Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (<b>13</b>-<b>18</b>)(<b>a</b>-<b>d</b>) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (<b>7</b>-<b>12</b>), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (<b>VIII</b>(<b>a</b>-<b>d</b>)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC₅₀ values lower than 5 μM, and for four of them (<b>16a</b>, <b>18b</b>, <b>18c</b> and <b>18d</b>), IC₅₀ ≈ 1 μM. Additionally, all compounds with IC₅₀ < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (<b>15c</b>, <b>15d</b> and <b>16d</b>) being selective to the A isoform, with their hLDHB IC₅₀ > 100 μM, and the other thirteen behaving as double inhibitors.