Background: Tuberculosis is a highly contagious disease that is one of the major causes of mortality worldwide and the leading infectious organism-related cause of death. Various tetrazole and quinazoline compounds have been successfully developed in the past for tuberculosis treatment. In this case, we planned to design the hybrid moieties by combining both tetrazole and quinazoline nuclei to create novel compounds with increased activity.
Methods: 6, 6-dimethyl-5, 6, 7, 9–tetrahydrotetrazolo [5, 1-b] Quinazolin-8(4H) -one derivatives were synthesized, characterized by using spectral data. The antitubercular activity of the synthesized compounds was tested against the H37RV strain of Mycobacterium tuberculosis. In order to identify the interactions with the target protein Mtb Pks13 Thioesterase domain in complex with an inhibitor, docking analysis of the final compounds was performed (Protein data bank ID: 5V41). To verify their drug-like potential, the synthesized compounds were subjected to Pharmacokinetic prediction experiments. Zebrafish larvae had been used to test the teratogenicity of the synthesized compounds.
Results: At 6.25 μg/mL, compounds F4 and F7 exhibited good efficacy against Mycobacterium tuberculosis strains. Docking studies aided in determining the most likely binding mode within the binding cavity of the concerned target protein.
Conclusion: Compounds containing p-fluorophenyl and p-nitrophenyl groups as substituents were found to have excellent anti-tubercular activity.
[http://dx.doi.org/10.1038/ng.3195] [PMID: 25599400]
[http://dx.doi.org/10.3389/fcimb.2018.00114] [PMID: 29755957]
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.07.007] [PMID: 27417938]
[http://dx.doi.org/10.1073/pnas.1600630113] [PMID: 27325754]
[http://dx.doi.org/10.1016/j.bmcl.2017.12.040] [PMID: 29289430]
[http://dx.doi.org/10.1016/j.bmcl.2012.10.125] [PMID: 23200244]
[http://dx.doi.org/10.1080/14756366.2017.1326110] [PMID: 28587532]
[http://dx.doi.org/10.1248/cpb.37.958] [PMID: 2766419]
[http://dx.doi.org/10.3109/14756366.2012.755622] [PMID: 23327639]
[http://dx.doi.org/10.3389/fchem.2020.590235] [PMID: 33425849]
[http://dx.doi.org/10.1002/bdrb.20260] [PMID: 20836125]