Molecular Diversity

, Volume 17, Issue 2, pp 271–283 | Cite as

Synthesis of novel spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles via a regioselective three-component [3+2] cycloaddition and their preliminary antimicrobial evaluation

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Abstract

A series of spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles hybrid compounds were prepared in good yields by regioselective, three-component, 1,3-dipolar cycloaddition reactions between \(\alpha , \beta \)-unsaturated ketones with furanyl substituents and unstable azomethine ylides, which were generated in situ from isatin and various types of amino acids. The synthesized compounds were screened for their antibacterial activities against a spectrum of pathogens. Preliminary studies identified compound 5c as a potent antimicrobial agent against drug-resistant bacteria. In addition, molecular docking studies indicated that compound 5c showed strong interactions with the active sites of lanosterol demethylase, dihydrofolate reductase, and topoisomerase II. This study provides an effective entry to the rapidly construction of a chemical library of heterocycles and compound 5c is one potent antibacterial lead for subsequent optimization.

Graphic Abstract

Keywords

\(1{, }3\)-Dipolar cycloaddition Azomethine ylides Antibacterial Multi-component reactions (MCRs) Spirooxindole derivatives 
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Notes

Acknowledgments

We wish to thank Professor Xiaokang Liu and Dr. Xiaoli Ji (Sichuan University) for providing an assessment of pharmacological test for all the compounds in this program. We also thank Dr. Jianyou Shi (People’s Hospital of Sichuan province), Dr. Zhihua Mao (Sichuan University) and Professor Jie Li (Zhejiang University) for good suggestions on the NMR and X-ray structure analysis. Financial support from National Natural Science Foundation of China (Nos.81102325, 81001357 and 81273471) and China Postdoctoral Science Foundation (No. 2012T50781) is gratefully acknowledged.

Supplementary material

11030_2013_9432_MOESM1_ESM.doc (7.2 mb)
Supplementary material 1 (doc 7361 KB)

References

  1. 1.
    Millemaggi A, Taylor RJK (2010) 3-Alkenyl-oxindoles: natural products, pharmaceuticals, and recent synthetic advances in tandem/telescoped approaches. Eur J Org Chem 2010(24): 4527–4547. doi: 10.1002/ejoc.201000643
  2. 2.
    Edwankar CR, Edwankar RV, Namjoshi OA, Rallapalli SK, Yang J, Cook JM (2009) Recent progress in the total synthesis of indole alkaloids. Curr Opin Drug Discov Devel 12:752–771PubMedGoogle Scholar
  3. 3.
    Trost BM, Brennan MK (2009) Asymmetric syntheses of oxindole and indole spirocyclic alkaloid natural products. Synthesis-Stuttgart 3003–3025. doi: 10.1055/s-0029-1216975
  4. 4.
    Bhaskar G, Arun Y, Balachandran C, Saikumar C, Perumal PT (2012) Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity. Eur J Med Chem 51:79–91. doi: 10.1016/j.ejmech.2012.02.024 PubMedCrossRefGoogle Scholar
  5. 5.
    Girgis AS, Stawinski J, Ismail NSM, Farag H (2012) Synthesis and QSAR study of novel cytotoxic spiro 3\(H\)-indole-3,2\(^{\prime }\)(1\(^{\prime }\)H)-pyrrolo 3,4-c pyrrole-2,3\(^{\prime }\),5\(^{\prime }\)(1H,2\(^{\prime }\)aH,4\(^{\prime }\)H)-triones. Eur J Med Chem 47:312–322. doi: 10.1016/j.ejmech.2011.10.058 Google Scholar
  6. 6.
    Anisetti R, Reddy MS (2012) Synthesis, antimicrobial, anti-inflammatory and antioxidant activity of novel Spiro (imidazo 4\(^{\prime }\),5\(^{\prime }\):4,5\(^{\prime }\)benzo 1,2-e 1,4 thiazepine)-9,3\(^{\prime }\)-indolines. J Sulfur Chem 33:363–372. doi: 10.1080/17415993.2012.683432 Google Scholar
  7. 7.
    Nicolaou KC, Sanchini S, Sarlah D, Lu G, Wu TR, Nomura DK, Cravatt BF, Cubitt B, de la Torre JC, Hessell AJ, Burton DR (2011) Design, synthesis, and biological evaluation of a biyouyanagin compound library. P Natl Acad Sci USA 108:6715–6720. doi: 10.1073/pnas.1015258108 CrossRefGoogle Scholar
  8. 8.
    Millard M, Pathania D, Grande F, Xu SL, Neamati N (2011) Small-molecule inhibitors of p53-MDM2 interaction: the 2006–2010 update. Curr Pharm Design 17:536–559CrossRefGoogle Scholar
  9. 9.
    Gomez-Monterrey I, Bertamino A, Porta A, Carotenuto A, Musella S, Aquino C, Granata I, Sala M, Brancaccio D, Picone D, Ercole C, Stiuso P, Campiglia P, Grieco P, Ianelli P, Maresca B, Novellino E (2010) Identification of the spiro(oxindole-3,3’-thiazolidine)-based derivatives as potential p53 activity modulators. J Med Chem 53:8319–8329. doi: 10.1021/jm100838z CrossRefGoogle Scholar
  10. 10.
    Anderton N, Cockrum PA, Colegate SM, Edgar JA, Flower K, Vit I, Willing RI (1998) Oxindoles from Phalaris coerulescens. Phytochemistry 48:437–439. doi: 10.1016/s0031-9422(97)00946-1 CrossRefGoogle Scholar
  11. 11.
    Edmondson S, Danishefsky SJ, Sepp-Lorenzino L, Rosen N (1999) Total synthesis of spirotryprostatin A, leading to the discovery of some biologically promising analogues. J Am Chem Soc 121:2147–2155. doi: 10.1021/ja983788i CrossRefGoogle Scholar
  12. 12.
    Paniagua-Perez R, Madrigal-Bujaidar E, Molina-Jasso D, Reyes-Cadena S, Alvarez-Gonzalez I, Sanchez-Chapul L, Perez-Gallaga J (2009) Antigenotoxic, antioxidant and lymphocyte induction effects produced by pteropodine. Basic Clin Pharmacol 104:222–227. doi: 10.1111/j.1742-7843.2008.00366.x CrossRefGoogle Scholar
  13. 13.
    Domling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89. doi: 10.1021/cr0505728 PubMedCrossRefGoogle Scholar
  14. 14.
    Hulme C, Gore V (2003) Multi-component reactions: emerging chemistry in drug discovery. From xylocain to crixivan. Curr Med Chem 10:51–80. doi: 10.2174/0929867033368600 PubMedCrossRefGoogle Scholar
  15. 15.
    Keshipour S, Shojaei S, Shaabani A (2012) A novel one-pot isocyanide-based four-component reaction: synthesis of highly functionalized 1\(H\)-pyrazolo 1,2-\(b\) phthalazine-1,2-dicarboxylates and 1\(H\)-pyrazolo 1,2-a pyridazine-1,2-dicarboxylates. Tetrahedron 68:6141–6145. doi:  10.1016/j.tet.2012.05.078 CrossRefGoogle Scholar
  16. 16.
    Naidu PS, Borah P, Bhuyan PJ (2012) Synthesis of some novel functionalized dihydropyrido 2,3-d pyrimidines via an one-pot three-component reaction catalysed by InCl3. Tetrahedron Lett 53: 4015–4017. doi: 10.1016/j.tetlet.2012.05.102 Google Scholar
  17. 17.
    Tisseh ZN, Ahmadi F, Dabiri M, Khavasi HR, Bazgir A (2012) A novel organocatalytic multi-component reaction: an efficient synthesis of polysubstituted pyrano-fused spirooxindoles. Tetrahedron Lett 53:3603–3606. doi: 10.1016/j.tetlet.2012.05.019 Google Scholar
  18. 18.
    Moulin E, Cormosw G, Giuseppone N (2012) Dynamic combinatorial chemistry as a tool for the design of functional materials and devices. Chem Soc Rev 41:1031–1049. doi: 10.1039/c1cs15185a PubMedCrossRefGoogle Scholar
  19. 19.
    Orru RVA, de Greef M (2003) Recent advances in solution-phase multicomponent methodology for the synthesis of heterocyclic compounds. Synthesis-Stuttgart 1471–1499: doi: 10.1055/s-2003-40507
  20. 20.
    Liu J, Sun HB, Liu XJ, Ouyang L, Kang TR, Xie YM, Wang XY (2012) Direct construction of novel exo’-selective spiropyrrolidine bisoxindoles via a three-component 1,3-dipolar cycloaddition reaction. Tetrahedron Lett 53:2336–2340. doi: 10.1016/j.tetlet.2012.02.099 CrossRefGoogle Scholar
  21. 21.
    Xie YM, Yao YQ, Sun HB, Yan TT, Liu J, Kang TR (2011) Facile synthesis of functionalized spiropyrrolizidine oxindoles via a three-component tandem cycloaddition reaction. Molecules 16:8745–8757. doi: 10.3390/molecules16108745 CrossRefGoogle Scholar
  22. 22.
    Periyasami G, Raghunathan R, Surendiran G, Mathivanan N (2008) Synthesis of novel spiropyrrolizidines as potent antimicrobial agents for human and plant pathogens. Bioorg Med Chem Lett 18:2342–2345. doi: 10.1016/j.bmcl.2008.02.065 PubMedCrossRefGoogle Scholar
  23. 23.
    Rajesh SM, Perumal S, Menendez JC, Yogeeswari P, Sriram D (2011) Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition. MedChemComm 2:626–630. doi: 10.1039/c0md00239a CrossRefGoogle Scholar
  24. 24.
    Arumugam N, Periyasami G, Raghunathan R, Kamalraj S, Muthumary J (2011) Synthesis and antimicrobial activity of highly functionalised novel beta-lactam grafted spiropyrrolidines and pyrrolizidines. Eur J Med Chem 46:600–607. doi: 10.1016/j.ejmech.2010.11.039 PubMedCrossRefGoogle Scholar
  25. 25.
    Kumar RR, Perumal S, Senthilkumar P, Yogeeswari P, Sriram D (2008) Discovery of antimycobacterial spiro-piperidin-4-ones: an atom economic, stereoselective synthesis, and biological intervention. J Med Chem 51:5731–5735. doi: 10.1021/jm800545k PubMedCrossRefGoogle Scholar
  26. 26.
    Kumar RR, Perumal S, Senthilkumar P, Yogeeswari P, Sriram D (2009) A facile synthesis and antimycobacterial evaluation of novel spiro-pyrido-pyrrolizines and pyrrolidines. Eur J Med Chem 44:3821–3829. doi: 10.1016/j.ejmech.2009.05.010 CrossRefGoogle Scholar
  27. 27.
    Maheswari SU, Balamurugan K, Perumal S, Yogeeswari P, Sriram D (2010) A facile 1,3-dipolar cycloaddition of azomethine ylides to 2-arylidene-1,3-indanediones: synthesis of dispiro-oxindolylpyrrolothiazoles and their antimycobacterial evaluation. Bioorg Med Chem Lett 20:7278–7282. doi: 10.1016/j.bmcl.2010.10.080 Google Scholar
  28. 28.
    Thangamani A (2010) Regiospecific synthesis and biological evaluation of spirooxindolopyrrolizidines via 3+2 cycloaddition of azomethine ylide. Eur J Med Chem 45:6120–6126. doi: 10.1016/j.ejmech.2010.09.051 PubMedCrossRefGoogle Scholar
  29. 29.
    Prasanna P, Balamurugan K, Perumal S, Yogeeswari P, Sriram D (2010) A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-pyrrolothiazolyloxindoles and their antitubercular evaluation. Eur J Med Chem 45:5653–5661. doi: 10.1016/j.ejmech.2010.09.019 PubMedCrossRefGoogle Scholar
  30. 30.
    Karthikeyan SV, Bala BD, Raja VPA, Perumal S, Yogeeswari P, Sriram D (2010) A highly atom economic, chemo-, regio- and stereoselective synthesis and evaluation of spiro-pyrrolothiazoles as antitubercular agents. Bioorg Med Chem Lett 20:350–353. doi: 10.1016/j.bmcl.2009.10.107 PubMedCrossRefGoogle Scholar
  31. 31.
    Basnet A, Thapa P, Karki R, Na Y, Jahng Y, Jeong BS, Jeong TC, Lee CS, Lee ES (2007) 2,4,6-Trisubstituted pyridines: synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship. Bioorg Med Chem 15:4351–4359. doi: 10.1016/j.bmc.2007.04.047 PubMedCrossRefGoogle Scholar
  32. 32.
    Nepali K, Singh G, Turan A, Agarwal A, Sapra S, Kumar R, Banerjee UC, Verma PK, Satti NK, Gupta MK, Suri OP, Dhar KL (2011) A rational approach for the design and synthesis of 1-acetyl-3,5-diaryl-4,5-dihydro(1\(H\))pyrazoles as a new class of potential non-purine xanthine oxidase inhibitors. Bioorg Med Chem 19:1950–1958. doi: 10.1016/j.bmc.2011.01.058 Google Scholar
  33. 33.
    Ouyang L, Huang YH, Zhao YW, He G, Xie YM, Liu J, He J, Liu B, Wei YQ (2012) Preparation, antibacterial evaluation and preliminary structure-activity relationship (SAR) study of benzothiazol- and benzoxazol-2-amine derivatives. Bioorg Med Chem Lett 22:3044–3049. doi: 10.1016/j.bmcl.2012.03.079 Google Scholar
  34. 34.
    Singh P, Verma P, Yadav B, Komath SS (2011) Synthesis and evaluation of indole-based new scaffolds for antimicrobial activities-identification of promising candidates. Bioorg Med Chem Lett 21:3367–3372. doi: 10.1016/j.bmcl.2011.04.001 PubMedCrossRefGoogle Scholar
  35. 35.
    Singh N, Pandey SK, Anand N, Dwivedi R, Singh S, Sinha SK, Chaturvedi V, Jaiswal N, Srivastava AK, Shah P, Siddiqui MI, Tripathi RP (2011) Synthesis, molecular modeling and bio-evaluation of cycloalkyl fused 2-aminopyrimidines as antitubercular and antidiabetic agents. Bioorg Med Chem Lett 21:4404–4408. doi: 10.1016/j.bmcl.2011.06.040 PubMedCrossRefGoogle Scholar
  36. 36.
    Discovery Studio, Version 3.1; Accelrys: San Diego, CA, 2011Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Guansheng Wu
    • 1
  • Liang Ouyang
    • 1
  • Jie Liu
    • 1
  • Shi Zeng
    • 1
  • Wei Huang
    • 2
  • Bo Han
    • 2
  • Fengbo Wu
    • 1
  • Gu He
    • 1
  • Mingli Xiang
    • 1
  1. 1.State Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduPeople’s Republic of China
  2. 2.State Key Laboratory Breeding Base of Systematic research, Development and Utilization of Chinese MedicineChengdu University of Traditional Chinese MedicineChengduPeople’s Republic of China

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