Medicinal Chemistry Research

, Volume 27, Issue 5, pp 1504–1516 | Cite as

Dipeptides as linker for multicomponent presentation—a facile, robust, and high-bioactivity yielding strategy

  • Honnegowdanahally K. Kumara
  • Suhas Ramesh
  • Doddahindaiah M. Suyoga Vardhan
  • J. Shiva Kumar
  • Dase Channe GowdaEmail author
Original Research


The need for multiple drugs arises when the response to pharmacological inflection is complicated and the disease conditions get worsened. The treatment requires a common platform to which multiple drugs are linked and this methodology is proven to be useful in drug delivery, biomaterial research, biomedicine, and vaccine development. In view of this, the present work is centered on dipeptides (KW/ KD/ KE/ kW/ kD/ kE), which are used as linkers and can potentially hold different functional group containing molecules (here, amino and carboxyl). First, we have demonstrated the incorporation of three components to the linker successfully followed by tetra component linking to those dipeptides, which contain trifunctional groups. To provide a proof of concept, these multisubstituted constructs were subjected to microbial growth suppression assay as well as anti-inflammatory assay. The biological results revealed that the multimers play a key role in enhancing the activity. Hence, the present system may be regarded as simple and straight forward which can be employed to develop various therapeutic agents as well as in different methodologies.


Multicomponent Dipeptides Linker Bioactivity 





1-Hydroxy benzotriazole




3-(4-Oxo-3,4-dihydroquinazolin-2-yl)propanoic acid


4-(4-Oxo-3,4-dihydroquinazolin-2-yl)butanoic acid



We gratefully acknowledge Department of Science and Technology (DST) New Delhi for awarding Inspire Fellowship, University Grant Commission (UGC) New Delhi for awarding BSR faculty fellowship and UGC-Post doctoral Fellowship (PDFSS). We also acknowledge DST-Purse and Instrumentation facility.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2168_MOESM1_ESM.docx (7.7 mb)
Supplementary Information(DOCX 7906 kb)


  1. Balouiri M, Sadiki M, Ibnsouda SK (2016) Methods for in vitro evaluating antimicrobial activity: A review. J Pharm Anal 6:71–79CrossRefPubMedGoogle Scholar
  2. Borras-Cuesta F, Fedon Y, Petit-Camurdan A (1988) Enhancement of peptide immunogenicity by linear polymerization. Eur J Immunol 18:199–200CrossRefPubMedGoogle Scholar
  3. Burstein S, Mcquain C, Salmonsen R, Seicol B (2012) N-Amino acid linoleoyl conjugates: anti-inflammatory activities. Bioorg Med Chem Lett 22:872–875CrossRefPubMedGoogle Scholar
  4. Collin F, Karkare S, Maxwell A (2011) Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol 92:479–497CrossRefPubMedPubMedCentralGoogle Scholar
  5. Hamamoto K, Kida Y, Zhang Y, Shimizu T, Kuwano K (2002) Antimicrobial activity and stability to proteolysis of small linear cationic peptides with D-amino acid substitutions. Microbiol Immunol 46:741–749CrossRefPubMedGoogle Scholar
  6. Heddle J, Maxwell A (2002) Quinolone-binding pocket of DNA gyrase: role of GyrB. Antimicrob Agents Chemother 46:1805–1815CrossRefPubMedPubMedCentralGoogle Scholar
  7. Keche AP, Hatnapure GD, Tale RH, Rodge AH, Kamble VM (2012) Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties. Bioorg Med Chem Lett 22:6611–6615CrossRefPubMedGoogle Scholar
  8. Kragol Jr. G, Otvos L (2001) Orthogonal solid-phase synthesis of tetramannosylated peptide constructs carrying three independent branched epitopes. Tetrahedron 57:957–966CrossRefGoogle Scholar
  9. Kumar R, Madhumathi BS, Nagaraja V (2014) Molecular basis for the differential quinolone susceptibility of mycobacterial DNA gyrase. Antimicrob Agents Chemother 58:2013–2020CrossRefPubMedPubMedCentralGoogle Scholar
  10. Kumara HK, Gowda DC (2017) Synthesis and SAR studies of bisthiourea derivatives of dipeptides Lys/lys-Asp, Lys/lys-Trp conjugated benzo[d]isoxazole as promising antioxidants. Int J Pept Res Ther 23:259–267CrossRefGoogle Scholar
  11. Kumara HK, Vardhan DMS, Kumar JS, Gowda DC (2017) Bisthiourea derivatives of dipeptide conjugated benzo[d]isoxazole as a new class of therapeutics: synthesis and molecular docking studies. Antiinflamm Antiallergy Agents Med Chem 16:123–133CrossRefPubMedGoogle Scholar
  12. Mezo G, de Oliveira E, Krikorian D, Feijlbrief M, Jakab A, Tsikaris V, Sakarellos C, Welling-Wester S, Andreu D, Hudecz F (2003) Synthesis and comparison of antibody recognition of conjugates containing herpes simplex virus type 1 glycoprotein D epitope VII. Bioconjugate Chem 14:1260–1269CrossRefGoogle Scholar
  13. Mozdzanowska K, Feng J, Eid M, Kragol G, Cudic Jr. M, Otvos L, Gerhard W (2003) Induction of influenza type A virus-specific resistance by immunization of mice with a synthetic multiple antigenic peptide vaccine that contains ectodomains of matrix protein 2. Vaccine 21:2616–2626CrossRefPubMedGoogle Scholar
  14. Ostrov DA, Prada JAH, Corsino PE, Finton KA, Le N, Rowe TC (2007) Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening. Antimicrob Agents Chemother 51:3688–3698CrossRefPubMedPubMedCentralGoogle Scholar
  15. Perez C, Paul M, Bazerque P (1990) An antibiotic assay by the agar-well diffusion method. Acta Biol Med Exp 15:113–115Google Scholar
  16. Rios JL, Recio MC, Villar A (1988) Screening methods for natural products with antimicrobial activity: A review of the literature. J Ethnopharmacol 23:127–149CrossRefPubMedGoogle Scholar
  17. Shantharam CS, Vardhan DMS, Suhas R, Sridhara MB, Gowda DC (2013) Inhibition of protein glycation by urea and thiourea derivatives of glycine/proline conjugated benzisoxazole analogue-synthesis and structure-activity studies. Eur J Med Chem 60:325–332CrossRefPubMedGoogle Scholar
  18. Sharma A, Suhas R, Chandan KV, Banu SH, Gowda DC (2013a) tert-Butyl 1,5-bis(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1,5-dioxopentan-2-ylcarbamate urea/thiourea derivatives as potent H+/K+-ATPase inhibitors. Bioorg Med Chem Lett 23:4096–4098CrossRefPubMedGoogle Scholar
  19. Sharma A, Suhas R, Gowda DC (2013b) Ureas/thioureas of benzo[d]isothiazole analog conjugated glutamic acid: Synthesis and biological evaluation. Arch Pharm Chem Life Sci 346:359–366CrossRefGoogle Scholar
  20. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN (1999) Membrane stabilizing activity—a possible mechanism of action for the anti-inflammatory activity of Cedrus deodarawood oil. Fitoterapia 70:251–257CrossRefGoogle Scholar
  21. Singh I, Singh VP (2000) Antifungal properties of aqueous and organic solution extracts of seed plants against Aspergillus flavus and A. niger. Phytomorphology 50:151–157Google Scholar
  22. Solomon VR, Haq W, Smilkstein M, Srivastava K, Puri SK, Katti SB (2010) 4-Aminoquinoline derived antimalarials: synthesis, antiplasmodial activity and heme polymerization inhibition studies. Eur J Med Chem 45:4990–4996CrossRefPubMedGoogle Scholar
  23. Suhas R, Chandrashekar S, Gowda DC (2011) Synthesis of elastin based peptides conjugated to benzisoxazole as a new class of potent antimicrobials—A novel approach to enhance biocompatibility. Eur J Med Chem 46:704–711CrossRefPubMedGoogle Scholar
  24. Suhas R, Gowda DC (2012) Design and synthesis of tryptophan containing peptides as potential analgesic and anti-inflammatory agents. J Pept Sci 18:535–540CrossRefPubMedGoogle Scholar
  25. Suresha GP, Suhas R, Wethroe K, Gowda DC (2011) Urea/thiourea derivatives of quinazolinone-lysine conjugates: Synthesis and structure-activity relationships of a new series of antimicrobials. Eur J Med Chem 46:2530–2540CrossRefPubMedGoogle Scholar
  26. Tam JP (1988) Synthetic peptide vaccine design: Synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci USA 85:5409–5413CrossRefPubMedPubMedCentralGoogle Scholar
  27. Tsikaris V, Sakarellos C, Cung MT, Marraud M, Sakarellos-Daitsiotis M (1996) Concept and design of a new class of sequential oligopeptide carriers (SOC) for covalent attachment of multiple antigenic peptides. Biopolymers 38:291–293CrossRefPubMedGoogle Scholar
  28. Vardhan DMS, Shantharam CS, Suhas R, Sridhara MB, Gowda DC (2013) Synthesis and SAR studies of urea and thiourea derivatives of Gly/Pro conjugated to piperazine analogue as potential AGE inhibitors. Protein Pept Lett 20:888–897CrossRefPubMedGoogle Scholar
  29. Wioleta K, Beatriz GT, David A (2010) Strategies and limitations in dendrimeric immunogen synthesis. The influenza virus M2e epitope as a case study. Bioconjugate Chem 21:102–110CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Honnegowdanahally K. Kumara
    • 1
  • Suhas Ramesh
    • 1
  • Doddahindaiah M. Suyoga Vardhan
    • 1
  • J. Shiva Kumar
    • 1
  • Dase Channe Gowda
    • 1
    Email author
  1. 1.Department of Studies in ChemistryUniversity of MysoreMysuruIndia

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