Generic placeholder image

Current Bioactive Compounds


ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

General Research Article

Synthesis, Antitubercular Activity, Molecular Modeling and Docking Studies of Novel Thiazolidin-4-One Linked Dinitrobenzamide Derivatives

Author(s): Karanveer Singh, Manish Sinha*, Shruti Kuletha, Baljeet Kaur , Amandeep Kaur , Dinesh K. Tripathi, Kishore K. Srivastava, Vanangamudi Murugesan, Rajala Srikala and Amrendra K. Chaudhary

Volume 16 , Issue 1 , 2020

Page: [64 - 71] Pages: 8

DOI: 10.2174/1573407214666180720150009

Price: $65


Background: Tuberculosis is a catastrophe sprawled across the world. The World Health Organization Global Tuberculosis Report 2017 inferred that there were an estimated 10.4 million people suffered from tuberculosis including 490000 Multidrug-Resistant TB (MDR-TB) cases. Several new lead molecules like dinitrobenzamide derivatives were found to be highly active against multidrugresistant strains of M. tuberculosis. To further explore the pharmacophoric space around the dinitobenzamide moiety, a series of compounds have been synthesized by linking it with the thiazolidin- 4-one. The presented work is an effort to study the biological effect of thiazolidin-4-one scaffold on dinitrobenzamide derivatives as antitubercular agents. A molecular modeling study was also performed on the synthesized molecules to reveal the requirements for further lead optimization.

Methods: The thiazolidin-4-one linked 3,5-dinitrobenzamide derivatives have been synthesized by onepot three-component condensation reaction of an amine, substituted aldehydes and thioglycolic acid in presence of N, N'-Dicyclohexylcarbodiimide (DCC). These compounds were evaluated against Mycobacterium tuberculosis H37Ra. A pharmacophore modeling approach has been used in order to explore the collection of possible pharmacophore queries of thiazolidin-4-one linked 3, 5-dinitrobenzamide derivatives against M. tuberculosis. The synthesized compounds were docked on to the M. tuberculosis DprE1 enzyme to identify the structural features requirement of these analogs against this potential target of M. tuberculosis.

Results: The synthesized compounds showed the antitubercular activity in the range of 6.25-50 μg/ml. The pharmacophore modeling suggests that the presence of aromatic moiety, thiazolidin-4-one ring and one of the nitro groups are significant for inhibiting the enzymatic activity. While docking studies showed that hydrophobic and hydrogen bond interactions of the aromatic moiety and nitro group crucial to inactivate the DprE1 enzyme.

Conclusion: The study showed that the linking of thiazolidin-4-one with dinitrobenzamide leads to compounds active against M. tuberculosis. These findings also suggested that further lead optimization would be carried out by focusing on the aromatic system along with electron-rich substituents placed on the thiazolidin-4-one for making better hydrophobic and hydrogen bond interactions with the DprE1 target.

Keywords: Thiazolidin-4-one, 3, 5-dinitrobenzamide derivatives, tuberculosis, synthesis, molecular modeling, docking.

Graphical Abstract
Dover, L.G.; Coxon, G.D. Current status and research strategies in tuberculosis drug development. J. Med. Chem., 2011, 54(18), 6157-6165.
[] [PMID: 21823589]
World Health Organization. Global Tuberculosis Report, 2017.
Ventura, T.L.B.; Silva, D.R.C.; Lassounskaia, E.; Maria, E.J.; Muzitano, M.F.; Oliveira, R.R. de Coumarine analogues with antimycobacterial and immunomodulatory activity. Curr. Bioact. Compd., 2015, 11(2), 109-115.
Ruchita, P.D.; Nanda, S.; Mathur, A. Novel isonicotinic acid analogs: synthesis, characterization, antibacterial and antimycobacterial (In vitro and In vivo) activity against sensitive and resistant strains. Curr. Bioact. Compd., 13(999), 1-12.
Bendagude, R.D.; Kondawar, M.S. Synthesis and molecular modeling studies of novel 2,4-Disubstituted-1, 5-diphenyl-1-h-imidazole derivatives as potential anti-tubercular agents. Curr. Bioact. Compd., 2017, 13(3), 244-258.
Panda, G.; Parai, M.K.; Das, S.K.; Shagufta, ; Sinha, M.; Chaturvedi, V.; Srivastava, A.K.; Manju, Y.S.; Gaikwad, A.N.; Sinha, S. Effect of substituents on diarylmethanes for antitubercular activity. Eur. J. Med. Chem., 2007, 42(3), 410-419.
[] [PMID: 17112639]
Ngo, H.X.; Green, K.D.; Gajadeera, C.S.; Willby, M.J.; Holbrook, S.Y.L.; Hou, C.; Garzan, A.; Mayhoub, A.S.; Posey, J.E.; Tsodikov, O.V.; Garneau-Tsodikova, S. Potent 1,2,4-Triazino[5,6 b]indole-3-thioether inhibitors of the kanamycin resistance enzyme eis from Mycobacterium tuberculosis. ACS Infect. Dis., 2018, 4(6), 1030-1040.
[] [PMID: 29601176]
Spain, M.; Wong, J.K-H.; Nagalingam, G.; Batten, J.M.; Hortle, E.; Oehlers, S.H.; Jiang, X.F.; Murage, H.E.; Orford, J.T.; Crisologo, P.; Triccas, J.A.; Rutledge, P.J.; Todd, M.H. Antitubercular bis-substituted Cyclam derivatives: Structure-activity relationships and in vivo studies. J. Med. Chem., 2018, 61(8), 3595-3608.
[] [PMID: 29558124]
Dawadi, S.; Boshoff, H.I.M.; Park, S.W.; Schnappinger, D.; Aldrich, C.C. Conformationally constrained cinnolinone nucleoside analogues as siderophore biosynthesis inhibitors for tuberculosis. ACS Med. Chem. Lett., 2018, 9(4), 386-391.
[] [PMID: 29670706]
(a) Christophe, T.; Jackson, M.; Jeon, H.K.; Fenistein, D.; Contreras-Dominguez, M.; Kim, J.; Genovesio, A.; Carralot, J.P.; Ewann, F.; Kim, E.H.; Lee, S.Y.; Kang, S.; Seo, M.J.; Park, E.J.; Skovierová, H.; Pham, H.; Riccardi, G.; Nam, J.Y.; Marsollier, L.; Kempf, M.; Joly-Guillou, M.L.; Oh, T.; Shin, W.K.; No, Z.; Nehrbass, U.; Brosch, R.; Cole, S.T.; Brodin, P. High content screening identifies decaprenyl-phosphoribose 2′ epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog., 2009, 5(10) e1000645
[] [PMID: 19876393]
(b) Brodin, P.; Christophe, T. High-content screening in infectious diseases. Curr. Opin. Chem. Biol., 2011, 15(4), 534-539.
[] [PMID: 21684803]
Wolucka, B.A. Biosynthesis of D-arabinose in mycobacteria - a novel bacterial pathway with implications for antimycobacterial therapy. FEBS J., 2008, 275(11), 2691-2711.
[] [PMID: 18422659]
Slepikas, L.; Chiriano, G.; Perozzo, R.; Tardy, S.; Kranjc, A.; Patthey-Vuadens, O.; Ouertatani-Sakouhi, H.; Kicka, S.; Harrison, C.F.; Scrignari, T.; Perron, K.; Hilbi, H.; Soldati, T.; Cosson, P.; Tarasevicius, E.; Scapozza, L.1. Perozzo, R.; Tardy, S.; Kranjc, A.; Patthey-Vuadens, O.; Ouertatani-Sakouhi, H.; Kicka, S.; Harrison, C.F.; Scrignari, T.; Perron, K.; Hilbi, H.; Soldati, T.; Cosson, P.; Tarasevicius, E.; Scapozza, L. In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA. J. Med. Chem., 2016, 59(24), 10917-10928.
[] [PMID: 26730986]
Samadhiya, P.; Sharma, R.; Srivastava, S.K.; Srivastava, S.D. Synthesis and biological evaluation of 4-thiazolidinone derivatives as antitubercular and antimicrobial agents. Arab. J. Chem., 2014, 7, 657-665.
Gomes, C.R.B.; Moreth, M.; Facchinetti, V.; de Souza, M.V.N.; Vellasco, W.T. Junior; Lourenco, M.C.S.; Cunico, W. Synthesis and antimycobacterial activity of 2-aryl-3-(arylmethyl)-1,3-thiazolidin-4-ones. Lett. Drug Des. Discov., 2010, 7(5), 353-358.
Molecular Operating Environment (MOE)2015.1001; Chemical Computing Group Inc; 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7. , 2017.
Langer, T.; Hoffmann, R.D. Pharmacophore modelling: applications in drug discovery. Expert Opin. Drug Discov., 2006, 1(3), 261-267.
[] [PMID: 23495846]
Makarov, V.; Lechartier, B.; Zhang, M.; Neres, J.; van der Sar, A.M.; Raadsen, S.A.; Hartkoorn, R.C.; Ryabova, O.B.; Vocat, A.; Decosterd, L.A.; Widmer, N.; Buclin, T.; Bitter, W.; Andries, K.; Pojer, F.; Dyson, P.J.; Cole, S.T. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol. Med., 2014, 6(3), 372-383.
[] [PMID: 24500695]
Lee, D.W.; Ha, H-J.; Lee, W.K. Selective mono-BOC protection of diamines. Synth. Commun., 2007, 37(5), 737-742.
König, W.; Geiger, R. Eine neue methode zur synthese von peptiden: Aktivierung der carboxylgruppe mit dicyclohexylcarbodiimid und 3-Hydroxy-4-oxo-3.4-dihydro-1.2.3-benzotriazin. Chem. Ber., 1970, 103(7), 2034-2040.
[] [PMID: 5433912]
Han, G.; Tamaki, M.; Hruby, V.J. Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group using HCl/dioxane (4 m). J. Pept. Res., 2001, 58(4), 338-341.
[] [PMID: 11606219]
Srivastava, T.; Haq, W.; Katti, S.B. Carbodiimide mediated synthesis of 4-thiazolidinones by one-pot three-component condensation. Tetrahedron, 2002, 58, 7619-7624.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy