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Synthesis, biological evaluation, quantitative-SAR and docking studies of novel chalcone derivatives as antibacterial and antioxidant agents

Abstract

In the present study, a series of chalcone derivatives including 17 new compounds were synthesised; their antibacterial activities against eleven bacteria, and their free radical-scavenging activities using DPPH were evaluated. All compounds showed significant antibacterial activities against both Gram-positive and Gram-negative bacteria. In particular, compound IIIf strongly inhibited Staphylococcus aureus (JMC 2151) and Enterococcus faecalis (CARS 2011-012) with MIC values of 6.25 µg mL1 and 12.5 µg mL1, respectively, which are comparable to that of the standard antibiotic, nalidixic acid. Compound IIIg also inhibited S. aureus with a MIC value similar to that of nalidixic acid (6.25 µg mL1). Furthermore, like nalidixic acid (MIC value of 25 µg mL1), compounds IIIa, IIIc and IIId inhibited Listeria monocytogenes (ATCC 43256) with MIC values of 25 µg mL1, 12.5 µg mL1 and 25 µg mL1, respectively. Quantitative structure-activity relationship (Q-SAR) studies using physicochemical calculations indicated that the antibacterial activities of chalcone derivatives correlated well with predicted physicochemical parameters (logP and PSA). Docking simulation by positioning the most active compound IIIf in the active site of the penicillin-binding protein (PBP-1b) of S. aureus was performed to explore the feasible binding mode. Furthermore, most of the compounds synthesised exhibited significant DPPH radical-scavenging activity, although compounds IIc and IIIc exhibited the greatest antioxidant activity with IC50 values of 1.68 µM and 1.44 µM, respectively, comparable to that of the standard antioxidant, ascorbic acid (1.03 µM).

References

  • Adam, M., Fraipont, C., Rhazi, N., Nguyen-Distèche, M., Lakaye, B., Frère, J. M., Devreese, B., Van Beeumen, J., van Heijenoort, Y., van Heijenoort, J., & Ghuysen, J. M. (1997). The bimodular G57-V577 polypeptide chain of the class B penicillin-binding protein 3 of Escherichia coli catalyzes peptide bond formation from thiolesters and does not catalyze glycan chain polymerization from the lipid II intermediate. Journal of Bacteriology, 179, 6005–6009.

    CAS  Article  Google Scholar 

  • Agrawal, N. N., & Soni, P. A. (2007). Synthesis of pyrazole and isooxazole in triethanolamine medium. Indian Journal of Chemistry, Section B, 46B, 532–534.

    CAS  Google Scholar 

  • Aichaoui, H., Guenadil, F., Kapanda, C. N., Lambert, D. M., McCurdy, C. R., & Poupaert, J. H. (2009). Synthesis and pharmacological evaluation of antioxidant chalcone derivatives of 2(3H)-benzoxazolones. Medicinal Chemistry Research, 18, 467–476. DOI: 10.1007/s00044-008-9143-y.

    CAS  Article  Google Scholar 

  • Alam, M. S., & Lee, D. U. (2011). Cytotoxic and antimicrobial properties of furoflavones and furochalcones. Journal of the Korean Society for Applied Biological Chemistry, 54, 725–730. DOI: 10.3839/jksabc.2011.109.

    CAS  Article  Google Scholar 

  • Alam, M. S., Nam, Y. J., & Lee, D. U. (2013). Synthesis and evaluation of (Z)-2,3-diphenylacrylonitrile analogs as anti-cancer and anti-microbial agents. European Journal of Medicinal Chemistry, 69, 790–797. DOI: 10.1016/j.ejmech.2013.08.031.

    CAS  Article  Google Scholar 

  • Alcaráz, L. E., Blanco, S. E., Puig, O. N., Tomás, F., & Ferretti, F. H. (2000). Antibacterial activity of flavonoids against methicillin-resistant Staphylococcus aureus strains. Journal of Theoretical Biology, 205, 231–240. DOI: 10.1006/jtbi.2000.2062.

    Article  Google Scholar 

  • Alves, M. J., Froufe, H. J. C., Costa, A. F. T., Santos, A. F., Oliveira, L. G., Osório, S. R. M., Abreu, R. M. V., Pintado, M., & Ferreira, I. C. F. R. (2014). Docking studies in target proteins involved in antibacterial action mechanisms: Extending the knowledge on standard antibiotics to antimicrobial mushroom compounds. Molecules, 19, 1672–1684. DOI: 10.3390/molecules19021672.

    Article  Google Scholar 

  • Awasthi, S. K., Mishra, N., Kumar, B., Sharma, M., Bhattacharya, A., Mishra, L. C., & Bhasin, V. K. (2009). Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro. Medicinal Chemistry Research, 18, 407–420. DOI: 10.1007/s00044-008-9137-9.

    CAS  Article  Google Scholar 

  • Battenberg, O. A., Yang, Y., Verhelst, S. H. L., & Sieber, S. A. (2013). Target profiling of 4-hydroxyderricin in S. aureus reveals seryl-tRNA synthetase binding and inhibition by covalent modification. Molecular BioSystems, 9, 343–351. DOI: 10.1039/c2mb25446h.

    CAS  Article  Google Scholar 

  • Berthelot, J., Benammar, Y., & Desmazières, B. (1995). Action of tetrabutylammonium tribromide with para-substituted chalcones in protic and aprotic media. Canadian Journal of Chemistry, 73, 1526–1530. DOI: 10.1139/v95-189.

    CAS  Article  Google Scholar 

  • Blois, M. S. (1958). Antioxidant determinations by the use of a stable free radical. Nature, 181, 1199–1200. DOI: 10.1038/1811199a0.

    CAS  Article  Google Scholar 

  • Charpentier, X., Chalut, C., Rémy, M. H., & Masson, J. M. (2002). Penicillin-binding proteins 1a and 1b form independent dimers in Escherichia coli. Journal of Bacteriology, 184, 3749–3752. DOI: 10.1128/jb.184.13.3749-3752.2002.

    CAS  Article  Google Scholar 

  • Cheenpracha, S., Karalai, C., Ponglimanont, C., Subhadhirasakul, S., & Tewtrakul, S. (2006). Anti-HIV-1 protease activity of compounds from Boesenbergia pandurata. Bioorganic & Medicinal Chemistry, 14, 1710–1714. DOI: 10.1016/j.bmc.2005.10.019.

    CAS  Article  Google Scholar 

  • Contreras-Martel, C., Amoroso, A., Woon, E. C., Zervosen, A., Inglis, S., Martins, A., Verlaine, O., Rydzik, A. M., Job, V., Luxen, A., Joris, B., Schofield, C. J., & Dessen, A. (2011). Structure-guided design of cell wall biosynthesis inhibitors that overcome β-lactam resistance in Staphylococcus aureus (MRSA). ACS Chemical Biology, 6, 943–951. DOI: 10.1021/cb2001846.

    CAS  Article  Google Scholar 

  • Desai, N. C., Satodiya, H. M., Kotadiya, G. M., & Vaghani, H. V. (2014). Synthesis and antibacterial and cytotoxic activities of new N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety. Archives of Pharmaceutical Chemistry in Life Sciences, 347, 523–532. DOI: 10.1002/ardp.201300466.

    CAS  Article  Google Scholar 

  • Dinkova-Kostova, A. T., Abeygunawardana, C., & Talalay, P. (1998). Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: Correlation of potencies as phase 2 enzyme inducers and radical scavengers. Journal of Medicinal Chemistry, 41, 5287–5296. DOI: 10.1021/jm980424s.

    CAS  Article  Google Scholar 

  • Markham, K. R., & Geiger, H. (1994). 1H nuclear magnetic resonance spectroscopy of flavonoids and their glycosides in hexadeuterodimethylsulfoxide. In J. B. Harborne (Ed.), The flavonoids: Advances in research since 1986 (Chapter 10, pp. 441–498). Boca Raton, FL, USA: Chapman & Hall/CRC.

    Google Scholar 

  • Kiat, T. S., Pippen, R., Yusof, R., Ibrahim, H., Khalid, N., & Rahman, N. A. (2006). Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease. Bioorganic & Medicinal Chemistry Letters, 16, 3337–3340. DOI: 10.1016/j.bmcl.2005.12.075.

    CAS  Article  Google Scholar 

  • Konaklieva, M. I. (2014). Molecular targets of β-lactam-based antimicrobials: Beyond the usual suspects. Antibiotics, 3, 128–142. DOI: 10.3390/antibiotics3020128.

    Article  Google Scholar 

  • Lahsasni, S. A., Al Korbi, F. H., & Abdel-Aziz Aljaber, N. (2014). Synthesis, characterization and evaluation of antioxidant activities of some novel chalcones analogues. Chemistry Central Journal, 8, 32–40. DOI: 10.1186/1752-153x-8-32.

    Article  Google Scholar 

  • Liu, X. L., Xu, Y. J., & Go, M. L. (2008). Functionalized chalcones with basic functionalities have antibacterial activity against drug sensitive Staphylococcus aureus. European Journal of Medicinal Chemistry, 43, 1681–1687. DOI: 10.1016/j.ejmech.2007.10.007.

    CAS  Article  Google Scholar 

  • Mahmoodi, N., Besharati-Seidani, T., Motamed, N., & Mahmoodi, N. O. (2014). Anti-cancerous effect of 4,4′-dihydroxychalcone ((2E,2′ E)-3,3′-(1,4-phenylene)bis(1-(4-hydroxyphenyl)prop-2-en-1-one)) on T47D breast cancer cell line. Annual Research & Review in Biology, 4, 2045–2052. DOI: 10.9734/arrb/2014/8484.

    Article  Google Scholar 

  • Modzelewska, A., Pettit, C., Achanta, G., Davidson, N. E., Huang, P., & Khan, S. R. (2006). Anticancer activities of novel chalcone and bis-chalcone derivatives. Bioorganic & Medicinal Chemistry, 14, 3491–3495. DOI: 10.1016/j.bmc.2006.01.003.

    CAS  Article  Google Scholar 

  • Muroi, H., Nihei, K., Tsujimoto, K., & Kubo, I. (2004). Synergistic effects of anacardic acids and methicillin against methicillin resistant Staphylococcus aureus. Bioorganic & Medicinal Chemistry, 12, 583–587. DOI: 10.1016/j.bmc.2003.10.046.

    CAS  Article  Google Scholar 

  • Murray, P. R., Rosenthal, K. S., & Pfaller, M. A. (2006). Microbiología médica (5th ed.). Madrid, Spain: Elsevier Espana. (in Spanish)

    Google Scholar 

  • Nielsen, S. F., Larsen, M., Boesen, T., Schønning, K., & Kromann, H. (2005). Cationic chalcone antibiotics. Design, synthesis, and mechanism of action. Journal of Medicinal Chemistry, 48, 2667–2677. DOI: 10.1021/jm049424k.

    CAS  Article  Google Scholar 

  • Nishino, C., Enoki, N., Tawata, S., Mori, A., Kobayashi, K., & Fukushima, M. (1987). Antibacterial activity of flavonoids against Staphylococcus epidermidis, a skin bacterium. Agricultural and Biological Chemistry, 51, 139–143. DOI: 10.1271/bbb1961.51.139.

    CAS  Google Scholar 

  • Nowakowska, Z. (2007). A review of anti-infective and antiinflammatory chalcones. European Journal of Medicinal Chemistry, 42, 125–137. DOI: 10.1016/j.ejmech.2006.09.019.

    CAS  Article  Google Scholar 

  • Piantadosi, C., Hall, I. H., Irvine, J. L., & Carlson, G. L. (1973). Cycloalkanones. 2. Synthesis and biological activity α,α′-dibenzylcycloalkanones. Journal of Medicinal Chemistry, 16, 770–795. DOI: 10.1021/jm00265a006.

    CAS  Article  Google Scholar 

  • Rahman, A. F. M. M., Alam, M. S., & Kadi, A. A. (2012). Synthesis and antimicrobial activity of novel tetrabromobis(substituted benzyl)cycloalkanones. Journal of the Serbian Chemical Society, 77, 717–723. DOI: 10.2298/jsc110408005m.

    Article  Google Scholar 

  • Robinson, T. P., Hubbard, R. B., IV, Ehlers, T. J., Arbiser, J. L., Goldsmith, D. J., & Bowen, J. P. (2005). Synthesis and biological evaluation of aromatic enones related to curcumin. Bioorganic & Medicinal Chemistry, 13, 4007–4013. DOI: 10.1016/j.bmc.2005.03.054.

    CAS  Article  Google Scholar 

  • Sauvage, E., Kerff, F., Terrak, M., Ayala, J. A., & Charlier, P. (2008). The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiology Reviews, 32, 234–258. DOI: 10.1111/j.1574-6976.2008.00105.x.

    CAS  Article  Google Scholar 

  • Seo, W. D., Kim, J. H., Kang, J. E., Ryu, H. W., Curtis-Long, M. J., Lee, H. S., Yang, M. S., & Park, K. H. (2005). Sulfonamide chalcone as a new class of α-glucosidase inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 5514–5516. DOI: 10.1016/j.bmcl.2005.08.087.

    CAS  Article  Google Scholar 

  • Sharma, M. C. (2014). Molecular modeling studies of substituted 3,4-dihydroxychalcone derivatives as 5-lipoxygenase and cyclooxygenase inhibitors. Medicinal Chemistry Research, 23, 1797–1818. DOI: 10.1007/s00044-013-0745-7.

    CAS  Article  Google Scholar 

  • Sivakumar, P. M., Priya, S., & Doble, M. (2009). Synthesis, biological evaluation, mechanism of action and quantitative structure-activity relationship studies of chalcones as antibacterial agents. Chemical Biology & Drug Design, 73, 403–415. DOI: 10.1111/j.1747-0285.2009.00793.x.

    CAS  Article  Google Scholar 

  • Spratt, B. G., Jobanputra, V., & Schwarz, U. (1977). Mutants of Escherichia coli which lack a component of penicillin-binding protein I are viable. FEBS Letters, 79, 374–378. DOI: 10.1016/0014-5793(77)80824-7.

    CAS  Article  Google Scholar 

  • Stewart, J. J. P. (2004). Optimization of parameters for semiempirical methods IV: extension of MNDO, AM1, and PM3 to more main group elements. Journal of Molecular Modeling, 10, 155–164. DOI: 10.1007/s00894-004-0183-z.

    CAS  Article  Google Scholar 

  • Sun, L. P., Gao, L. X., Ma, W. P., Nan, F. J., Li, J., & Piao, H. R. (2012). Synthesis and biological evaluation of 2,4,6-trihydroxychalcone derivatives as novel protein tyrosine phosphatase 1B inhibitors. Chemical Biology & Drug Design, 80, 584–590. DOI: 10.1111/j.1747-0285.2012.01431.x.

    CAS  Article  Google Scholar 

  • Tenover, F. C., & McDonald, L. C. (2005). Vancomycin-resistant staphylococci and enterococci: epidemiology and control. Current Opinion in Infectious Diseases, 18, 300–305. DOI: 10.1097/01.qco.0000171923.62699.0c.

    CAS  Article  Google Scholar 

  • Terrak, M., Ghosh, T. K., van Heijenoort, J., Van Beeumen, J., Lampilas, M., Aszodi, J., Ayala, J. A., Ghuysen, J. M., & Nguyen-Distèche, M. (1999). The catalytic, glycosyl transferase and acyl transferase modules of the cell wall peptidoglycan-polymerizing penicillin-binding protein 1b of Escherichia coli. Molecular Microbiology, 34, 350–364. DOI: 10.1046/j.1365-2958.1999.01612.x.

    CAS  Article  Google Scholar 

  • Tökés, A. L., Litkei, G., & Szilágyi, L. (1992). N-Heterocycles by cyclization of 2′-Nhr-chalcones, 2′-Nhr-chalcone dibromides and 2′-Nhr-α-azidochalcones. Synthetic Communications, 22, 2433–2445. DOI: 10.1080/00397919208021640.

    Article  Google Scholar 

  • Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31, 455–461. DOI: 10.1002/jcc.21334.

    CAS  Google Scholar 

  • Varinska, L., van Wijhe, M., Belleri, M., Mitola, S., Perjesi, P., Presta, M., Koolwijk, P., Ivanova, L., & Mojzis, J. (2012). Anti-angiogenic activity of the flavonoid precursor 4-hydroxychalcone. European Journal of Pharmacology, 691, 125–133. DOI: 10.1016/j.ejphar.2012.06.017.

    CAS  Article  Google Scholar 

  • Walsh, C. (2000). Molecular mechanisms that confer antibacterial drug resistance. Nature, 406, 775–781. DOI: 10.1038/35021219.

    CAS  Article  Google Scholar 

  • Winter, E., Chiaradia, L. D., de Cordova, C. A. S., Nunes, R. J., Yunes, R. A., & Creczynski-Pasa, T. B. (2010). Naphthylchalcones induce apoptosis and caspase activation in a leukemia cell line: The relationship between mitochondrial damage, oxidative stress, and cell death. Bioorganic & Medicinal Chemistry, 18, 8026–8034. DOI: 10.1016/j.bmc.2010.09.025.

    CAS  Article  Google Scholar 

  • Wróblewski, A. E., Maniukiewicz, W., & Karolczak, W. (2000). Unusual reactivity of cis-2-benzoyl-1-benzyl-3-phenylaziridine with P-nucleophiles-ring opening vs. the Abramov reaction. Journal of the Chemical Societry, Perkin Transactions 1, 2000, 1433–1437. DOI: 10.1039/a909521g.

    Article  Google Scholar 

  • Yousif, S. Y., Broome-Smith, J. K., & Spratt, B. G. (1985). Lysis of Escherichia coli by β-lactam antibiotics: Deletion analysis of the role of penicillin-binding proteins 1A and 1B. Journal of General Microbiology, 131, 2839–2845. DOI: 10.1099/00221287-131-10-2839.

    CAS  Google Scholar 

  • Zhao, P. L., Liu, C. L., Huang, W., Wang, Y. Z., & Yang, G. F. (2007). Synthesis and fungicidal evaluation of novel chalcone-based strobilurin analogues. Journal of Agricultural and Food Chemistry, 55, 5697–5700. DOI: 10.1021/jf071064x.

    CAS  Article  Google Scholar 

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Alam, M.S., Rahman, S.M.M. & Lee, DU. Synthesis, biological evaluation, quantitative-SAR and docking studies of novel chalcone derivatives as antibacterial and antioxidant agents. Chem. Pap. 69, 1118–1129 (2015). https://doi.org/10.1515/chempap-2015-0113

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Keywords

  • chalcones
  • antibacterial
  • antioxidant
  • physicochemical properties
  • docking study