Design, Synthesis and Biological Evaluation of Carbazole Derivatives as Antitubercular and Antibacterial Agents

Author(s): Satheeshkumar Sellamuthu, Mohammad F. Bhat, Ashok Kumar, Gopal Nath, Sushil K. Singh*.

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 1 , 2019

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Abstract:

Background: The neuroleptic chlorpromazine has been reported for antitubercular activity but the associated antipsychotic activity restricted its clinical presentation.

Objectives: Novel derivatives of carbazole having structural similarity with chlorpromazine were designed, in an attempt to reduce the associated side effects, while retaining the antitubercular activity.

Materials and Methods: The designed molecules were synthesized and screened for antitubercular and antibacterial activities. The blood-brain barrier (BBB) permeability and mammalian cell (VERO) cytotoxicity (CC50) were examined to determine the safety of compounds.

Results: Among the developed compounds, 14c, 15c, 16c and 17c were found to be promising against Mtb H37Rv at MIC of 1.56 µg/ml. They were also effective against S. aureus and E. coli at MIC of 0.98 and 7.81 µg/ml, respectively. The BBB permeability of the compounds was found to be less than chlorpromazine. Therefore, the developed compounds are expected to have diminished antipsychotic effect. The compounds were further marked safe against mammalian VERO cells at CC50 > 90 µg/ml.

Conclusion: The profound antitubercular activity with a concomitant reduction in BBB permeability of carbazole derivatives can pave new vista in the discovery of antitubercular drugs.

Keywords: Antibacterial, antitubercular, BBB permeability, carbazole, cytotoxicity, molecular property, OSIRIS DataWarrior.

[1]
Organization, W.H. Global tuberculosis report 2016. 2016. [Accessed on Jan 18, 2018].
[2]
Falzon, D.; Schünemann, H.J.; Harausz, E.; González-Angulo, L.; Lienhardt, C.; Jaramillo, E.; Weyer, K. World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update. Eur. Respir. J., 2017, 49(3), 1602308.
[3]
Schito, M.; Hanna, D.; Zumla, A. Tuberculosis eradication versus control. Int. J. Infect. Dis., 2017, 56, 10-13.
[4]
Kumar, A.; Chettiar, S.; Parish, T. Current challenges in drug discovery for tuberculosis. Expert Opin. Drug Discov., 2017, 12(1), 1-4.
[5]
Jerome, G.; Frederic, L.M.; Nacer, L.; Wendy, B.; Anil, K.; Koen, A. New Anti-Tuberculosis Drugs in Clinical Development: An Overview. Curr. Bioact. Compd., 2009, 5(2), 137-154.
[6]
Chong, C.R.; Sullivan, D.J. New uses for old drugs. Nature, 2007, 448(7154), 645-646.
[7]
Tiberi, S.; Buchanan, R.; Caminero, J.A.; Centis, R.; Arbex, M.A.; Salazar, M.; Potter, J.; Migliori, G.B. The challenge of the new tuberculosis drugs. Presse Med., 2017, 46(2 Pt 2), e41-e51.
[8]
Scalacci, N.; Brown, A.K.; Pavan, F.R.; Ribeiro, C.M.; Manetti, F.; Bhakta, S.; Maitra, A.; Smith, D.L.; Petricci, E.; Castagnolo, D. Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis. Eur. J. Med. Chem., 2017, 127, 147-158.
[9]
Crowle, A.J.; Douvas, G.S.; May, M.H. Chlorpromazine: a drug potentially useful for treating mycobacterial infections. Chemotherapy, 1992, 38(6), 410-419.
[10]
Ma, C.; Case, R.J.; Wang, Y.; Zhang, H-J.; Tan, G.T.; Van Hung, N.; Cuong, N.M.; Franzblau, S.G.; Soejarto, D.D.; Fong, H.H.; Pauli, G.F. Anti-tuberculosis constituents from the stem bark of Micromelum hirsutum. Planta Med., 2005, 71(3), 261-267.
[11]
Choi, T.A.; Czerwonka, R.; Fröhner, W.; Krahl, M.P.; Reddy, K.R.; Franzblau, S.G.; Knölker, H.J. Synthesis and activity of carbazole derivatives against Mycobacterium tuberculosis. ChemMedChem, 2006, 1(8), 812-815.
[12]
Lourenço, M.C.; de Souza, M.V.; Pinheiro, A.C.; Ferreira, M.L.; Gonçalves, R.S.; Nogueira, T.C.M.; Peralta, M.A. Evaluation of anti-tubercular activity of nicotinic and isoniazid analogues. ARKIVOC, 2007, 15, 181-191.
[13]
Bharti, S.K.; Nath, G.; Tilak, R.; Singh, S.K. Synthesis, anti-bacterial and anti-fungal activities of some novel Schiff bases containing 2,4-disubstituted thiazole ring. Eur. J. Med. Chem., 2010, 45(2), 651-660.
[14]
Chabukswar, A.; Kuchekar, B.; Lokhande, P.; Tryambake, M.; Pagare, B.; Kadam, V.; Jagdale, S.; Chabukswar, V. Design, Synthesis and Evaluation of Antibacterial Activity of Novel Indazole Derivatives. Curr. Bioact. Compd., 2013, 9(4), 263-269.
[15]
Di, L.; Kerns, E.H.; Fan, K.; McConnell, O.J.; Carter, G.T. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem., 2003, 38(3), 223-232.
[16]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[17]
Sander, T.; Freyss, J.; von Korff, M.; Reich, J.R.; Rufener, C. OSIRIS, an entirely in-house developed drug discovery informatics system. J. Chem. Inf. Model., 2009, 49(2), 232-246.
[18]
Maghrabi, A.H.A.; McGuffin, L.J. ModFOLD6: an accurate web server for the global and local quality estimation of 3D protein models. Nucleic Acids Res., 2017, 45(W1), W416-W421.
[19]
McGuffin, L.J.; Buenavista, M.T.; Roche, D.B. The ModFOLD4 server for the quality assessment of 3D protein models. Nucleic Acids Res., 2013, 41(W1), W368-W72.
[20]
Laskowski, R.A.; MacArthur, M.W.; Moss, D.S.; Thornton, J.M. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Cryst., 1993, 26(2), 283-291.
[21]
Lovell, S.C.; Davis, I.W.; Arendall, W.B., III; de Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Cα ϕ ϕ,ψ and Cβ deviation. Proteins, 2003, 50(3), 437-450.
[22]
Eisenberg, D.; Lüthy, R.; Bowie, J.U. VERIFY3D: Assessment of protein models with three-dimensional profiles. Methods Enzymol., 1997, 277, 396-404.
[23]
Colovos, C.; Yeates, T.O. Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci., 1993, 2(9), 1511-1519.
[24]
Shen, J.; Zhang, W.; Fang, H.; Perkins, R.; Tong, W.; Hong, H. Homology modeling, molecular docking, and molecular dynamics simulations elucidated α-fetoprotein binding modes. BMC Bioinformatics, 2013, 14(14), S6.
[25]
Styczynski, M.P.; Jensen, K.L.; Rigoutsos, I.; Stephanopoulos, G. BLOSUM62 miscalculations improve search performance. Nat. Biotechnol., 2008, 26(3), 274-275.
[26]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[27]
Munoz-Bellido, J.L.; Munoz-Criado, S.; Garcìa-Rodrìguez, J.A. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. Int. J. Antimicrob. Agents, 2000, 14(3), 177-180.
[28]
Gautam, N.; Guleria, A.; Sharma, M.K.; Gupta, S.K.; Goyal, A.; Gautam, D.C. Synthesis and Biological Evaluation of Some Novel 10H-Phenothiazines, their Sulfones and Nucleosides as Possible Antimicrobial Agents. Curr. Bioact. Compd., 2014, 10(3), 189-195.
[29]
Sellamuthu, S.; Bhat, M.; Kumar, A.; Singh, S. Phenothiazine: A better Scaffold against Tuberculosis. Mini Rev. Med. Chem., 2018, 18(17), 1442-1451.
[30]
Sellamuthu, S.; Singh, M.; Kumar, A.; Singh, S.K. Type-II NADH Dehydrogenase (NDH-2): A promising therapeutic target for antitubercular and antibacterial drug discovery. Expert Opin. Ther. Targets, 2017, 21(6), 559-570.


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Article Details

VOLUME: 15
ISSUE: 1
Year: 2019
Page: [83 - 97]
Pages: 15
DOI: 10.2174/1573407214666180226125501
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