Skip to main content

Advertisement

SpringerLink
Log in

Synthesis and antimalarial activity of quinoline-substituted furanone derivatives and their identification as selective falcipain-2 inhibitors

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

3-[(2-Chloroquinolin-3-yl) methylene]-5-phenylfuran-2(3H)-one derivatives (6a–j and 7a–j) have been synthesized and evaluated for their antimalarial activity. Three compounds 7d, 7f, and 7g showed excellent activity (0.50–0.72 µg/mL). In addition, six compounds were active in range below 5 µg/mL. A preliminary structure–activity relationship analysis of the series suggested that electropositive character is beneficial for antimalarial activity. Falcipain-2 was identified as potential target for the compounds by in silico studies. The docking studies of synthesized compounds on falcipain-2 revealed vital interactions and their binding conformation. Compound 7d and 7f could be used as lead to develop selective falcipain-2 inhibitors as they showed good inhibition of the enzyme in enzyme assay studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

FP-2:

Falcipain-2

FP-3:

Falcipain-3

DMF:

N,N-dimethylformamide

PDB:

Protein data bank

SAR:

Structure–activity relationship

References

  • Bermudez LE, Kolonoski P, Seitz LE, Petrofsky M, Reynolds R, Wu M, Young LS (2004) SRI-286, a thiosemicarbazole, in combination with mefloquine and moxifloxacin for treatment of murine Mycobacterium avium complex disease. Antimicrob Agents Chemother 48(9):3556–3558

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Butcher GA, Sinden RE, Curtis C (2000) Malaria: new ideas, old problems, new technologies. Parasitol Today 16(2):43–44

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Chen R, He M, Pang R, Tan Z, Yang M (2009) Design, synthesis, and biological evaluation of novel quinoline derivatives as HIV-1 Tat–TAR interaction inhibitors. Bioorg Med Chem 17(5):1948–1956

    Article  PubMed  Google Scholar 

  • Cohn OM, Narine B, Tarnowski B (1981) A versatile new synthesis of quinolines and related fused pyridines, Part 5. The synthesis of 2-chloroquinoline-3-carbaldehydes. J Chem Soc Perkin Trans 1, pp 1520–1530

  • Dorey G, Lockhart B, Lestage P, Casara P (2000) New quinolinic derivatives as centrally active antioxidants. Bioorg Med Chem Lett 10(9):935–939

    Article  CAS  PubMed  Google Scholar 

  • Dua VK, Sinha SN, Biswas S, Valecha N, Puri SK, Sharma VP (2002) Isolation and antimalarial activity of peroxydisulfate oxidation products of primaquine. Bioorg Med Chem Lett 12(24):3587–3589

    Article  CAS  PubMed  Google Scholar 

  • Glide, version 5.5 (2009) Schrödinger, LLC, New York

  • Jayaprakash S, Iso Y, Wan B, Franzblau SG, Kozikowski AP (2006) Design, synthesis, and SAR studies of mefloquine-based ligands as potential antituberculosis agents. Chem Med Chem 1(6):593–597

    Article  CAS  PubMed  Google Scholar 

  • Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS (2009) Structure of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implication for substructure specificity. J Med Chem 52(3):852–857

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kouznetsov VV, Meléndez Gómez CM, Derita MG, Svetaz L, Ed Olmo, Zacchino SA (2012) Synthesis and antifungal activity of diverse C-2 pyridinyl and pyridinylvinyl substituted quinolones. Bioorg Med Chem 20(21):6506–6512

    Article  CAS  PubMed  Google Scholar 

  • Lamazzi C, Leonce S, Pfeiffer B, Renard P, Guillaumet G, Reese CW, Besson T (2000) Expeditious synthesis and cytotoxic activity of new cyanoindolo[3,2-c]quinolines and benzimidazo [1,2-c]quinazolines. Bioorg Med Chem Lett 10(19):2183–2185

    Article  CAS  PubMed  Google Scholar 

  • Lell B, Faucher JF, Missinou MA, Borrmanna S, Dangelmaiera O, Horton J, Kremsnera PG (2000) Malaria chemoprophylaxis with tafenoquine: a randomised study. Lancet 355(9220):2041–2045

    Article  CAS  PubMed  Google Scholar 

  • Liu GB, Xu JL, He CC, Chen G, Xu Q, Xu HX, Li JX (2009) Synthesis and evaluation of a novel series of quinoline derivatives with immunosuppressive activity. Bioorg Med Chem 17(15):5433–5441

    Article  CAS  PubMed  Google Scholar 

  • Luo Z, Zeng C, Wang F, He H, Wang C, Du H, Hu L (2009) Synthesis and biological activities of quinoline derivatives as HIV-1 integrase inhibitors. Chem Res Chin Univ 25:841–845

    CAS  Google Scholar 

  • Mane UR, Li H, Huang J, Gupta RC, Nadkarni SS, Giridhar R, Naik PP, Yadav MR (2012) Pyrido[1,2-a]pyrimidin-4-ones as antiplasmodial falcipain-2 inhibitors. Bioorg Med Chem 20(21):6296–6304

    Article  CAS  PubMed  Google Scholar 

  • Mao J, Yuan H, Wang Y, Wan B, Pieroni M, Huang Q, Breemen RB, Kozikowski AP, Franzblau SG (2009) From serendipity to rational antituberculosis drug discovery of mefloquine-isoxazole carboxylic acid esters. J Med Chem 52(22):6966–6978

    Article  CAS  PubMed  Google Scholar 

  • Marrero J, Ospina CA, Rodríguez AD, Baran P, Zhao H, Franzblau SG, Barriac EO (2006) New diterpenes of the pseudopterane class from two closely related Pseudopterogorgia species: isolation, structural elucidation, and biological evaluation. Tetrahedron 62(29):6998–7008

    Article  CAS  Google Scholar 

  • Martínez MG, Giménez PC, Gómez AB, Franck X, Fournet A, Hocquemiller R, Figadère B, Casado NE (2005) Nematocidal and trichomonacidal activities of 2-substituted quinolines. Farmaco 60(3):219–224

    Article  Google Scholar 

  • Meléndez Gómez CM, Kouznetsov VV, Sortino MA, Alvarez SL, Zacchino SA (2008) In vitro antifungal activity of polyfunctionalized 2-(hetero) arylquinolines prepared through imino Diels-Alder reactions. Bioorg Med Chem 16(17):7908–7920

    Article  PubMed  Google Scholar 

  • Musiol R, Jampilek J, Buchta V, Silva L, Niedbala H, Podeszwa B, Palka A, Majerz-Maniecka K, Oleksyn B, Polanski J (2006) Antifungal properties of new series of quinoline derivatives. Bioorg Med Chem 14(10):3592–3598

    Article  CAS  PubMed  Google Scholar 

  • Oddy HG (1923) Some preparations from maleic and fumaric acids. J Am Chem Soc 45:2156–2160

    Article  CAS  Google Scholar 

  • Papa D, Schwenk E, Villani F, Klingsberg E (1948) beta-Aroylacrylic acids. J Am Chem Soc 70:3356–3360

    Article  CAS  PubMed  Google Scholar 

  • Pellerano C, Savini L, Massarelli P, Bruni G, Fiaschi AI (1990) New quinoline derivatives: synthesis and evaluation for antiinflammatory and analgesic properties. Farmacol 45(3):84–269

    Google Scholar 

  • Pillay P, Vleggaar R, Maharaj VJ, Smith PJ, Lategan CA, Choutaeu F, Chibale K (2007) Antiplasmodial hirsutinolides from Vernonia staehelinoides and their utilization towards a simplified pharmacophore. Phytochemistry 68(8):1200–1205

    Article  CAS  PubMed  Google Scholar 

  • Shenai BR, Sijwali PS, Singh A, Rosenthal PJ (2000) Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J Biol Chem 275(37):29000–29010

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge the University Grants Commission, Govt. of India, New Delhi for providing financial support (F. No. 36-110/2008 (SR)). We do not have any competing financial interests with regard to this work. We also thank DBT, Ministry of Science and Technology, Govt of India for providing Bioinformatics facility. The authors are thankful to NIMR, Dwarka for helping us in carrying out the falcipain-2 activity.

Author information

Authors and Affiliations

  1. Drug Design and Medicinal Chemistry Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, 110062, India

    Mymoona Akhter, Rikta Saha, Omprakash Tanwar, Md. Mumtaz Alam & M. S. Zaman

  2. Bioinformatics Facility, Jamia Hamdard, New Delhi, 110062, India

    Mymoona Akhter

Authors
  1. Mymoona Akhter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rikta Saha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Omprakash Tanwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Md. Mumtaz Alam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. S. Zaman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mymoona Akhter.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akhter, M., Saha, R., Tanwar, O. et al. Synthesis and antimalarial activity of quinoline-substituted furanone derivatives and their identification as selective falcipain-2 inhibitors. Med Chem Res 24, 879–890 (2015). https://doi.org/10.1007/s00044-014-1139-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-014-1139-1

Keywords

Search

Navigation