Design, synthesis and anti-Mycobacterium tuberculosis evaluation of new thiazolidin-4-one and thiazolo[3,2-a][1,3,5]triazine derivatives

In response to the urgent need to encounter infection diseases, and upon increasing concerns about the devastating effects of tuberculosis (TB), the promising thiazolidin-4-one scaffold was used as a starting point to design and synthesize seventeen new compounds, relying on the pharmacophoric features of different anti-Mycobacterium tuberculosis and antibacterial active compounds. Thiazolidin-4-one was elaborated to result in bifunctioning formation, and further ring fusion into a thiazolo[3,2-a][1,3,5]triazine, which was hybridized with different heterocyclic rings and sulfonamide moieties. All the newly synthesized compounds were evaluated for their activity against drug sensitive (DS), multi-drug resistant (MDR) and extensive drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains. Additionally, their anti-bacterial activity against several bronchitis causing-bacteria (ATCC) and their antifungal activity were assessed. Several compounds showed promising results regarding all of the mentioned assays without any antifungal activities. Particularly, compound 3 showed a promising activity against the three Mtb strains (DS, MDR and XDR) with MIC of 2.49, 9.91 and 39.72 mu M, respectively. Furthermore, compound 7c revealed antituberculosis activity with MIC of 2.28, 18.14 and 36.31 mu M against DS, MDR and XDR strains, respectively. Both of compounds 3 and 7c surpassed azithromycin on several bronchitis causing-bacteria and showed enhanced inhibitory activity against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA), with IC50 of 3.90 and 2.47 mu M, respectively. The enzymatic activity was augmented by the binding characteristics of 3 and 7c in the InhA active site. Further investigations confirmed their safety on normal cell lines, and promising predicted ADME characteristics.

Automated summary

This study focuses on the design and synthesis of new compounds to evaluate their activity against Mycobacterium tuberculosis and bronchitis-causing bacteria. Several compounds showed promising results, particularly compound 3 and 7c, which demonstrated strong antibacterial and inhibitory activity against Mycobacterium tuberculosis.