一系列合成的取代的2-氨基-4,6-二芳基嘧啶(4a-o)的磺酰基硫脲衍生物(7a-o)对某些人碳酸酐酶(hCA)具有显着的抑制活性,包括HCAI,II,IX,和XII同工型。通过体外酶法实验验证了合成的磺酰基硫脲衍生物的抑制作用。7a(KI=46.14nM),7j(KI=48.92nM),和7m(KI=62.59nM)(对于同工型hCAI);7f(KI=42.72nM),7i(KI=40.98nM),和7j(KI=33.40nM)(对于同种型hCAII);7j(KI=228.5nM),7m(KI=195.4nM),和7n(KI=210.1nM)(对于同种型hCAIX);7l(KI=116.9nM),7m(KI=118.8nM),和7n(KI=147.2nM)(对于同工型hCAXII),与452.1、327.3、437.2和338.9nM的KI值相比,分别,标准药物AAZ。这些化合物对胞质同工型hCAI和肿瘤相关同工型hCAIX和hCAXII也具有明显更有效的抑制作用。此外,对潜在的抑制性化合物进行分子对接和分子动力学模拟的计算机筛选。体外和计算机研究的结果表明,化合物7a,7j,7m是该系列中最有前途的衍生物,因为它们对所研究的hCAI有显著影响,II,IX,和XII同工型,分别。结果表明,磺酰基硫脲部分深深地容纳在活性位点,并与受体中的锌离子相互作用。
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.