibacterial efficacy of miconazole in vitro. Mycoses, 2017, 60(8), 552-557.
[http://dx.doi.org/10.1111/myc.12620] [PMID: 28370366]
[9]
Alsterholm, M.; Karami, N.; Faergemann, J. Antimicrobial activity of topical skin pharmaceuticals - an in vitro study. Acta Derm. Venereol., 2010, 90(3), 239-245.
[http://dx.doi.org/10.2340/00015555-0840] [PMID: 20526539]
[10]
Bonamore, A. Boffi, Alberto. Flavohemoglobin: Structure and reactivity. IUBMB Life, 2008, 60(1), 19-28.
[http://dx.doi.org/10.1002/iub.9] [PMID: 18379989]
[11]
Karakurt, A.; Özalp, M.; Işık, Ş.; Stables, J.P.; Dalkara, S. Synthesis, anticonvulsant and antimicrobial activities of some new 2-acetylnaphthalene derivatives. Bioorg. Med. Chem., 2010, 18(8), 2902-2911.
[http://dx.doi.org/10.1016/j.bmc.2010.03.010] [PMID: 20363141]
[12]
Karakurt, A.; Dalkara, S.; Özalp, M.; Özbey, S.; Kendi, E.; Stables, J.P. Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivatives and their anticonvulsant and antimicrobial activities. Eur. J. Med. Chem., 2001, 36(5), 421-433.
[http://dx.doi.org/10.1016/S0223-5234(01)01223-5] [PMID: 11451531]
[13]
Dogan, I.S.; Sarac, S.; Sari, S.; Kart, D.; Essiz Gokhan, S.; Vural, I.; Dalkara, S. New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies. Eur. J. Med. Chem., 2017, 130, 124-138.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.035] [PMID: 28242548]
[14]
Kumar, V.; Kaur, K.; Karelia, D.N.; Beniwal, V.; Gupta, G.K.; Sharma, A.K.; Gupta, A.K. Synthesis and biological evaluation of some 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones: Antibacterial, DNA photocleavage, and anticancer activities. Eur. J. Med. Chem., 2014, 81, 267-276.
[15]
Immediata, T.; Day, A.R. β-naphthyl derivatives of ethanolamine and n-substituted ethanolamines. J. Org. Chem., 1940, 5(5), 512-527.
[http://dx.doi.org/10.1021/jo01211a005]
[16]
Godefroi, E.F.; Heeres, J.; Van Cutsem, J.; Janssen, P.A.J. Preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J. Med. Chem., 1969, 12(5), 784-791.
[http://dx.doi.org/10.1021/jm00305a014] [PMID: 4897900]
[17]
Karakurt, A.; Alagoz, M.A.; Sayoglu, B.; Calis, U.; Dalkara, S. Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester derivatives and evaluation of their anticonvulsant activity. Eur. J. Med. Chem., 2012, 57, 275-282.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.037] [PMID: 23085104]
[18]
Clinical and Laboratory Standards Institute. Reference method for Broth dilution antifungal susceptibility testing of yeasts; Approved standard, 3rd Ed. M27-A3, Vol28, No: 14 2008.
[19]
Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard, 8th Ed. M07-A8, Vol29, No: 2, 2009.
[20]
Altschul, S.F.; Gish, W.; Miller, W.; Myers, E.W.; Lipman, D.J. Basic local alignment search tool. J. Mol. Biol., 1990, 215(3), 403-410.
[http://dx.doi.org/10.1016/S0022-2836(05)80360-2] [PMID: 2231712]
[21]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[22]
Banks, J.L.; Beard, H.S.; Cao, Y.; Cho, A.E.; Damm, W.; Farid, R.; Felts, A.K.; Halgren, T.A.; Mainz, D.T.; Maple, J.R.; Murphy, R.; Philipp, D.M.; Repasky, M.P.; Zhang, L.Y.; Berne, B.J.; Friesner, R.A.; Gallicchio, E.; Levy, R.M. Integrated Modeling Program, Applied Chemical Theory (IMPACT). J. Comput. Chem., 2005, 26(16), 1752-1780.
[http://dx.doi.org/10.1002/jcc.20292] [PMID: 16211539]
[23]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[24]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[25]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID: 15027866]
[26]
Sari, S.; Karakurt, A.; Uslu, H.; Kaynak, F.B.; Çalış, Ü.; Dalkara, S. New (arylalkyl)azole derivatives showing anticonvulsant effects could have VGSC and/or GABAAR affinity according to molecular modeling studies. Eur. J. Med. Chem., 2016, 124, 407-416.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.032] [PMID: 27597416]
[27]
Stoodley, R.J. Molecular rearrangements; Org. Reac. Mech, 1972, pp. 265-267.
[http://dx.doi.org/10.1002/9780470067062.ch14]
[28]
El Hammi, E.; Warkentin, E.; Demmer, U.; Limam, F.; Marzouki, N.M.; Ermler, U.; Baciou, L. Structure of Ralstonia eutropha flavohemoglobin in complex with three antibiotic azole compounds. Biochemistry, 2011, 50(7), 1255-1264.
[http://dx.doi.org/10.1021/bi101650q] [PMID: 21210640]
[29]
Laskowski, R.A.; MacArthur, M.W.; Moss, D.S.; Thornton, J.M. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Cryst., 1993, 26(2), 283-291.
[http://dx.doi.org/10.1107/S0021889892009944]

Rights & Permissions Print Cite
Article Metrics
24
© 2024 Bentham Science Publishers | Privacy Policy