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Anti-Infective Agents

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ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

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Research Article

Design, Synthesis and Biological Profiling of Novel Phenothiazine Derivatives as Potent Antitubercular Agents

Author(s): Sushil K. Singh*, Gopal Nath, Ashok Kumar and Satheesh K. Sellamuthu

Volume 17, Issue 1, 2019

Page: [50 - 65] Pages: 16

DOI: 10.2174/2211352516666180730121013

Abstract

Background: Neuroleptic phenothiazines have been reported for antitubercular activity, but the unwanted side effect (antipsychotic activity) restricted their use as antitubercular drugs.

Objective: The study aimed to carry out development of phenothiazine based antitubercular agents by modifying/removing the chemical group(s)/ linker(s) of chlorpromazine essential for exerting an antipsychotic effect.

Methods: The designed molecules were filtered with a cut-off of docking score < 2.0 Kcal/mol against dopamine receptors, so that their binding with the receptor would be reduced to produce no/ less antipsychotic effect. The molecules were then synthesized and screened against M. tuberculosis H37Rv. They were further screened against a gram-positive (S. aureus) and a gram-negative (E. coli) bacterial strains to evaluate the spectrum of activity. The ability of the compounds to cross the blood-brain barrier (BBB) was also analyzed. The compounds were further examined for cytotoxicity (CC50) against mammalian VERO cells.

Results: Compounds 14p, 15p and 16p were found to be the most effective against all the strains viz. M. tuberculosis H37Rv, S. aureus and E. coli with MIC of 1.56µg/ml, 0.98µg/ml and 3.91µg/ml, respectively. Further, BBB permeability was found to be diminished in comparison to chlorpromazine, which would ultimately reduce the unwanted antipsychotic activity. They were also found to be free from toxicity against VERO cells.

Conclusion: The designed strategy, to enhance the antitubercular activity with concomitant reduction of dopamine receptor binding and BBB permeability was proved to be fruitful.

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

Graphical Abstract

[1]
Nguta, J.M.; Appiah-Opong, R.; Nyarko, A.K.; Yeboah-Manu, D.; Addo, P.G.A. Current perspectives in drug discovery against tuberculosis from natural products. Int. J. Mycobacteriol., 2015, 4(3), 165-183.
[2]
Lee, J.Y. Diagnosis and Treatment of Extrapulmonary Tuberculosis. Tuberculosis Res. Dis., 2015, 78(2), 47-55.
[3]
Organization, W.H. Global tuberculosis report 2016. 2016.
[4]
Martins, M.; Schelz, Z.; Martins, A.; Molnar, J.; Hajös, G.; Riedl, Z.; Viveiros, M.; Yalcin, I.; Aki-Sener, E.; Amaral, L. In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis. Int. J. Antimicrob. Agents, 2007, 29(3), 338-340.
[5]
Parrish, N.M.; Dick, J.D.; Bishai, W.R. Mechanisms of latency in Mycobacterium tuberculosis. Trends Microbiol., 1998, 6(3), 107-112.
[6]
Schaberg, T.; Bauer, T.; Castell, S.; Dalhoff, K.; Detjen, A.; Diel, R.; Greinert, U.; Hauer, B.; Lange, C.; Magdorf, K. Recommendations for therapy, chemoprevention and chemoprophylaxis of tuberculosis in adults and children. German Central Committee against Tuberculosis (DZK), German Respiratory Society (DGP) Pneumologie (Stuttgart, Germany), 2012, 66(3), 133-171.
[7]
Conover, M.S.; Hadjifrangiskou, M.; Palermo, J.J.; Hibbing, M.E.; Dodson, K.W.; Hultgren, S.J. Metabolic requirements of Escherichia coli in intracellular bacterial communities during urinary tract infection pathogenesis. MBio, 2016, 7(2), e00104-e00116.
[8]
Fellner, C. Companies Take Aim at MRSA Infections. Pharm. Therap., 2016, 41(2), 126.
[9]
Vesenbeckh, S.; Krieger, D.; Bettermann, G.; Schönfeld, N.; Bauer, T.T.; Rüssmann, H.; Mauch, H. Neuroleptic drugs in the treatment of tuberculosis: Minimal inhibitory concentrations of different phenothiazines against Mycobacterium tuberculosis. Tuberculosis, 2016, 98, 27-29.
[10]
Maitra, A.; Bates, S.; Kolvekar, T.; Devarajan, P.V.; Guzman, J.D.; Bhakta, S. Repurposing-a ray of hope in tackling extensively drug resistance in tuberculosis. Int. J. Infect. Dis., 2015, 32, 50-55.
[11]
Amaral, L.; Boeree, M.J.; Gillespie, S.H.; Udwadia, Z.F.; Van Soolingen, D. Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! Int. J. Antimicrob. Agents, 2010, 35(6), 524-526.
[12]
He, C-X.; Meng, H.; Zhang, X.; Cui, H-Q.; Yin, D-L. Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents. Chin. Chem. Lett., 2015, 26(8), 951-954.
[13]
Amaral, L.; Kristiansen, J.E.; Viveiros, M.; Atouguia, J. Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: A review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. J. Antimicrob. Chemother., 2001, 47(5), 505-511.
[14]
Feinberg, A.P.; Snyder, S.H. Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine. Proc. Natl. Acad. Sci. USA, 1975, 72(5), 1899-1903.
[15]
Jaszczyszyn, A.; Gąsiorowski, K.; Świątek, P.; Malinka, W.; Cieślik-Boczula, K.; Petrus, J.; Czarnik-Matusewicz, B. Chemical structure of phenothiazines and their biological activity. Pharmacol. Rep., 2012, 64(1), 16-23.
[16]
Madrid, P.B.; Polgar, W.E.; Toll, L.; Tanga, M.J. Synthesis and antitubercular activity of phenothiazines with reduced binding to dopamine and serotonin receptors. Bioorg. Med. Chem. Lett., 2007, 17(11), 3014-3017.
[17]
Kitchen, D.B.; Decornez, H.; Furr, J.R.; Bajorath, J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat. Rev. Drug Discov., 2004, 3(11), 935.
[18]
Satheeshkumar, S.; Amer, H.A.; Hojjat Ghasemi, G.; Gopal, N.; Sushil, K.S. Preliminary studies on ligand-based design and evaluation of new mycobacterial ATP synthase inhibitors. Curr. Drug Ther., 2018, 13(1), 56-73.
[19]
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.
[20]
Bharti, S.K.; Nath, G.; Tilak, R.; Singh, S. 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.
[21]
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.
[22]
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.
[23]
Hassan, F.; Abdul-Hameed, A.; Alshanon, A.; Abdullah, M.; Huri, H.Z.; Hairunisa, N.; Yousif, E. Antitumor activity for gold (III) complex by high content screening technique (HCS) and cell viability assay. Asian J. Biochem., 2015, 10(6), 252.
[24]
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.
[25]
Maghrabi, A.H.; McGuffin, L.J. ModFOLD6: An accurate web server for the global and local quality estimation of 3D protein models. Nucleic Acids Res., 2017, gkx332.
[26]
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-W372.
[27]
Satheeshkumar, S.; Mohammad Faizan, B.; Ashok, K.; Gopal, N.; Sushil Kumar, S. Design, Synthesis and biological evaluation of carbazole derivatives as antitubercular and antibacterial agents. Curr. Bioact. Compd., 2018, 14, 1-15.
[28]
Lovell, S.C.; Davis, I.W.; Arendall, W.B.; de Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Cα geometry: ϕ, ψ and Cβ deviation. Proteins: Str. Fun. Bioinform., 2003, 50(3), 437-450.
[29]
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. Crystallography., 1993, 26(2), 283-291.
[30]
Colovos, C.; Yeates, T.O. Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci., 1993, 2(9), 1511-1519.
[31]
Eisenberg, D.; Lüthy, R.; Bowie, J.U. VERIFY3D: Assessment of protein models with three-dimensional profiles. Methods Enzymol., 1997, 277, 396-404.
[32]
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.

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