Abstract
The present study deals with the synthesis of novel spiro[azetidine-2,3′-indole]-2′,4(1′H)-dione derivative from the reactions of 3-(phenylimino)-1,3-dihydro-2H-indol-2-one derivatives with chloracetyl chloride in the presence of triethylamine (TEA). All the compounds were characterized using IR, 1H-NMR, MS, and elemental analysis. They were screened for their antibacterial and antifungal activities. The bacterial strains used were Gram-positive Staphylococcus aureus (MTCC-96) and Gram-negative Escherichia coli (MTCC-521) and Pseudomonas aeruginosa (MTCC-647). The antifungal screening was done on Candida albicans (MTCC-183) and Asperigillus niger (MTCC-343) fungal strains. Results revealed that, compounds (7a), (7b), (7c), (7d), and (7e) showed very good activity with MIC value of 6.25–12.5 μg/ml against three evaluated bacterial strains and the remaining compounds showed good to moderate activity comparable to standard drugs as antibacterial agents. Compounds (7c) and (7h) displayed equipotent antifungal activity in comparison to standard drugs. Amoxicillin, gentamycin, and streptomycin were used as standard drugs for antibacterial activity while fluconazole and itraconazole were used as standard drugs for antifungal activity. Structure–activity relationship study of the compounds showed that the presence of electron withdrawing group substitution at 5′ and 7′ positions of indoline ring and on ortho or para position of phenyl ring increases both antibacterial and antifungal activity of the compound. Henceforth, our findings will have a good impact on chemists and biochemists for further investigations in search of spiro-fused antimicrobial agents.
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References
Alcaide B, Almendros P (2004) β-Lactams as versatile synthetic intermediates for the preparation of heterocycles of biological interest. Curr Med Chem 11:1921–1949
Alonso E, Pozo C, González J (2002) Staudinger reactions of unsymmetrical cyclic ketenes: a synthetically useful approach to spiro β-lactams and derivatives. Reaction mechanism and theoretical studies. J Chem Soc Perkin Trans 1:571–576
Arjona O, Csákÿ AG, Murcia MC, Plumet J (2002) The Staudinger reaction of imines derived from 7-oxanorbornenone: formation of spiranic oxazinone versus β-lactam rings. Tetrahedron Lett 43:6405–6408
Barba V, Hernández C, Rojas-Lima S, Farfán N, Santillan R (1999) Preparation of N-aryl-substituted spiro- β-lactams via Staudinger cycloaddition. Can J Chem 77:2025–2032
Basak A, Ghosh SC (2004) L-Proline-mediated one-pot synthesis of 3-exomethylene β-lactams via Kinugasa reaction. Synlett 9:1637–1639
Bose AK, Garratt S, Pelosi JJ (1963) Synthesis of some spirobarbiturates. J Org Chem 28:730–733
Brown MJ (1989) Literature review of the ester enolate imine condensation. Heterocycles (Sendai) 29:2225–2244
Clader JW (2004) The discovery of ezetimibe: a view from outside the receptor. J Med Chem 47:1–9
Collins AH (1976) Microbiological methods, 2nd edn. Butterworth, London
Cruickshank R, Duguid JP, Marion BP (1975) Medicinal microbiology, vol 2, 12th edn. Churchill Livingstone, London, p 196
De Kimpe N, Rees CW (1996) Comprehensive heterocyclic chemistry II. Pergamon, UK, p 507
Deshmukh A, Bhawal BM, Krishnaswamy D, Govande VV, Shinkre BA, Jayanthi A (2004) Azetidin-2-ones, synthon for biologically important compounds. Curr Med Chem 11:1889–1920
Francis JS, Doherty MC, Lopatin U, Johnston CP, Sinha G, Ross T, Cai M, Hansel NN, Perl T, Ticehurst JR (2004) Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis 40:100–107
Holton RA, Liu JH (1993) A novel asymmetric synthesis of cis-3-hydroxy-4-aryl azetidin-2-ones. Bioorg Med Chem Lett 3:2475–2478
Isaacs NS (1976) Synthetic routes to β-lactams. Chem Soc Rev 5:181–202
Khan ZK (1997) In vitro and in vivo screening techniques for bioactivity screening and evaluation. In: Proceedings of international workshop UNIDO-CDRI, p 210
Khasanov AB, Ramirez-Weinhouse MM, Webb TR, Thiruvazhi M (2004) Novel asymmetric approach to proline-derived spiro-β-lactams. J Org Chem 69:5766–5769
Kruszewska D, Sahl HG, Bierbaum G, Pag U, Hynes SO, Ljungh A (2004) Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model. J Antimicrob Chemother 54:648–653
Manhas MS, Chib JS, Chiang YH, Bose AK (1969) Studies on lactams—XII: synthesis of some spiro-β-lactams. Tetrahedron 25:4421–4426
Marvel CS, Hiers GS (1941) Preparation of isatin. Org Synth Coll 1:327
Moriconi EJ, Kelly JF (1966) β-Lactams containing an exocyclic double bond. J Am Chem Soc 88:3657–3658
Nishikawa T, Kajii S, Isobe M (2004) Synthesis of model compound containing an indole spiro-β-lactam moiety with vinylchloride in chartellines. Chem Lett 33:440–441
Ojima I, Delaloge F (1997) Asymmetric synthesis of building-blocks for peptides and peptidomimetics by means of the β-lactam synthon method. Chem Soc Rev 26:377–386
Singh GS (2000) Synthesis of novel spiroazetidinones by selective lactam-carbonyl cleavage in 1-aryl/cyclohexyl-3,3-diphenyl-1′-(diphenylacetyl) spiro [azetidin-2,3′-indoline]-2′,4-diones. J Heterocycl Chem 37:1355–1356
Singh GS (2003) Recent progress in the synthesis and chemistry of azetidinones. Tetrahedron 59:7631–7649
Singh GS (2004a) Beta-lactams in the new millennium. Part-I: monobactams and carbapenems. Mini Rev Med Chem 4:69–92
Singh GS (2004b) Beta-lactams in the new millennium. Part-II: cephems, oxacephems, penams and sulbactam. Mini Rev Med Chem 4:93–109
Singh SB, Mehrotra KN (1982) Syntheses of N-substituted 3,3,4-triphenyl-4-benzoylazetidin-2-ones and 3,3-diphenyl spiro (acenaphthen-1-one-2, 4-azetidin-2-ones); novel examples exhibiting a high reactivity of imino group in ketoimines. Can J Chem 60:1901–1906
Singh GS, Mrnolotsi BJ (2006) Reactions of a-diazoketones with indolinone imines: synthesis of new 1,3,3-triaryl-1′-methylspiro-(azetidine-2,3′-indoline)-2′,4-diones. J Heterocycl Chem 43:1665–1668
Singh SG, Pheko T (2008) Formation and antimicrobial activity of 2-azetidinones from selective ester cleavage in 1,3,3-trisubstituted4-[2′-(o -diarylacyl)hydroxyphenyl]-2-azetidinones. Indian J Chem 47B:159–162
Singh GS, Siddiqui N, Pandeya SN (1992) Synthesis and anticonvulsant and anti inflammatory activities of new 3-aryl/alkylimino-1-methylindol-2-ones. Arch Pharm Res 15:272–274
Singh GS, Dohooghe M, Katritzky AR, Taylor R (2008) Comprehensive heterocyclic chemistry III, vol 2. Elsevier, New York, p 1
Somogyi L (2001) Transformation of isatin 3-acylhydrazones under acetylating conditions: synthesis and structure elucidation of 1, 5-disubstituted 3-acetylspiro [oxindole-3,2-[1,3,4] oxadiazolines]. Bull Chem Soc Jpn 74:873–881
Varma RS (1998) Antifungal agents: past. present and future prospects. National Academy of Chemistry & Biology, Lucknow
Vine KL, Locke JM, Ranson M, Pyne SG, Bremner JB (2007) In vitro cytotoxicity evaluation of some substituted isatin derivatives. Bioorg Med Chem 15:931–938
Zanobini A, Gensini M, Magull J, Vidovi D, Kozhushkov SI, Brandi A, de Meijere A (2004) A convenient new synthesis of 3-substituted β-lactams formally derived from 1-(aminomethyl) cyclopropanecarboxylic acids. Eur J Org Chem 20:4158–4166
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The authors are grateful to the Head, Zydus Research Center, for providing 1H-NMR, mass spectral, elemental analysis and Ganpat University for providing financial support.
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Shah, R.J., Modi, N.R., Patel, M.J. et al. Design, synthesis and in vitro antibacterial and antifungal activities of some novel spiro[azetidine-2,3′-indole]-2,4(1′H)-dione. Med Chem Res 20, 587–594 (2011). https://doi.org/10.1007/s00044-010-9354-x
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DOI: https://doi.org/10.1007/s00044-010-9354-x