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 ( h CAs), including h CA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by in vitro enzymatic assays. 7a ( K I = 46.14 nM), 7j ( K I = 48.92 nM), and 7m ( K I = 62.59 nM) (for isoform h CA I); 7f ( K I = 42.72 nM), 7i ( K I = 40.98 nM), and 7j ( K I = 33.40 nM) (for isoform h CA II); 7j ( K I = 228.5 nM), 7m ( K I = 195.4 nM), and 7n ( K I = 210.1 nM) (for isoform h CA IX); 7l ( K I = 116.9 nM), 7m ( K I = 118.8 nM), and 7n ( K I = 147.2 nM) (for isoform h CA XII) in comparison with K I 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 h CA I and tumor‐associated isoforms h CA IX and h CA 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 h CA 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.