Functionalization of 2-Amino-4-chloropyridine as Potential In Vitro Inhibitors of Urease Enzyme: Synthesis, Kinetics and In Silico Studies

Urease inhibition is therapeutically important for the treatment of diseases such as peptic and duodenal ulcers, and urolithiasis (kidney stone disease) caused by the ureolytic bacteria. Functionalization of 2-amino-4-chloropyridine scaffold was conducted by using single step chemical transformation to yield thiourea, and imine derivatives (1-35). Among these, compounds 3, and 16-35 were identified as new compounds. All analogous exhibited significant urease inhibition activity with IC50 in the range of 8.36-55.8 mu M. Acetohydroxamic acid (IC50=20.4 +/- 0.23 mu M) was used as standard. All synthesized compounds were characterized by using spectroscopic techniques such as H-1-NMR, C-13-NMR, NOESY, COSY, HMBC, HSQC, IR, UV, and mass spectrometry. Furthermore, kinetic studies were performed in order to determine the mode of interaction of these compounds with urease enzyme. Molecular docking and kinetic studies revealed that the compounds 25, and 26 are competitive inhibitors of urease enzyme. All the compounds were tested for their cytotoxicity against normal cell line and were found to be non-cytotoxic.