Synthesis of N-alkyl (aril)-tetra pyrimidine thiones and investigation of their human carbonic anhydrase I and II inhibitory effects

Tetrahydropyrimidine thiones, which are cyclic thiocarbamides derivatives, were synthesised from thiourea, beta-diketones and substituted benzaldehydes. A tautomeric form of these derivatives incorporates the thiol functionality, which is known to interact with metal ions from metalloenzymes active sites, such as the carbonic anhydrases (CAs, EC 4.2.1.1) among others. This is a superfamily of widespread enzymes, which catalyses a crucial biochemical reaction, the reversible hydration of carbon dioxide to bicarbonate and protons (H+). The newly synthesised N-alkyl (aril)-tetrahydropyrimidine thiones were tested for inhibition of the cytosolic human isoforms I and II (hCA I and II). Both isoforms were effectively inhibited by the newly synthesised thiones. K-i values were in the range of 218.5 +/- 23.9-261.0 +/- 41.5 pM for hCA I, and of 181.8 +/- 41.9-273.6 +/- 41.4 pM for hCA II, respectively. This under-investigated class of derivatives may bring interesting insights in the field of non-sulphonamide CA inhibitors.