Glycoconjugate Journal

, Volume 32, Issue 3–4, pp 127–140 | Cite as

Click inspired synthesis of antileishmanial triazolyl O-benzylquercetin glycoconjugates

  • Pratibha Dwivedi
  • Kunj B. Mishra
  • Bhuwan B. Mishra
  • Nisha Singh
  • Rakesh K. Singh
  • Vinod K. TiwariEmail author
Original Article


The 1,3-dipolar cycloaddition of deoxy-azido sugars 1 with O-benzylquercetin alkynes (57) to afford regioselective triazole-linked O-benzylquercetin glycoconjugates (810) was investigated in the presence of CuI/DIPEA in dichloromethane. All the developed glycoconjugates (810) were evaluated for anti-leishmanial activity against the promastigotes and amastigotes of Leishmania donovani.

Graphical Abstract

Click Inspired Synthesis of Antileishmanial Triazolyl O-Benzylquercetin Glycoconjugates


Carbohydrates Antileishmanial Agents Flavonoids Quercetin Click chemistry Glycoconjugates 



Fetal bovine serum


3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide


inhibitory concentrations


selective Index

SIRC cell line

Statens Seruminstitut Rabbit Corneal (SIRC) cell line

MIA PaCa cell line

MIA PaCa pancreatic epithelial cell lines.



This research was supported by Department of Science and Technology (DST), New Delhi under Women Scientist-A scheme (SR/WOS-A/CS-83/2011 (G) dated 17.07.2012). VKT thanks BHU and CDRI, Lucknow for providing spectroscopic analysis and CSIR New Delhi for the funding.

Supplementary material

10719_2015_9582_MOESM1_ESM.doc (28 kb)
ESM 1 (DOC 28 kb)


  1. 1.
    Mishra, B.B., Tiwari, V.K.: Natural products: an evolving role in future drug discovery. Eur. J. Med. Chem. 46, 4769–4807 (2011)CrossRefPubMedGoogle Scholar
  2. 2.
    Wong, I.L.K., Chan, K.F., Chen, Y.F., Lun, Z.R., Chan, T.H., Chow, L.M.C.: In vitro and in vivo efficacy of novel flavonoid dimers against cutaneous leishmaniasis. Antimicrob. Agents Chemother. 58, 3379–3388 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Singh, N., Mishra, B.B., Bajpai, S., Singh, R.K., Tiwari, V.K.: Natural product based leads to fight against leishmaniasis. Bioorg. Med. Chem. 22, 18–45 (2014)CrossRefPubMedGoogle Scholar
  4. 4.
    Mishra, B.B., Singh, R.K., Srivastava, A., Tripathi, V., Tiwari, V.K.: Fighting against leishmaniasis: search of alkaloids as future true potential anti-leishmanial agents. Mini-Rev. Med. Chem. 9, 107–123 (2009)CrossRefPubMedGoogle Scholar
  5. 5.
    Singh, Y., Spinelli, N., De Francq, E., Dumy, P.: A novel heterobifunctional linker for facile access to bioconjugates. Org. Biomol. Chem. 4, 1413–1419 (2006)CrossRefPubMedGoogle Scholar
  6. 6.
    Virta, P., Katajisto, J., Niittymaki, T., Lonnberg, H.: Solid-orted synthesis of oligomeric bioconjugates. Tetrahedron 59, 5137–5174 (2003)CrossRefGoogle Scholar
  7. 7.
    Dedola, S., Nepogodiev, S.A., Field, R.A.: Recent applications of the CuI-catalysed huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry. Org. Biomol. Chem. 5, 1006–1017 (2007)CrossRefPubMedGoogle Scholar
  8. 8.
    Bock, V.D., Hiemstra, H., van-Maarseveen, J.H.: CuI-catalyzed alkyne-azide “click” cycloadditions from a mechanistic and synthetic perspective. Eur. J. Org. Chem. 51–68 (2006)Google Scholar
  9. 9.
    Binder, W.H., Sachsenhofer, R.: ‘Click’ chemistry in polymer and materials science. Macromol. Rapid Commun. 28, 15–54 (2007)CrossRefGoogle Scholar
  10. 10.
    Binder, W.H., Sachsenhofer, R.: Click’ chemistry in polymer and material science: an update. Rapid. Commun. 29, 952–981 (2008)CrossRefGoogle Scholar
  11. 11.
    Kolb, H.C., Finn, M.G., Sharpless, K.B.: Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001)CrossRefGoogle Scholar
  12. 12.
    Gallos, J.K., Koumbis, A.E.: 1,3-dipolar cycloadditions in the synthesis of carbohydrate mimics. Part 1: nitrile oxides and nitronates. Curr. Org. Chem. 7, 397–426 (2003)CrossRefGoogle Scholar
  13. 13.
    Koumbis, A.E., Gallos, J.K.: 1,3-dipolar cycloadditions in the synthesis of carbohydrate mimics. Part 2: nitrones and oximes. Curr. Org. Chem. 7, 585–628 (2003)CrossRefGoogle Scholar
  14. 14.
    Koumbis, A.E., Gallos, J.K.: 1,3-dipolar cycloadditions in the synthesis of carbohydrate mimics. Part 3: azides, diazo compounds and other dipoles. Curr. Org. Chem. 7, 771–797 (2003)CrossRefGoogle Scholar
  15. 15.
    Szeja, W., Swierk, P., Grynkiewicz, G., Rusin, A., Papaj, K.: An approach to C-glycosidic conjugates of isoflavones. Heterocycl. Commun. 19, 133–138 (2013)CrossRefGoogle Scholar
  16. 16.
    Xiao, J., Chen, T., Cao, H.: Advances in the biotechnological glycosylation of valuable flavonoids. Biotech. Adv. 32, 1145–1156 (2014)CrossRefGoogle Scholar
  17. 17.
    Olivero-Verbel, J., Pacheco-Londono, L.: Structure–activity relationships for the anti-HIV activity of flavonoids. J. Chem. Inf. Comput. Sci. 42, 1241–1246 (2002)CrossRefPubMedGoogle Scholar
  18. 18.
    Bae, E.A., Han, M.J., Lee, M., Kim, D.H.: In vitro inhibitory effect of aome flavonoids on rotavirus infectivity. Biol. Pharm. Bull. 23, 1122–1124 (2000)CrossRefPubMedGoogle Scholar
  19. 19.
    Gupta, P., Sharma, U., Gupta, P., Siripurapu, K.B., Maurya, R.: Evolvosides C-E, flavonol-4-O-triglycosides from Evolvulus alsinoides and their anti-stress activity. Bioorg. Med. Chem. 21, 1116–1122 (2013)CrossRefPubMedGoogle Scholar
  20. 20.
    Makino, T., Kanemaru, M., Okuyama, S., Shimizu, R., Tanaka, H., Mizukami, H.: Anti-allergic effects of enzymatically modified isoquercitrin (α-oligoglucosyl quercetin 3-O-glucoside), quercetin 3-O-glucoside, α-oligoglucosyl rutin, and quercetin, when administered orally to mice. J. Nat. Med. 67, 881–886 (2013)CrossRefPubMedGoogle Scholar
  21. 21.
    Kong, C.S., Lee, J.I., Kim, Y.A., Kim, J.A., Bak, S.S., Hong, J.W., Park, H.Y., Yea, S.S., Seo, Y.: Evaluation on anti-adipogenic activity of flavonoid glucopyranosides from Salicornia herbacea. Process Biochem. 47, 1073–1078 (2012)CrossRefGoogle Scholar
  22. 22.
    Huisgen, R.: 1,3-dipolar cyloadditions past and future. Angew. Chem. Int. Ed. 2, 565–598 (1963)CrossRefGoogle Scholar
  23. 23.
    Varki, A.: Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3, 97–130 (1993)CrossRefPubMedGoogle Scholar
  24. 24.
    Tiwari, V.K., Mishra, R.C., Sharma, A., Tripathi, R.P.: Carbohydrate based potential chemotherapeutic agents: recent developments and their scope in future drug discovery. Mini-Rev. Med. Chem. 12, 1497–1519 (2012)CrossRefPubMedGoogle Scholar
  25. 25.
    Cao, H., Hwang, J., Chen, X.: Carbohydrate-containing natural products in medicinal chemistry. In: Tiwari, V.K., Mishra, B.B. (eds.) Opportunity, challenge and scope of natural products in medicinal chemistry, pp. 166–180. Research Signpost Publication, Trivandrum (2011)Google Scholar
  26. 26.
    Kushwaha, D., Dwivedi, P., Kuanar, K.S., Tiwari, V.K.: Click reaction in carbohydrate chemistry: recent developments and future perspective. Curr. Org. Syn. 10, 90–135 (2013)CrossRefGoogle Scholar
  27. 27.
    Tiwari, V.K., Kumar, A., Schmidt, R.R.: Disaccharide-containing macrocycles by click chemistry and intramolecular glycosylation. Eur. J. Org. Chem. 29452956 (2012).Google Scholar
  28. 28.
    Kuijpers, B.H.M., Groothuys, S., Keerweer, A.R., Quaedflieg, P.J.L.M., Blaquw, R.H., Van Delft, F.L., Rutjes, F.P.J.T.: Expedient synthesis of triazole-linked glycosyl amino acids and peptides. Org. Lett. 6, 3123–3126 (2004)CrossRefPubMedGoogle Scholar
  29. 29.
    Bouktaib, M., Lebrun, S., Atmani, A., Rolando, C.: Hemisynthesis of all the O-monomethylated analogues of quercetin including the major metabolites, through selective protection of phenolic functions. Tetrahedron 58, 10001–10009 (2002)CrossRefGoogle Scholar
  30. 30.
    Singh, A., Mishra, B.B., Kale, R.R., Kushwaha, D., Tiwari, V.K.: A convenient synthesis of novel glycosyl azetidines under mitsunobu reaction conditions. Synth. Commun. 42, 3598–3613 (2012)CrossRefGoogle Scholar
  31. 31.
    Mishra, K.B., Tiwari, V.K.: Click chemistry inspired synthesis of morpholine-fused triazoles. J. Org. Chem. 79, 5752–5762 (2014)CrossRefPubMedGoogle Scholar
  32. 32.
    Kumar, D., Mishra, A., Mishra, B.B., Tiwari, V.K.: Synthesis of glycoconjugate benzothiazoles via cleavage of benzotriazole ring. J. Org. Chem. 78, 899–909 (2013)CrossRefPubMedGoogle Scholar
  33. 33.
    Kushwaha, D., Singh, R.S., Tiwari, V.K.: Fluorogenic dual click derived bis-glycoconjugated triazolocoumarins for selective recognition of Cu(II) ion. Tetrahedron Lett. 55, 4532–4536 (2014)CrossRefGoogle Scholar
  34. 34.
    Kumar, D., Mishra, K.B., Mishra, B.B., Mondal, S., Tiwari, V.K.: Click chemistry inspired highly facile synthesis of triazolyl ethisterone glycoconjugates. Steroids 80, 71–79 (2014)CrossRefPubMedGoogle Scholar
  35. 35.
    Mishra, K.B., Mishra, B.B., Tiwari, V.K.: Efficient synthesis of ethisterone glycoconjugate via bis-triazole. Carbohydrate Res. 399, 2–7 (2014)CrossRefGoogle Scholar
  36. 36.
    Sousa, M.C., Varandas, R., Santos, R.C., Santos-Rosa, M., Alves, V., Salvador, J.A.R.: Antileishmanial activity of semisynthetic lupane triterpenoids betulin and betulinic acid derivatives: synergistic effects with miltefosine. PLoS ONE 9, e89939 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Mishra, B.B., Gour, J.K., Kishore, N., Singh, R.K., Tripathi, V., Tiwari, V.K.: An antileishmanial prenyloxy-naphthoquinone from roots of plumbago zeylanica. Nat. Prod. Res. 27, 480–485 (2013)CrossRefPubMedGoogle Scholar
  38. 38.
    Mittra, B., Saha, A., Chowdhury, A.R., Pal, C., Mandal, S., Mukhopadhyay, S., Bandyopadhyay, S., Majumder, H.K.: Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis. Mol. Med. 6, 527–541 (2000)CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Lewin, G., Cojean, S., Guptac, S., Verma, A., Puri, S.K., Loiseau, P.M.: In vitro antileishmanial properties of new flavonoids against Leishmania donovani. Biomed. Prevent. Nutrit. 1, 168–171 (2011)CrossRefGoogle Scholar
  40. 40.
    Sundar, S., Olliaro, P.L.: Miltefosine in the treatment of leishmaniasis: clinical evidence for informed clinical risk management. Ther. Clin. Risk Manag. 3, 733–740 (2007)PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Pratibha Dwivedi
    • 1
  • Kunj B. Mishra
    • 1
  • Bhuwan B. Mishra
    • 1
  • Nisha Singh
    • 2
  • Rakesh K. Singh
    • 2
  • Vinod K. Tiwari
    • 1
    Email author
  1. 1.Department of Chemistry, Centre of Advanced Study, Faculty of ScienceBanaras Hindu UniversityVaranasiIndia
  2. 2.Department of Biochemistry, Faculty of ScienceBanaras Hindu UniversityVaranasiIndia

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