Synthesis And Urease Inhibition Studies Of Gallocatechin Isosteres

Helicobacter pylori is a Gram-negative microaerophilic bacterium that infects up to50%of the world’s human population. It could cause many grastroduodenal diseases such as gastritis, gastric, duodenal ulcers and gastric cancer. Ureases are a group of highly proficient enzymes, widely distributed in a variety of bacteria such as H. prylori and Proteus mirabilis. Therefore, approaches based on urease inhibition are currently considered as front line treatment for infections caused by urease-producing bacteria.We focused attention on nature products which inhibit the activity of urease. It is report that gallocatechin have been shown strongly urease inhibition activity. To obtain novel urease inhibitors with good bioavailability and low toxicity, isostere principle was used to synthesize two series of compounds based on gallocatechin. These compounds were characterized by1H NMR spectra and X-ray crystallography. The urease inhibition activity of synthesized compounds and commercially available flavones was evaluated by H. prylori. Among all the tested compounds, gallocatechin isosteres showed potential inhibition activities, especially12a (IC50=0.85μM),20e (IC50=0.083μM) and20n (ICso=0.72μM) comparable to acetohydroxamic acid (ICso=17μM),a clinical urease inhibitor. We further study the inhibition mechanism of genistein, resveratrol,20e,12a and quercetin. The results showed that genistein, resveratrol,20e,12a and quercetin were belonged to reversible inhibitor. The inhibition resveratrol,20e, quercetin were defined to be non-competitive and their inhibition constants (Ki) were calculated to be5.39μg/mL,0.49μg/mL,2.82μg/mL respectively. While12a was mixed of competitive and uncompetitive inhibitor with the inhibition constant (Ki) of0.016μg/mL.20e was a mixed inhibitor with the inhibition constant (Ki) of0.0028μg/mL.