Appraisal of novel azomethine–thioxoimidazolidinone conjugates as ecto-5′-nucleotidase inhibitors: synthesis and molecular docking studies

Purinergic signaling is regulated by a group of extracellular enzymes called ectonucleotidases. One of its members i.e., ecto-5′-nucleotidase (h-e5′NT) is involved in the final step of the enzymatic hydrolysis cascade that is the conversion of adenosine monophosphate (AMP) to adenosine and therefore, involves the regulation of adenosine level in extracellular space. The overexpression of h-e5′NT has been observed in various pathological conditions such as hypoxia, inflammation and cancers, and led to various complications. Hence, the identification of a potent as well as selective inhibitor of h-e5′NT is of greater importance in therapeutic treatment of various diseases. Azomethine-thioxoimidazolidinone derivatives were studied for their inhibition potential against e5′NT enzyme along with cytotoxic potential against cancer cell lines possessing overexpression of e5′NT enzyme. The derivative (E)-3-((4-((3-methoxybenzyl)oxy)benzylidene)amino)-2-thioxoimidazolidin-4-one (4g) displayed selective and significant inhibition towards h-e5′NT with an IC(50) value of 0.23 ± 0.08 μM. While two other derivatives i.e., (E)-3-(((5-bromothiophen-2-yl)methylene)amino)-2-thioxoimidazolidin-4-one (4b) and 2-thioxo-3-((3,4,5-trimethoxybenzylidene)amino)imidazolidin-4-one (4e), exhibited non-selective potent inhibitory behavior against both human and rat enzymes. Moreover, these derivatives (4b, 4e and 4g) were further investigated for their effect on the expression of h-e5′NT using quantitative real time polymerase chain reaction. Additionally, molecular docking and DFT studies were also performed to determine the putative binding mode of potent inhibitors within the enzyme active site. HOMO, LUMO, ΔE, and molecular electrostatic potential maps were computed by DFT and the charge transfer regions within the molecules were identified to find out the regions for electrophilic and nucleophilic attack.