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Antimicrobial activity and cytotoxicity of some 2-amino-5-alkylidene-thiazol-4-ones

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Abstract

We report a small, focused library of 30 diverse 2-amino-5-alkylidene-thiazol-4-ones that was assayed in a whole-cell antibacterial screen against a panel of several bacterial strains and a yeast. Most of the compounds exhibited modest to significant antibacterial activity against Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus, and no activity against Salmonella typhimurium and Escherichia coli. The antibacterial activity depends markedly upon substituents on the thiazol-4-one core, and the most potent compound assayed (\((Z)\)-4-((2-(4-methylpiperidin-1-yl)-4-oxothiazol-5(4H)-ylidene)methyl)benzonitrile) reached a minimal inhibitory concentration (MIC) value of \(10\,\upmu \hbox {g/mL}\) on P. aeruginosa strain. An important feature of the tested compounds is their low influence on cell viability, as determined in a HEK-293 metabolic activity assay. In light of the encouraging in vitro antimicrobial assay results against several bacterial strains, we have generated a pharmacophore model using the Discovery studio 3.0 package (Accelrys Inc., San Diego, USA), which exposed the spatial arrangement of key molecular properties responsible for our observed MIC results. Considering the absence of a defined target and the limitation of the described approach to pool different scaffolds, the calculated pharmacophore model could be used for library enrichment to identify compounds with a thiazolidinone scaffold with improved antimicrobial potency and physico-chemical properties.

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Abbreviations

ATCC:

American Type Culture Collection

DMEM:

Dulbecco’s Modified Eagle Medium

MIC:

Minimal inhibitory concentration

NCCLS:

National Committee for Clinical Laboratory Standards

SBDD:

Structure-based drug discovery

References

  1. Chopra I (2013) The 2012 Garrod lecture: discovery of antibacterial drugs in the 21st century. J Antimicrob Chemother 68:496–505. doi:10.1093/jac/dks436

    Article  PubMed  CAS  Google Scholar 

  2. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40. doi:10.1038/nrd2201

    Article  PubMed  CAS  Google Scholar 

  3. Gwynn MN, Portnoy A, Rittenhouse SF, Payne DJ (2010) Challenges of antibacterial discovery revisited. Ann N Y Acad Sci 1213:5–19. doi:10.1111/j.1749-6632.2010.05828.x

    Article  PubMed  Google Scholar 

  4. Tomašić T, Zidar N, Kovač A, Turk S, Simčič M, Blanot D, Muller-Premru M, Filipič M, Grdadolnik SG, Zega A, Anderluh M, Gobec S, Kikelj D, Peterlin Mašič L (2010) 5-Benzylidenethiazolidin-4-ones as multitarget inhibitors of bacterial Mur ligases. ChemMedChem 5:286–295. doi:10.1002/cmdc.200900449

    Article  PubMed  Google Scholar 

  5. Zidar N, Tomašić T, Šink R, Rupnik V, Kovač A, Turk S, Patin D, Blanot D, Martel CC, Dessen A, Premru MM, Zega A, Gobec S, Peterlin Mašič L, Kikelj D (2010) Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase. J Med Chem 53:6584. doi:10.1021/jm100285g

    Article  PubMed  CAS  Google Scholar 

  6. Anderluh M, Jukic M, Petric R (2009) Three-component one-pot synthetic route to 2-amino-5-alkylidene-thiazol-4-ones. Tetrahedron 65:344–350. doi:10.1016/j.tet.2008.10.045

    Article  CAS  Google Scholar 

  7. Vicini P, Geronikaki A, Anastasia K, Incerti M, Zani F (2006) Synthesis and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones. Bioorg Med Chem 14:3859–3864. doi:10.1016/j.bmc.2006.01.043

    Article  PubMed  CAS  Google Scholar 

  8. Vicini P, Geronikaki A, Incerti M, Zani F, Dearden J, Hewitt M (2008) 2-Heteroarylimino-5-benzylidene-4-thiazolidinones analogues of 2-thiazolylimino-5-benzylidene-4-thiazolidinones with antimicrobial activity: synthesis and structure–activity relationship. Bioorg Med Chem 16:3714–3724. doi:10.1016/j.bmc.2008.02.001

    Article  PubMed  CAS  Google Scholar 

  9. Apostolidis I, Liaras K, Geronikaki A, Hadjipavlou-Litina D, Gavalas A, Soković M, Glamočlija J, Ćirić A (2013) Synthesis and biological evaluation of some 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones as dual anti-inflammatory/antimicrobial agents. Bioorg Med Chem 21:532–539. doi:10.1016/j.bmc.2012.10.046

    Article  PubMed  CAS  Google Scholar 

  10. Bondock S, Khalifa W, Fadda AA (2007) Synthesis and antimicrobial evaluation of some new thiazole, thiazolidinone and thiazoline derivatives starting from 1-chloro-3,4-dihydronaphthalene-2-carboxaldehyde. Eur J Med Chem 42:948–954. doi:10.1016/j.ejmech.2006.12.025

    Google Scholar 

  11. Küçükgüzel G, Kocatepe A, De Clercq E, Sahin F, Güllüce M (2006) Synthesis and biological activity of 4-thiazolidinones, thiosemicarbazides derived from diflunisal hydrazide. Eur J Med Chem 41:353–359. doi:10.1016/j.ejmech.2005.11.005

    Article  PubMed  Google Scholar 

  12. Trivedi VP, Undavia NK, Trivedi PB (2005) Synthesis and biological activity of some new 4-thiazolidinone derivatives. ChemInform 36. doi:10.1002/chin.200513170

  13. Omar K, Geronikaki A, Zoumpoulakis P, Camoutsis C, Sokovic M, Ciric A, Glamoclija J (2010) Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs. Bioorg Med Chem 18:426–432. doi:10.1016/j.bmc.2009.10.041

    Article  PubMed  CAS  Google Scholar 

  14. Feitoza DD, Alves AJ, de Lima JG, Araujo JM, Aguiar JS, Rodrigues MD, Silva TG, do Nascimento SC, Goes AJD (2010) Synthesis, antimicrobial and cytotoxic activities of 5-benzylidene-2-[(pyridine-4-ylmethylene)hydrazono]-thiazolidin-4-one and 2-[(pyridine-4-ylmethylene) hydrazono]-thiazolidin-4-one derivatives. Quimica Nova 35:694–698. doi:10.1590/S0100-40422012000400007

    Google Scholar 

  15. Ma YF, Stern RJ, Scherman MS, Vissa VD, Yan WX, Jones VC, Zhang FQ, Franzblau SG, Lewis WH, McNeil MR (2001) Drug targeting Mycobacterium tuberculosis cell wall synthesis: genetics of dTDP–rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP–glucose to dTDP–rhamnose. Antimicrob Agents Chemother 45:1407–1416. doi:10.1128/AAC.45.5.1407-1416.2001

    Article  PubMed  CAS  Google Scholar 

  16. Helm JS, Hu Y, Chen L, Gross B, Walker S (2003) Identification of active-site inhibitors of MurG using a generalizable, high-throughput glycosyltransferase screen. J Am Chem Soc 125:11168–11169. doi:10.1021/ja036494s

    Article  PubMed  CAS  Google Scholar 

  17. National Committee for Clinical Laboratory Standards (2003) Performance standards for antimicrobial susceptibility testing: eleventh informational supplement, M100-S11. National Committee for Clinical Laboratory Standard, Wayne

  18. Sarker SA, Nahar L, Kumarasamy Y (2007) Microtitre plate-based antibacterial assay incorporating resazurin as an indicator of cell growth, and its application in the in vitro antibacterial screening of phytochemicals. Methods 42:321–324. doi:10.1016/j.ymeth.2007.01.006

    Article  PubMed  CAS  Google Scholar 

  19. Cell viability protocols and applications guide. http://worldwide.promega.com/~/media/files/resources/paguide/a4/chap4a4.pdf?la=en. Promega Publications. Accessed 12 April 2013

  20. Moitessier N, Henry C, Maigret B, Chapleur Y (2004) Combining pharmacophore search, automated docking, and molecular dynamics simulations as a novel strategy for flexible docking. Proof of concept: docking of arginine–glycine–aspartic acid-like compounds into the \(\alpha _{v}\beta _{3}\) binding site. J Med Chem 47:4178–4187. doi: 10.1021/jm0311386

    Article  PubMed  CAS  Google Scholar 

  21. Kapetanovic IM (2008) Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach. Chem Biol Interact 171:165–176. doi:10.1016/j.cbi.2006.12.006

    Article  PubMed  CAS  Google Scholar 

  22. Guido RVC, Oliva G, Andricopulo AD (2008) Virtual screening and its integration with modern drug design technologies. Curr Med Chem 15:37–46. doi:10.2174/092986708783330683

    Article  PubMed  CAS  Google Scholar 

  23. Acharya C, Coop A, Polli JE, Mackerell AD Jr (2011) Recent advances in ligand-based drug design: relevance and utility of the conformationally sampled pharmacophore approach. Curr Comput Aided Drug Des 7:10–22. doi:10.2174/157340911793743547

    Article  PubMed  CAS  Google Scholar 

  24. Lu Y, Wang Y, Xu Z, Yan X, Luo X, Jiang H, Zhu W (2009) C-X\(\ldots \)H contacts in biomolecular systems: how they contribute to protein–ligand binding affinity. J Phys Chem 113:12615–12621. doi: 10.1021/jp906352e

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The financial support of this work by EUR-INTAFAR Project and Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. 172044) is gratefully acknowledged. The authors thank Robert McKenzie for careful reading of the manuscript and all the useful suggestions.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 , Ljubljana, Slovenia

    Marko Jukič & Marko Anderluh

  2. Department of Chemistry, Faculty of Science and Mathematics, University of Nis, Višegradska 33, 18000 , Nis, Serbia

    Aleksandra Ɖorđević

  3. Department of Chemistry, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 , Nis, Serbia

    Jelena Lazarević & Andrija Šmelcerović

  4. Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 , Ljubljana, Slovenia

    Martina Gobec

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  1. Marko Jukič
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  2. Aleksandra Ɖorđević
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  3. Jelena Lazarević
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  4. Martina Gobec
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  5. Andrija Šmelcerović
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  6. Marko Anderluh
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Correspondence to Andrija Šmelcerović or Marko Anderluh.

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Jukič, M., Ɖorđević, A., Lazarević, J. et al. Antimicrobial activity and cytotoxicity of some 2-amino-5-alkylidene-thiazol-4-ones. Mol Divers 17, 773–780 (2013). https://doi.org/10.1007/s11030-013-9474-6

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  • DOI: https://doi.org/10.1007/s11030-013-9474-6

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