Skip to main content
SpringerLink
Log in

Rational design, synthesis and evaluation of novel-substituted 1,2,3-triazolylmethyl carbazoles as potent inhibitors of Mycobacterium tuberculosis

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

Abstract

Herein, we describe synthesis and antitubercular evaluation of novel-substituted 1,2,3-triazolylmethyl carbazoles rationally designed by incorporating two pharmacophoric heterocycles, viz. carbazole and triazole in one molecular frame. The new compounds 4a–z and 4aa–ac were obtained in very good yields using copper-catalysed Huisgen [3 + 2] cycloaddition reaction of 9-propynyl-9H-carbazole (2) with various aryl/alkyl azides 3a–z and 3aa–ac. Evaluation of all 29 new analogues for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) resulted two compounds 4x and 4z (MIC: 6.25 μg/mL) as most promising antitubercular agents with low cytotoxicity.

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
Fig. 2
Fig. 3
Scheme1
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abubakar I, Zignol M, Falzon D, Raviglione M, Ditiu L, Masham S, Adetifa I, Ford N, Cox H, Lawn SD, Marais BJ, McHugh TD, Mwaba P, Bates M, Lipman M, Zijenah L, Logan S, McNerney R, Zumla A, Sarda K, Nahid P, Hoelscher M, Pletschette M, Memish ZA, Kim P, Hafner R, Cole S, Migliori GB, Maeurer M, Schito M, Zumla A (2013) Drug-resistant tuberculosis: time for visionary political leadership. Lancet Infect Dis 13:529–539

    Article  PubMed  Google Scholar 

  • Addla D, Jallapally A, Gurram D, Yogeeswari P, Sriram D, Kantevari S (2014) Rational design, synthesis and antitubercular evaluation of novel 2-(trifluoromethyl)phenothiazine-[1,2,3]triazole hybrids. Bioorg Med Chem Lett 24:233–236

    Article  CAS  PubMed  Google Scholar 

  • Agalave SG, Maujan SR, Pore VS (2011) Click chemistry: 1,2,3-triazoles as pharmacophores. Chem Asian J 6:2696–2718

    Article  CAS  PubMed  Google Scholar 

  • Berg R, Straub BF (2013) Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition. Beilstein J Org Chem 9:2715–2750

    Article  PubMed Central  PubMed  Google Scholar 

  • Boechat N, Ferreira VF, Ferreira SB, de Lourdes G, Ferreira M, de da Silva CF, Bastos MM, Dos S, Costa M, Lourenço MC, Pinto AC, Krettli AU, Aguiar AC, Teixeira BM, da Silva NV, Martins PR, Bezerra FA, Camilo AL, da Silva GP, Costa CC (2011) Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. J Med Chem 54:5988–5999

    Article  CAS  PubMed  Google Scholar 

  • Choi TA, Czerwonka R, Fröhner W, Krahl MP, Reddy KR, Franzblau SG, Knölker HJ (2006) Synthesis and activity of carbazole derivatives against Mycobacterium tuberculosis. Chem Med Chem 1:812–815

    Article  CAS  PubMed  Google Scholar 

  • Daley CL, Caminero JA (2013) Management of multidrug resistant tuberculosis. Semin Respir Crit Care Med 34:44–59

    Article  PubMed  Google Scholar 

  • Dash M (2013) Drug resistant tuberculosis: a diagnostic challenge. Postgrad Med 59:196–202

    Article  CAS  Google Scholar 

  • García A, Bocanegra-García V, Palma-Nicolás JP, Rivera G (2012) Recent advances in antitubercular natural products. Eur J Med Chem 49:1–23

    Article  PubMed  Google Scholar 

  • Ghodbane R, Drancourt MR (2013) Non-human sources of Mycobacterium tuberculosis. Tuberculosis 93:589–595

    Article  PubMed  Google Scholar 

  • Gonzaga DT, da Rocha DR, de da Silva CF, Ferreira VF (2013) Recent advances in the synthesis of new antimycobacterial agents based on the 1H–1,2,3-triazoles. Curr Top Med Chem 13:2850–2865

    Article  CAS  PubMed  Google Scholar 

  • Hai-Bin Z, Guan-Sai L, Zhu-Jun Y (2007) Short and efficient total synthesis of luotonin A and 22-hydroxyacuminatine using a common cascade strategy. J Org Chem 72:6270–6272

    Article  Google Scholar 

  • Isaakidis P, Rangan S, Pradhan A, Ladomirska J, Reid T, Kielmann K (2013) ‘I cry every day’: experiences of patients co-infected with HIV and multidrug-resistant tuberculosis. Trop Med Int Health 18:1128–1133

    Article  PubMed  Google Scholar 

  • Kantevari S, Yempala T, Surineni G, Sridhar B, Yogeeswari P, Sriram D (2011) Synthesis and antitubercular evaluation of novel dibenzo[b, d]furan and 9-methyl-9H-carbazole derived hexahydro-2H-pyrano[3,2-c] quinolines via povarov reaction. Eur J Med Chem 46:4827–4833

    Article  CAS  PubMed  Google Scholar 

  • Kharaneko OI, Shishkina SV, Shishkin OV, Kibalnyi AV, Dulenko VI (2004) Concerting the product of [2 + 2] cyclodimerization of 9-allenyl carbazole. Chem Heterocycl Comp 40:1427–1434

    Article  CAS  Google Scholar 

  • Knölker HJ, Reddy KR (2008) Chemistry and biology of carbazole alkaloids. Alkaloids Chem Biol 65:1–410

    Article  PubMed  Google Scholar 

  • Kolb HC, Sharpless KB (2003) The growing impact of click chemistry on drug discovery. Drug Discov Today 8:1128–1137

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Kumar AM, Gupta D, Kanchar A, Mohammed S, Srinath S, Tripathy S, Rajasekaran S, Chan PL, Swaminathan S, Dewan PK (2012) Global guidelines for treatment of tuberculosis among persons living with HIV: unresolved issues. Int J Tuberc Lung Dis 16:573–578

    Article  CAS  PubMed  Google Scholar 

  • Lawn SD, Mwaba P, Bates M, Piatek A, Alexander H, Marais BJ, Cuevas LE, McHugh TD, Zijenah L, Kapata N, Abubakar I, McNerney R, Hoelscher M, Memish ZA, Migliori GB, Kim P, Maeurer M, Schito M, Zumla A (2013) Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 13:349–361

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Chen C, He W, Huang P, Liu M, Wang Q, Guo H, Bolla K, Lu Y, Song F, Dai H, Liu M, Zhang L (2012) Exploring anti-TB leads from natural products library originated from marine microbes and medicinal plants. Antonie Van Leeuwenhoek 102:447–461

    Article  CAS  PubMed  Google Scholar 

  • Ma C, Case RJ, Wang Y, Zhang HJ, Tan GT, Van Hung N, Cuong NM, Franzblau SG, Soejarto DD, Fong HH, Pauli GF (2005) Anti-tuberculosis constituents from the stem bark of Micromelum hirsutum. Planta Med 71:261–267

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nathan C (2014) Drug-resistant tuberculosis: a new shot on goal. Nat Med 20:121–123

    Article  CAS  PubMed  Google Scholar 

  • Ngo LT, Okogun JI, Folk WR (2013) 21st Century natural product research and drug development and traditional medicines. Nat Prod Rep 30:584–592

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Okunade AL, Elvin-Lewis MP, Lewis WH (2004) Natural antimycobacterial metabolites: current status. Phyto chemistry 65:1017–1032

    CAS  Google Scholar 

  • Patpi SR, Pulipati L, Yogeeswari P, Sriram D, Jain N, Sridhar B, Murthy R, Anjana Devi T, Kalivendi SV, Kantevari S (2012) Design, synthesis and structure–activity correlations of novel dibenzo[b, d]furan, dibenzo[b, d]thiophene and N-methyl carbazole clubbed 1,2,3-triazoles as potent inhibitors of Mycobacterium tuberculosis. J Med Chem 55:3911–3922

    Article  CAS  PubMed  Google Scholar 

  • Putapatri SR, Kanwal A, Banerjee SK, Kantevari S (2014) Synthesis of novel l-rhamnose derived acyclic C-nucleosides with substituted 1,2,3-triazole core as potent sodium-glucose co-transporter (SGLT) inhibitor. Bioorg Med Chem Lett 24:1528–1531

    Article  CAS  PubMed  Google Scholar 

  • Salomon CE, Schmidt LE (2012) Natural products as leads for tuberculosis drug development. Curr Top Med Chem 12:735–765

    Article  CAS  PubMed  Google Scholar 

  • Schmidt AW, Reddy KR, Knölker HJ (2012) Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem Rev 112:3193–3228

    Article  CAS  PubMed  Google Scholar 

  • Swaminathan S, Narendran G, Venkatesan P, Iliayas S, Santhanakrishnan R, Menon PA, Padmapriyadarsini C, Ramachandran R, Chinnaiyan P, Suhadev M, Sakthivel R, Narayanan PR (2010) Efficacy of a 6 month versus 9 month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial. Am J Respir Crit Care Med 181:743–751

    Article  PubMed  Google Scholar 

  • Thirumurugan P, Matosiuk D, Jozwiak K (2013) Click chemistry for drug development and diverse chemical-biology applications. Chem Rev 113:4905–4979

    Article  CAS  PubMed  Google Scholar 

  • Vainio MJ, Kogej T, Raubacher F, Sadowski J (2013) Scaffold hopping by fragment replacement. J Chem Inf Mod 53:1825–1835

    Article  CAS  Google Scholar 

  • Yempala T, Sridevi JP, Yogeeswari P, Sriram D, Kantevari S (2013) Design, synthesis and antitubercular evaluation of novel 2-substituted-3H-benzofuro benzofurans via palladium-copper catalysed Sonagashira coupling reaction. Bioorg Med Chem Lett 23:5393–5936

    Article  CAS  PubMed  Google Scholar 

  • Yempala T, Sridevi JP, Yogeeswari P, Sriram D, Kantevari S (2014) Rational design and synthesis of novel dibenzo[b, d]furan-1,2,3-triazole conjugates as potent inhibitors of Mycobacterium tuberculosis. Eur J Med Chem 71:160–167

    Article  CAS  PubMed  Google Scholar 

  • Zhou B, He Y, Zhang X, Xu J, Luo Y, Wang Y, Franzblau SG, Yang Z, Chan RJ, Liu Y, Zheng J, Zhang ZY (2010) Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proc Natl Aca Sci 107:4573–4578

    Article  CAS  Google Scholar 

  • Zumla A, George A, Sharma V, Herbert N, Baroness MI (2013a) WHO’s 2013 global report on tuberculosis: successes, threats, and opportunities. Lancet 382:1765–1767

    Article  PubMed  Google Scholar 

  • Zumla A, Raviglione M, Hafner R, von Reyn CF (2013b) Tuberculosis. New Engl J Med 368:745–755

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are thankful to Dr. Lakshmi Kantham, Director and Dr. V. Jayathirtha Rao, Head, Crop Protection Chemicals Division, CSIR-IICT, Hyderabad, INDIA for their continuous encouragement, support and financial assistance through CSIR-12th FYP Projects (ORIGIN, CSC0108; DENOVA, CSC0205 and INTELCOAT, CSC0114). GS is thankful to UGC for Granting SRF.

Author information

Authors and Affiliations

  1. Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, Telangana, India

    Goverdhan Surineni & Srinivas Kantevari

  2. Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, 500 078, Telangana, India

    Perumal Yogeeswari & Dharmarajan Sriram

  3. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, Telangana, India

    Srinivas Kantevari

Authors
  1. Goverdhan Surineni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Perumal Yogeeswari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dharmarajan Sriram
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Srinivas Kantevari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Srinivas Kantevari.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2496 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Surineni, G., Yogeeswari, P., Sriram, D. et al. Rational design, synthesis and evaluation of novel-substituted 1,2,3-triazolylmethyl carbazoles as potent inhibitors of Mycobacterium tuberculosis . Med Chem Res 24, 1298–1309 (2015). https://doi.org/10.1007/s00044-014-1210-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-014-1210-y

Keywords

Search

Navigation