New acetylphenol-based acyl thioureas broaden the scope of drug candidates for urease inhibition: synthesis, in vitro screening and in silico analysis.

Helicobacter pylori urease remains a validated drug target for the eradication of pervasive chronic stomach infection that leads to severe human health diseases such as gastritis and stomach cancer. The increased failure of current treatment protocols because of resistance to broadband antibiotics, severe side effects and low compliance underscore the need for a targeted eradication therapy. Therefore, in the present research, we have developed a new series of acetylphenol-based acyl thioureas that can potentially provide a new template for drug candidates to inhibit urease enzyme. Newly synthesized compounds 7a-j were evaluated for urease inhibitory strength using thiourea as a positive control. In vitro inhibitory results revealed that all the tested compounds were significantly potent than the standard drug. The most active lead 7f competitively inhibited the enzyme and displayed an IC ₅₀ value of 0.054 ± 0.002 μM, a ~413-fold strong inhibitory potential than thiourea (IC ₅₀  = 22.3 ± 0.031 μM). Various insightful structure-activity relationships were developed showing the key structural requirements for potent inhibitory effects. Molecular docking analysis of 7f inside the active pocket of urease suggested several important interactions with amino acid residues such as ILE411, MET637, ARG439, GLN635, ALA636 and ALA440. Finally, pharmacokinetic properties suggested that the tested derivatives are safe to develop as low-molecular-weight drugs to treat ureolytic bacterial infections.
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