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

Urease is essential to <i>Helicobacter pylori</i> 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 (<b>5a-j</b>). 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 <b>5j</b> exhibited an excellent non-competitive urease inhibitory effect with an IC₅₀ value of 0.44 ± 0.23 µM. Apart from <i>in vitro</i> investigation, the molecular docking revealed a strong affinity of <b>5j</b> within the active site of urease exhibiting a binding energy of -7.9 kcal/mol. Succinctly, the lead inhibitor <b>5j</b> exhibited noteworthy IC₅₀ and effective binding free energy which emphasizes its strong binding potential.