Design and synthesis of novel triazole linked pyrrole derivatives as potent Mycobacterium tuberculosis inhibitors
- 322 Downloads
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.
KeywordsAntitubercular activity Stetter reaction Paal–Knorr synthesis Click chemistry Trisubstituted pyrrole derivatives
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Rogoza LN, Salakhutdinov NF, Tolstikov GA (2010) Antituberculosis activity of natural and synthetic compounds. Chem Sustain Dev 18:343–375Google Scholar
- 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
- 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
- World Health Organization (2014) Global tuberculosis report (2014) WHO/HTM/TB/2014.08: WHOGoogle Scholar