Title:Synthesis, Antitubercular Activity, Molecular Modeling and Docking Studies of Novel Thiazolidin-4-One Linked Dinitrobenzamide Derivatives
Volume: 16
Issue: 1
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
Affiliation:
- Laureate Institute of Pharmacy, Kathog, Kangra. Himachal Pradesh,India
Keywords:
Thiazolidin-4-one, 3, 5-dinitrobenzamide derivatives, tuberculosis, synthesis, molecular modeling, docking.
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
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.