Sulfonyl thiourea derivatives from 2-aminodiarylpyrimidines: In vitro and in silico evaluation as potential carbonic anhydrase I, II, IX, and XII inhibitors.

A series of synthesized sulfonyl thiourea derivatives (7a-o) of substituted 2-amino-4,6-diarylpyrimidines (4a-o) exhibited the remarkable inhibitory activity against some the human carbonic anhydrases (hCAs), including hCA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by in vitro enzymatic assays. 7a (KI  = 46.14 nM), 7j (KI  = 48.92 nM), and 7m (KI  = 62.59 nM) (for isoform hCA I); 7f (KI  = 42.72 nM), 7i (KI  = 40.98 nM), and 7j (KI  = 33.40 nM) (for isoform hCA II); 7j (KI  = 228.5 nM), 7m (KI  = 195.4 nM), and 7n (KI  = 210.1 nM) (for isoform hCA IX); 7l (KI  = 116.9 nM), 7m (KI  = 118.8 nM), and 7n (KI  = 147.2 nM) (for isoform hCA XII) in comparison with KI values of 452.1, 327.3, 437.2, and 338.9 nM, respectively, of the standard drug AAZ. These compounds also had significantly more potent inhibitory action against cytosolic isoform hCA I and tumor-associated isoforms hCA IX and hCA XII. Furthermore, the potential inhibitory compounds were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7a, 7j, and 7m were the most promising derivatives in this series due to their significant effects on studied hCA I, II, IX, and XII isoforms, respectively. The results showed that the sulfonyl thiourea moiety was accommodated deeply in the active site and interacted with the zinc ion in the receptors.