AUTHOR=Akash Muhammad , Zaib Sumera , Ahmad Matloob , Sultan Sadia , Al-Hussain Sami A. 

TITLE=Synthesis and biological evaluation of pyridylpiperazine hybrid derivatives as urease inhibitors

JOURNAL=Frontiers in Chemistry

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1371377

DOI=10.3389/fchem.2024.1371377

ISSN=2296-2646

ABSTRACT=<p>Urease, a nickel-dependent enzyme found in various life forms, catalyzes urea breakdown, concluding nitrogen metabolism by generating ammonia and carbamate. This process causes a rise in pH, supports the survival of pathogens, and can lead to infections such as gastric disorders like ulcers and cancer in humans. <italic>Helicobacter pylori</italic> employs urease for survival in the acidic environment of the stomach and in protein synthesis. To treat such infections and inhibit the growth of pathogens, it is mandatory to obstruct urease activity; therefore, derivatives of 1-(3-nitropyridin-2-yl)piperazine were synthesized (<bold>5a-o</bold>; <bold>7a-k</bold>). All these newly synthesized compounds were investigated for urease inhibition by <italic>in vitro</italic> inhibition assays. The results showed that <bold>5b</bold> and <bold>7e</bold> are the most active inhibitors, having IC<sub>50</sub> values of 2.0 ± 0.73 and 2.24 ± 1.63 µM, respectively. These IC<sub>50</sub> values are lower than the IC<sub>50</sub> value of the standard thiourea, which was 23.2 ± 11.0 µM. The hemolysis potential of <bold>5b, 5c, 5i, 7e,</bold> and <bold>7h</bold> was also determined; <bold>7e</bold> and <bold>7h</bold> exhibited good biocompatibility in human blood cells. Through <italic>in silico</italic> analysis, it was shown that both these potent inhibitors develop favorable interactions with the active site of urease, having binding energies of −8.0 (<bold>5b</bold>) and −8.1 (<bold>7e</bold>) kcal/mol. The binding energy of thiourea was −2.8 kcal/mol. Moreover, <bold>5b and 7e</bold> have high gastrointestinal permeability as predicted via computational analysis. On the other hand, the IC<sub>50</sub> value and binding energy of precursor compound <bold>3</bold> was 3.90 ± 1.91 µM and −6.1 kcal/mol, respectively. Consequently, <bold>5b</bold> and <bold>7e</bold> can serve as important inhibitors of urease.</p>