Skip to content
2000
Volume 22, Issue 5
  • ISSN: 1570-1794
  • E-ISSN: 1875-6271

Abstract

Background and Objectives

Despite the well-known antibacterial activity of cephalosporins, their analogous spirocyclic derivatives have not been adequately evaluated. Thus, this work aimed to prepare a series of novel 3-spirocephalosporins and evaluate their antibacterial activity.

Materials and Methods

Novel 3-spirocephalosporins were prepared through a one-pot thioalkylation of chloromethyl cephalosporin GCLE with a range of 1,2,4-triazolidine-3-thiones, followed by intramolecular Michael addition to the generated dihydrothiazine ring. The reaction was performed at room temperature under basic conditions (K2CO3, acetone, H2O). The antibacterial activities of the synthesized compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria.

Results

Most targets were obtained in moderate yield, and their structures were confirmed by 1H and 13C NMR spectral techniques. All the tested compounds exhibited antibacterial activity against methicillin-resistant .

Conclusion

Seven novel thiazolidine-bearing 3-spirocephalosporins were prepared, and most of them were potent against Gram-positive bacteria. Likely, the replacement of 1,2,4-triazolidine-3-thiones with other heterocycles containing bidentate nucleophiles in advantageous positions could lead to different biologically active spirocephalosporins.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cos/10.2174/0115701794287416241119111826
2025-01-30
2025-10-23

  • From This Site

    /content/journals/cos/10.2174/0115701794287416241119111826
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. AlcaideB. AragoncilloC. AlmendrosP. Comprehensive Heterocyclic Chemistry-III; Katritzky, A.R.; Ramsden, C.A.; Scriven, E. TaylorR. Elsevier200811110.1016/B978‑008044992‑0.00202‑9
     [Google Scholar]
  2. LeeH.W. KangT.W. ChaK.H. KimE.N. ChoiN.H. KimJ.W. HongC.I.I. Il. 2-chloro-4,6-dimethoxy-1,3,5-triazine: A new effective and convenient coupling reagent for cephalosporin derivatives.Synth. Commun.19982881339134910.1080/00397919808006831
     [Google Scholar]
  3. GlinkaT. HuieK. ChoA. LudwikowM. BlaisJ. GriffithD. HeckerS. DudleyM. Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in 3-(heteroarylthio)cephems. Discovery of RWJ-333441 (MC-04,546).Bioorg. Med. Chem.200311459160010.1016/S0968‑0896(02)00431‑5 12538024
     [Google Scholar]
  4. BuynakJ.D. VogetiL. DoppalapudiV.R. SolomonG.M. ChenH. Cephalosporin-derived inhibitors of β-Lactamase. Part 4: The C3 substituent.Bioorg. Med. Chem. Lett.200212121663166610.1016/S0960‑894X(02)00205‑6 12039585
     [Google Scholar]
  5. TehraniK.H.M.E. WadeN. MashayekhiV. BrüchleN.C. JespersW. VoskuilK. PesceD. van HarenM.J. van WestenG.J.P. MartinN.I. Novel Cephalosporin conjugates display potent and Selective inhibition of Imipenemase-Type Metallo-β-Lactamases.J. Med. Chem.202164139141915110.1021/acs.jmedchem.1c00362 34182755
     [Google Scholar]
  6. JústizO.H. Fernández-LafuenteR. GuisánJ.M. NegriP. PaganiG. PregnolatoM. TerreniM. One-Pot Chemoenzymatic synthesis of 3‘-Functionalized Cephalosporines (Cefazolin) by three consecutive Biotransformations in fully aqueous medium.J. Org. Chem.199762269099910610.1021/jo971166u
     [Google Scholar]
  7. PitlikJ. Cycloaddition and related reactions of cephalosporin antibiotics.Bioorg. Med. Chem.1995391157118110.1016/0968‑0896(95)00088‑X 8564409
     [Google Scholar]
  8. FazakerleyH. GilbertD.A. GregoryG.I. LazenbyJ.K. LongA.G. Cephalosporanic acids. Part V. The action of bidentate nucleophiles on cephalosporanic acids. J. Chem. Soc. C Org.Chem196719591963
     [Google Scholar]
  9. BruneauP. HennequinL.F. QuéréL. ScherrmannM.C. SiretP.J. Synthesis and structure elucidation of new spirocephams.Tetrahedron Lett.199031497141714410.1016/S0040‑4039(00)97262‑9
     [Google Scholar]
  10. KoglerH. LattrellR. SchubertW. WeberM. Formation of a novel 3-spiro cephalosporin by a base catalysed rearrangement.Tetrahedron Lett.198930151931193410.1016/S0040‑4039(00)99617‑5
     [Google Scholar]
  11. MiyauchiM. HaruyamaH. YodaK. KawamotoI. Transformation of 3-thiazoliomethylcephalosporin into 3-spirocephalosporin by intramolecular Michael addition.Bioorg. Med. Chem. Lett.19933112447245010.1016/S0960‑894X(01)80975‑6
     [Google Scholar]
  12. ZhaoA. HorsfallL. HulmeA. New methods for the synthesis of spirocyclic cephalosporin analogues.Molecules20212619603510.3390/molecules26196035 34641579
     [Google Scholar]
  13. Suresh KumarG.V. Rajendra PrasadY. MallikarjunaB.P. ChandrashekarS.M. Synthesis and pharmacological evaluation of clubbed isopropylthiazole derived triazolothiadiazoles, triazolothiadiazines and mannich bases as potential antimicrobial and antitubercular agents.Eur. J. Med. Chem.201045115120512910.1016/j.ejmech.2010.08.023 20797808
     [Google Scholar]
  14. HugginsW.M. MinrovicB.M. CoreyB.W. JacobsA.C. MelanderR.J. SommerR.D. ZurawskiD.V. MelanderC. 1,2,4-Triazolidine-3-thiones as narrow spectrum antibiotics against multidrug-resistant acinetobacter baumannii.ACS Med. Chem. Lett.201781273110.1021/acsmedchemlett.6b00296 28105270
     [Google Scholar]
  15. DemirbasN. KaraogluS.A. DemirbasA. SancakK. Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo- [1,2,4]triazole derivatives.Eur. J. Med. Chem.200439979380410.1016/j.ejmech.2004.06.007 15337292
     [Google Scholar]
  16. PalaskaE. ŞahinG. KelicenP. DurluN.T. AltinokG. Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones.Farmaco200257210110710.1016/S0014‑827X(01)01176‑4 11902651
     [Google Scholar]
  17. LiZ. GuZ. YinK. ZhangR. DengQ. XiangJ. Synthesis of substituted-phenyl-1,2,4-triazol-3-thione analogues with modified d-glucopyranosyl residues and their antiproliferative activities.Eur. J. Med. Chem.200944114716472010.1016/j.ejmech.2009.05.030 19560842
     [Google Scholar]
  18. ChandrashekharM. NayakV.L. RamakrishnaS. MallavadhaniU.V. Novel triazole hybrids of myrrhanone C, a natural polypodane triterpene: Synthesis, cytotoxic activity and cell based studies.Eur. J. Med. Chem.201611429330710.1016/j.ejmech.2016.03.013 27015609
     [Google Scholar]
  19. ShakerR.M. The chemistry of mercapto- and thione- substituted 1,2,4-triazoles and their utility in heterocyclic synthesis.ARKIVOC2006200695911210.3998/ark.5550190.0007.904
     [Google Scholar]
  20. RameshR. LalithaA. Facile and green chemistry access to 5‐aryl‐1,2,4‐Triazolidine‐3‐thiones in aqueous medium.ChemistrySelect2016192085208910.1002/slct.201600348
     [Google Scholar]
  21. ManeM.M. PoreD.M. A novel one pot multi-component strategy for facile synthesis of 5-aryl-[1,2,4]triazolidine-3-thiones.Tetrahedron Lett.201455486601660410.1016/j.tetlet.2014.10.052
     [Google Scholar]
  22. PatilP.J. SalunkeG.D. DeshmukhM.B. HangirgekarS.P. ChandamD.R. SankpalS.A. Thiamine hydrochloride catalyzed Synthesis of 1,2,4‐Triazolidine‐3‐thiones in Aqueous Medium.ChemistrySelect2019445130711307810.1002/slct.201903646
     [Google Scholar]
  23. KhataviS.Y. KantharajuK. Waste to wealth: Agro-waste catalyzed green method synthesis of 5-aryl-1,2,4-triazolidine-3-thiones and 1,2,4-triazospiro-3-thiones.Org. Commun.202114240254
     [Google Scholar]
  24. RameshR. LalithaA. PEG-assisted two-component approach for the facile synthesis of 5-aryl-1,2,4-triazolidine-3-thiones under catalyst-free conditions.RSC Advances2015563511885119210.1039/C5RA07726E
     [Google Scholar]
  25. BauerA.W. KirbyW.M.M. SherrisJ.C. TurckM. Antibiotic susceptibility testing by a standardized single disk method.Am. J. Clin. Pathol.1966454_ts49349610.1093/ajcp/45.4_ts.493 5325707
     [Google Scholar]
  26. WiseE.M.Jr ParkJ.T. Penicillin: Its basic site of action as an inhibitor of a peptide cross-linking reaction in cell wall mucopeptide synthesis.Proc. Natl. Acad. Sci. USA1965541758110.1073/pnas.54.1.75 5216369
     [Google Scholar]
  27. ZwayyerN.H. Synthesis, Characterization, and Antibacterial Activity Study of Novel Spiro-Cephalosporins.Master's Thesis, University of Misan2023
     [Google Scholar]
/content/journals/cos/10.2174/0115701794287416241119111826
Loading
Synthesis of Novel 3-spirocephalosporins and Evaluation of their Antibacterial Activity
Curr. Org. Synth. 22, 620 (2025); https://doi.org/10.2174/0115701794287416241119111826
/content/journals/cos/10.2174/0115701794287416241119111826
/content/journals/cos/10.2174/0115701794287416241119111826
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 3-spirocephalosporins; antibacterial activity; dihydrothiazine ring; intramolecular Michael addition; thioalkylation; triazolidine-3-thiones

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test