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

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

Journal Name: Current Bioactive Compounds

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Abstract:

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 fell ill with tuberculosis including 490000 multidrug-resistant TB (MDR-TB) cases. Several new lead molecules like dinitrobenzamide derivatives though found active against M. tuberculosis suffering problem of resistance. A series of compounds have been synthesized by linking dinitrobenzamide with the thiazolidin-4-one. The presented work is an effort to study the effect of thiazolidine-4-one on dinitrobenzamide derivatives for their antitubercular activity. The study also reveals pharmacophore requirements for lead optimization. Method: The thiazolidine-4-one linked 3,5-dinitrobenzamide derivatives have been synthesized by exploring a one pot multi component reaction of an amine, substituted aldehydes and thioglycolic acid. 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 M. tuberculosis DprE14 to explorer the structural features present in the synthesized compounds against this potential target for antitubercular drugs. Results: The synthesized compounds showed the activity in the range of 6.25-50 µg/ml. The pharmacophore modeling suggest that presence of aromatic moiety, thiazolidinone ring and one of the nitro group are important for the activity. While Docking studies showing hydrophobic and hydrogen bond interactions of aromatic moiety and nitro group with DprE14 enzyme. Conclusion: The study showed that the linking of thiazolidine-4-one with dinitrobenzamide leads to compounds active against M. tuberculosis. The findings also suggests that for the lead optimization we have to focus on the aromatic group present on the thiazolidine-4-one for hydrophobic interaction and presence of nitro group is must for hydrogen bond interactions.

Keywords: Thiazolidine-4-one, 3, 5-dinitrobenzamide derivatives, tuberculosis, synthesis, Molecular Modeling, Docking

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(E-pub Ahead of Print)
DOI: 10.2174/1573407214666180720150009
Price: $95

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