Abstract
Two series of novel and highly functionalised dispiropyrrolidines were synthesized using 1,3-dipolar cycloaddition reaction. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv using the Promega reagent BacTiter-Glo™ Microbial Cell Viability (BTG). Molecular docking analysis was carried out for the active compounds against the target enzyme enoyl-ACP reductase (InhA) to understand the possible binding mode. Of the 24 novel synthesized compounds, seven dispiropyrrolidines revealed inhibition with EC50 <25 µM. Compound 5b 7′-(4-chlorophenyl)-5′,6′,7′,7a′-tetrahydrodispiro[indan-2,5′-pyrrolo[1,2-c]-[1,3]thiazole-6′,2″-indan]-1,3,1″-trione was found to be the most active with EC50 of 10.52 µM, and was 2.2-fold more active than cycloserine. The docking result revealed that 5b had good affinity with the catalytic residues in InhA, forming hydrophobic and mild polar interactions with the important amino acids in the active site.
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Ali MA, Samy JG, Manogaran E, Sellappan V, Hasan MZ, Ahsan MJ, Pandian S, ShaharYar M (2009) Synthesis and antimycobacterial evaluation of novel 5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-indenyl-5,4-substituted phenyl methanone analogues. Bioorg Med Chem Lett 19(24):7000–7002
Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR Jr (1994) inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263(5144):227–230
Bellina F, Rossi R (2006) Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions. Tetrahedron 62(31):7213–7256
Brimble MA, Park JH, Taylor CM (2003) Synthesis of the spiroacetal fragment of broussonetine H. Tetrahedron 59(31):5861–5868
Cade CE, Dlouhy AC, Medzihradszky KF, Salas-Castillo SP, Ghiladi RA (2010) Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities. Protein Sci 19(3):458–474
Chiang C-Y, Centis R, Migliori GB (2010) Drug-resistant tuberculosis: past, present, future. Respirology 15(3):413–432
Collins L, Franzblau SG (1997) Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41(5):1004–1009
Crooks PA, Rosenberg HE (1978) Synthesis of spiro[tetralin-2,2′-pyrrolidine] and spiro[indan-2,2′-pyrrolidine] derivatives as potential analgesics. J Med Chem 21(6):585–587
He X, Alian A, Stroud R, Ortiz de Montellano PR (2006) Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem 49(21):6308–6323
He X, Alian A, Ortiz de Montellano PR (2007) Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg Med Chem 15(21):6649–6658
Introduction (2008). Tuberculosis 88 (2):85–86
Kuo MR, Morbidoni HR, Alland D, Sneddon SF, Gourlie BB, Staveski MM, Leonard M, Gregory JS, Janjigian AD, Yee C, Musser JM, Kreiswirth B, Iwamoto H, Perozzo R, Jacobs WR, Sacchettini JC, Fidock DA (2003) Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data. J Biol Chem 278(23):20851–20859
Lawn SD, Zumla AI (2011) Tuberculosis. Lancet 378(9785):57–72
Mitchison DA (2000) Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 4(9):796–806
Musser JM, Kapur V, Williams DL, Kreiswirth BN, van Soolingen D, van Embden JDA (1996) Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance. J Infect Dis 173(1):196–202
Pawlowski A, Jansson M, Sköld M, Rottenberg ME, Källenius G (2012) Tuberculosis and HIV co-infection. PLoS Pathog 8(2):e1002464
Pellegrini C, Weber M, Borschberg H-J (1996) Total synthesis of (+)-elacomine and (−)-isoelacomine, two hitherto unnamed oxindole alkaloids from Elaeagnus commutata. Helv Chim Acta 79(1):151–168
Stylianakis I, Kolocouris A, Kolocouris N, Fytas G, Foscolos GB, Padalko E, Neyts J, De Clercq E (2003) Spiro[pyrrolidine-2,2′-adamantanes]: synthesis, anti-influenza virus activity and conformational properties. Bioorg Med Chem Lett 13(10):1699–1703
Timmins GS, Deretic V (2006) Mechanisms of action of isoniazid. Mol Microbiol 62(5):1220–1227
Tsuge O, Kanemasa S (1989) Recent advances in azomethine ylide chemistry. In: Alan RK (ed) Advances in heterocyclic chemistry, vol 45. Academic Press, New York, pp 231–349
Usui T, Kondoh M, Cui CB, Mayumi T, Osada H (1998) Tryprostatin A, a specific and novel inhibitor of microtubule assembly. Biochem J 333(3):543–548
Wei AC, Ali MA, Choon TS, Quah CK, Fun H-K (2011) 7′-Phenyl-5′,6′,7′,7a′-tetrahydrodipiro[indan-2,5′-pyrrolo[1,2-c][1,3]thiazole-6′,2″-indan]-1,3,1″-trione. Acta Crystallographica Section E 67(12):o3218–o3219
Wei AC, Ali MA, Choon TS, Arshad S, Razak IA (2012a) 7′-Phenyl-1′,3′,5′,6′,7′,7a′-hexahydrodipiro[acenaphthylene-1,5′-pyrrolo[1,2-c]thiazole-6′,2″-indane]-2,1″(1H)-dione. Acta Crystallogr Sect E 68(4):o1265–o1266
Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS, Arumugam N, Almansour AI, Osman H (2012b) Antimycobacterial activity: a facile three-component [3 + 2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines. Bioorg Med Chem Lett 22(15):4930–4933
Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS (2013) A facile three-component [3 + 2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents. Bioorg Med Chem Lett 23(5):1383–1386
WHO (2013) Global tuberculosis report
Yuroff A, Fan F, Butler B, Collins M (2008) Application of the BacTiter-Glo™ assay for rapid enumeration and screening of antimicrobial compounds for mycobacterium avium complex bacteria. Promega Notes 98:8–10
Zhang Y (2005) The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol 45:529–564
Zhang Y, Heym B, Allen B, Young D, Cole S (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358(6387):591–593
Acknowledgments
The authors wish to express their thanks to Pharmacogenetic and Novel Therapeutic Research, Institute for Research in Molecular Medicine, Universiti of Sains Malaysia, Penang for the research facilities. This work was supported by National Institutes of Health and the National Institute of Allergy and Infectious Diseases, Contract No. HHSN272201100012I for the biological evaluation. The funding of this project was through Research Grant No. RUC (1001/PSK/8620012) and RU 1001/PKIMIA/811221.
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Wei, A.C., Ali, M.A., Yoon, Y.K. et al. Antimycobacterial activity and in silico study of highly functionalised dispiropyrrolidines. Med Chem Res 24, 818–828 (2015). https://doi.org/10.1007/s00044-014-1181-z
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DOI: https://doi.org/10.1007/s00044-014-1181-z