Design, synthesis and biological evaluation of benzo-[d]-imidazo-[2,1-b]-thiazole and imidazo-[2,1-b]-thiazole carboxamide triazole derivatives as antimycobacterial agents

In the search for new anti-mycobacterial agents, we revealed the importance of imidazo-[2,1-b]-thiazole and benzo-[d]-imidazo-[2,1-b]-thiazole carboxamide derivatives. We designed, in silico ADMET predicted and synthesized four series of novel imidazo-[2,1-N-thiazole and benzo-[d]-imidazo-[2,1-b]-thiazole carboxamide analogues in combination with piperazine and various 1,2,3 triazoles. All the synthesized derivatives were characterized by H-1 NMR, C-13 NMR, HPLC and MS spectral analysis and evaluated for in vitro antitubercular activity. The most active benzo-[d]-imidazo-E2,1-N-thiazole derivative IT10, carrying a 4-nitro phenyl moiety, displayed IC90 of 7.05 mu M and IC50 of 2.32 mu M against Mycobacterium tuberculosis (Mtb) H37Ra, while no acute cellular toxicity was observed (>128 mu M) towards the MRC-5 lung fibroblast cell line. Another benzo-[d]-imidazo-[2,1-b]-thiazole compound, IT06, which possesses a 2,4-dichloro phenyl moiety, also showed significant activity with IC50 2.03 mu M and IC90 15.22 mu M against the tested strain of Mtb. Furthermore, the selected hits showed no activity towards a panel of non-tuberculous mycobacteria (NTM), thus suggesting a selective inhibition of Mtb by the tested imidazo-[2,1-b]-thiazole derivatives over the selected panel of NTM. Molecular docking and dynamics studies were also carried out for the most active compounds IT06 and IT10 in order to understand the putative binding pattern, as well as stability of the protein-ligand complex, against the selected target Pantothenate synthetase of Mtb.

Automated summary

In the search for new anti-mycobacterial agents, the importance of imidazo-[2,1-b]-thiazole and benzo-[d]-imidazo-[2,1-b]-thiazole carboxamide derivatives was revealed. Several series of novel derivatives were designed, predicted, and synthesized. The most active derivatives showed selective inhibition against Mycobacterium tuberculosis and no activity against non-tuberculous mycobacteria. Molecular docking and dynamics studies were also conducted to understand the binding pattern and stability of the protein-ligand complex.