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Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2985–2999 | Cite as

Design and synthesis of novel triazole linked pyrrole derivatives as potent Mycobacterium tuberculosis inhibitors

  • M. Lakshmi Devi
  • P. Lakshmi Reddy
  • P. Yogeeswari
  • D. Sriram
  • T. Veera Reddy
  • B. V. Subba Reddy
  • R. Narender
Original Research
  • 322 Downloads

Abstract

This research is focused on the rational approach to design and synthesis of a novel series of triazole linked pyrrole derivatives through a sequential Paal–Knorr reaction and Click chemistry. These new molecules were screened against Mycobacterium tuberculosis H37Rv and found to display promising anti-mycobacterial activity. Among various compounds, 7g and 7l were identified as leads with minimum inhibitory concentration value 0.78 (μg/mL), which are more effective than standard drugs such as pyrazinamide, ethambutol, and ciprofloxacin and less active than isoniazid and rifampicin. These molecules (minimum inhibitory concentration values <12.5 μg/mL) were also screened against HEK-293T cancer cell lines. Most of these molecules are less toxic but possess higher selectivity index, which indicates the suitability of these compounds for further evaluation.

Keywords

Antitubercular activity Stetter reaction Paal–Knorr synthesis Click chemistry Trisubstituted pyrrole derivatives 

Notes

Acknowledgements

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 also P.L.R. thankful to UGC, New Delhi, India for the financial support in the form of fellowships.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1997_MOESM1_ESM.doc (1.8 mb)
Supplementary Information

References

  1. Ackermann L, Potukuchi HK (2010) Regioselective syntheses of fully-substituted 1,2,3-triazoles: the CuAAC/C–H bond functionalization nexus. Org Biomol Chem 8:4503–4513CrossRefPubMedGoogle Scholar
  2. Antonino L, Riccardo D, Francesco M, Alessio T, Annamaria M, Giampaolo B, Anna Maria A (2014) 1,2,3-Triazole in heterocyclic compounds, endowed with biological activity, through 1,3-dipolar cycloadditions. Eur J Org Chem 16:3289–3306Google Scholar
  3. Bellina F, Rossi R (2006) Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions. Tetrahedron 62:7213–7256CrossRefGoogle Scholar
  4. Biava M, Porretta GC, Cappelli A, Vomero S, Manetti F, Botta M, Sautebin L, Rossi A, Makovec F, Anzini M (2005) 1,5-diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors. J Med Chem 48:3428–343CrossRefPubMedGoogle Scholar
  5. Biava M, Porretta GC, Poce G, De Logu A, Saddi M, Meleddu R, Manetti F, De Rossi E, Botta M (2008) 1,5-diphenylpyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings. J Med Chem 51:3644–3648CrossRefPubMedGoogle Scholar
  6. Boechat N, Ferreira VF, Ferreira SB, Ferreira MdeLG, da Silva FdeC, Bastos MM, Costa MdosS, Lourenço MCS, Pinto AC, Krettli AU, Aguiar A, Caroline Teixeira BM, da Silva NV, Martins PRC, Bezerra FAFM, Camilo ALS, da Silva GP, Costa Carolina CP (2011) Novel 1,2,3-triazole derivatives for use against mycobacterium tuberculosis H37Rv (ATCC 27294) strain. J Med Chem 54:5988–5999CrossRefPubMedGoogle Scholar
  7. Deepak KB, Garima K, Saqib K, Anil KT, Ramandeep S, Diwan SR (2014) Synthesis of novel 1,2,3-triazole derivatives of isoniazid and their in vitro and in vivo antimycobacterial activity evaluation. Eur J Med Chem 81:301–313CrossRefGoogle Scholar
  8. Deidda D, Lampis G, Fioravanti R, Biava M, Porretta GC, Zanett S, Pompei R (1998) Bactericidal activities of the pyrrole derivative BM212 against multidrug-resistant and intramacrophagic mycobacterium tuberculosis strains. Antimicrob Agents Chemother 42:3035–3037CrossRefPubMedPubMedCentralGoogle Scholar
  9. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Hernandez A, Degnan MT, Cook MB, Quenzer VK, Ferguson RM, Gilman RH (1998) Rapid, low-technology MIC determination with clinical mycobacterium tuberculosis isolates by using the microplate alamar blue assay. J Clin Microbiol 36:362–366PubMedPubMedCentralGoogle Scholar
  10. Gerlier D, Thomasset N (1986) Use of MTT colorimetric assay to measure cell activation. Immunol Methods 94:57–63CrossRefGoogle Scholar
  11. Jabeena K, Irfan H, Laxmi Gayatri J, Leela Prasad Y, Naresh N, Gousia C, Ajay M, Saxenab AK, Alamc MS, Qazic GN, Sampath Kumar HM (2014) Design and synthesis of novel 1,2,3-triazole derivatives of coronopilin as anti-cancer compounds. Eur J Med Chem 82:255–262CrossRefGoogle Scholar
  12. Ji L, Zhou GQ, Qian C, Chen XZ (2014) Synthesis of 1,2,3-triazoles from azide-derivatised aminocyclitols by catalytic diazo transfer and CuAAC click chemistry. Eur J Org Chem 2:3622–3636CrossRefGoogle Scholar
  13. Kamal A, Hussaini SMA, Faazil S, Poornachandra Y, Narender Reddy G, Ganesh Kumar C, Vikrant Singh R, Rani C, Rashmi S, Khan IA, Jagadeesh Babu N (2013) Anti-tubercular agents. Part 8: synthesis, antibacterial and antitubercular activity of 5-nitrofuran based 1,2,3-triazoles. Bioorg Med Chem Lett 23:6842–6846CrossRefPubMedGoogle Scholar
  14. Kavitha M, Suresh Kumar G, Amanda LH, Elizabeth SM, Minjia Z, Nagendra Rao S, Deviprasad RG, Barbara JM, Joanna BG, Gregory DC, Ian JG, Lizbeth H (2014) Repurposing cryptosporidium inosine 5′-monophosphate dehydrogenase inhibitors as potential antibacterial agents. ACS Med Chem Lett 5:846–850CrossRefGoogle Scholar
  15. Krystian P, Katarzyna K, Joanna D, Piotr P (2014) Structure and evaluation of antibacterial and antitubercular properties of new basic and heterocyclic 3-formylrifamycin SV derivatives obtained via ‘click chemistry’ approach. Eur J Med Chem 84:651–676CrossRefGoogle Scholar
  16. La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggier V, Sisinni L, Bolognesi A, Rensen WM, Miele A, Nalli M, Alfonsi R, Di Marcotullio L, Gulino A, Brancale A, Novellino E, Dondio G, Vultaggio S, Varasi M, Mercurio C, Hamel E, Lavia P, Silvestri R (2014) New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer. J Med Chem 57:6531–6552CrossRefPubMedPubMedCentralGoogle Scholar
  17. Marriner GA, Nayyar A, Eugene U, Wong SY, Mukherjee T, Via LE, Carroll M, Edwards RL, Gruber TD, Choi I, Lee J, Arora K, England KD, Boshoff HIM, Barry CE (2011) The medicinal chemistry of tuberculosis chemotherapy. Top Med Chem 7:47–124CrossRefGoogle Scholar
  18. Naresh S, Moni S, Chauhan PMS (2010) Recent advances in the design and synthesis of heterocycles as antitubercular agents. Future Med Chem 2:1469–1500CrossRefGoogle Scholar
  19. Nicolaou L, Demopoulos VJ (2003) Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides. J Med Chem 46:417–426CrossRefPubMedGoogle Scholar
  20. Ramachandrana R, Rania M, Senthana S, Jeong YT, Kabilana S (2011) Synthesis, spectral, crystal structure and in vitro antimicrobial evaluation of imidazole/benzotriazole substituted piperidin-4-one derivatives. Eur J Med Chem 46:1926–1934CrossRefGoogle Scholar
  21. Rangappa SK, Siddappa AP, Srinivasa B, Bhari MN (2015) Triazole: a promising antituburcular agent. Chem Biol Drug Des 86:410–423CrossRefGoogle Scholar
  22. Reddy PL, Kumar KP, Satyanarayana S, Narender R, Reddy BVS (2012) An efficient synthesis of 2-aryl-1,4-diketones via hydroacylation of enones. Tetrahedron Lett 53:1546–1549CrossRefGoogle Scholar
  23. Rogoza LN, Salakhutdinov NF, Tolstikov GA (2010) Antituberculosis activity of natural and synthetic compounds. Chem Sustain Dev 18:343–375Google Scholar
  24. Sandeep G, Mona S, Kumar GM, Kapil N, Raman G (2011) New drug regimens for old disease tuberculosis: a review. Int J Res Ayurv Pharm 2:126–131Google Scholar
  25. Shrinivas DJ, Uttam AM, Sheshagiri RD, Haresh HK, Tejraj MA, Aravind MB (2014) Synthesis, characterization, biological activity, and 3D-QSAR studies on some novel class of pyrrole derivatives as antitubercular agents. Med Chem Res 23:1123–1147CrossRefGoogle Scholar
  26. Gholap SS (2016) Pyrrole: an emerging scaffold for construction of valuable therapeutic agents. Eur J Med Chem 110:13–31CrossRefPubMedGoogle Scholar
  27. Thomas B, George D, Jyoti H (2014) Synthesis of pharmaceutically important 1,3,4-thiadiazole derivatives as antimicrobials. Res Rev J Chem 3:50–53Google Scholar
  28. Walsh CT, Garneau-Tsodikova S, Howard-Jones AR (2006) Biological formation of pyrroles: nature’s logic and enzymatic machinery. Nat Prod Rep 23:517–531CrossRefPubMedGoogle Scholar
  29. World Health Organization (2014) Global tuberculosis report (2014) WHO/HTM/TB/2014.08: WHOGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of ChemistryVikrama Simhapuri UniversityNelloreIndia
  2. 2.Crop Protection ChemicalsIndian Institute of Chemical TechnologyTarnakaIndia
  3. 3.Department of PharmacyBirla Institute of Technology & Science-PilaniHyderabad CampusIndia
  4. 4.Natural Product ChemistryIndian Institute of Chemical TechnologyTarnakaIndia

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