Discovery of isatin-thiazole conjugates as potent urease inhibitors; synthesis, biochemical screening and computational studies

Urease is essential to Helicobacter pylori metabolism and plays role in stomach cancer, gastritis, peptic ulcer, hepatic coma, urinary tract infection, liver encephalopathy, and pyelonephritis. Therefore, inhibition of urease is an appealing approach to treat bacterial infections.
The present work describes the synthesis of a series of ten new bioactive isatin-thiazole conjugates (5a-j). The target adducts were characterized using fourier transform infrared (FT-IR), 1H- and 13C- nuclear magnetic resonance imaging (NMR) spectroscopy. The compounds were obtained using a multistep strategy that included nitration, alkylation, condensation and cyclization sequence. Subsequently, these compounds were screened for their urease inhibition potential.
All the compounds showed better inhibitory potential than the positive control, thiourea with IC50 ranging from 0.44 to 8.70 µM. However, compound 5j exhibited an excellent non-competitive urease inhibitory effect with an IC50 value of 0.44 ± 0.23 µM. Apart from in vitro investigation, the molecular docking revealed a strong affinity of 5j within the active site of urease exhibiting a binding energy of -7.9 kcal/mol. Succinctly, the lead inhibitor 5j exhibited noteworthy IC50 and effective binding free energy which emphasizes its strong binding potential.