Novel 2-arylthiazolidin-4-one-thiazole hybrids with potent activity against Mycobacterium tuberculosis.

ABSTRACT

Substituted aldehydes, ethyl 2-(2-amino-thiazol-4-yl)acetate), and 2-mercaptoacetic acid, in a three-component one-pot green synthetic approach afforded 2-arylthiazolidin-4-one- thiazole hybrids(T1-T13). Compounds showed good anti-tubercular activity towards sensitive M. tuberculosis strain. Compound T8 was as potent as isoniazide (INH) with MIC = 0.12 µg/ml. Compounds T2 and T13 showed potent activity with MIC = 0.48 µg/ml. Other compounds showed moderate to good anti-tubercular activity towards MDR M. tuberculosis strain with MIC range 1.95-125 µg/ml. Compounds T2, T8, T9, and T13 showed anti-tubercular activity towards XDR M. tuberculosis strain with MIC range 7.81-125 µg/ml. Compounds T2 and T8 were capable of inhibiting M. tuberculosis InhA enzyme in-vitro with IC50 = 1.3 ± 0.61 µM and 1.06 ± 0.97 µM, respectively. Molecular docking simulation showed that T2 and T8 were also capable of interacting at the catalytic site of InhA enzyme in a similar mode to the native ligand through binding with NAD+ and Tyr158. The 3D- QSAR study highlighted the relevance of substitution of phenyl group at position-2 of thiazolidin-4-one where bulky electronegative substitution at position-4 of the phenyl ring favored the activity against M. tuberculosis H37R. Additionally, compounds showed good antibacterial activity against bronchitis causing bacteria M. pneumoniae, S. pneumonia, K. pneumonia, and B. pertussis compared to Azithromycin. In-silico studies of ADMET descriptors and drug-likeness were conducted for all synthesized compounds. Compounds showed good oral bioavailability, good gastrointestinal absorption and showed no signs of adverse effects to the liver or CNS. Compounds showed no potential carcinogenicity as well.