Discovery of Thiopyrimidinone Derivatives as a New Class of Human Aldose Reductase Inhibitors

Abstract

Diabetes is a chronic metabolic disorder characterized by insufficient insulin production, the cells’ inability to use this insulin, or a combination of both, leading to secondary complications such as diabetic neuropathy and retinopathy. One way to prevent or control such complications is the use of aldose reductase (AR) inhibitors. In this work, we synthesized and tested new candidates for human AR inhibition containing a 2-thiopyrimidin-4-one heterocycle as a central ring. The fifteen derivatives were tested in vitro and their binding modes were evaluated via molecular docking simulations. AR inhibition assays showed that all synthesized compounds were able to inhibit the AR enzyme at 50 μM. From these results, seven compounds were noteworthy and had their half maximal inhibitory concentration (IC50) values estimated, ranging from 2.0 to 14.5 μM. Molecular docking simulations showed that these compounds bind specifically to the catalytic subpocket and the results indicate a good association between in vitro and in silico studies.

Discovery of novel heterocyclic derivatives containing oxadiazolone or pyrimidinone cores as DPP‐4 inhibitors

“…2‐Thiopyrimidin‐4‐ones ( 12a‐c ) were obtained from a modified methodology, described initially by Kambe and coworkers [37], in which aromatic aldehydes ( 11a‐c ) reacted with ethyl cyanoacetate, thiourea, and potassium carbonate in refluxing ethanol. Once obtained, the product was further functionalized by S ‐alkylation [38] with N ‐(3‐bromopropyl) phthalimide, yielding the target compounds ( 13a‐c ). This reaction is driven by a thiol/thione tautomeric equilibrium in certain solvents: the thione form is favored in solvents with high dielectric constant, while the thiol form is favored in solvents with low dielectric constant, like acetone [39, 40].…”

“…Compounds 13a‐c were synthesized using the methodology described by Lins and coworkers [38], in which derivative 6‐aryl‐2‐thiopirimidin‐4‐one 12a‐c (0.1 g; 0.4 mmol), N ‐(3‐bromopropyl)phthalimide (0.16 g; 0.6 mmol), triethylamine (0.06 g; 0.6 mmol) and 10 mL of acetone were added in round‐bottom flask and stirred under room temperature for 12 h. The reaction was followed by TLC using hexane/ethyl acetate 1:1 (v/v) as an eluting system. After the completion of the reaction, aqueous HCl solution was added to the round‐bottom flask until acidification.…”

“…All compounds 12a [64], 12b, and 12c [65] were synthesized previously, and their data were compared with previous literature. Compounds 13a-c were synthesized using the methodology described by Lins and coworkers [38], in which derivative 6-aryl-2-thiopirimidin-4-one 12a-c (0.1 g; 0.4 mmol),…”

Biologically active thio‐pyrimidinones from base‐catalyzed thiol‐ene coupling with maleimides

“…Among all synthesized and tested compounds, the best lead was 2‐[(5‐cyano‐6‐oxo‐4‐[ p ‐tolyl]‐1,6‐dihydropyrimidin‐2‐yl)thio] acetic acid, a thiopyrimidinone containing an acid group on the sulfur side chain. This compound exhibited an IC 50 value of 2.0 micromolar on human AR [34].…”