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Synthesis, enzyme inhibitory kinetics, and computational studies of novel 1‐(2‐(4‐isobutylphenyl) propanoyl)‐3‐arylthioureas as Jack bean urease inhibitors
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-11-07 , DOI: 10.1111/cbdd.13090 Tanzeela Abdul Fattah 1 , Aamer Saeed 1 , Pervaiz Ali Channar 1 , Zaman Ashraf 2 , Qamar Abbas 3 , Mubashir Hassan 3 , Fayaz Ali Larik 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-11-07 , DOI: 10.1111/cbdd.13090 Tanzeela Abdul Fattah 1 , Aamer Saeed 1 , Pervaiz Ali Channar 1 , Zaman Ashraf 2 , Qamar Abbas 3 , Mubashir Hassan 3 , Fayaz Ali Larik 1
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In this article, synthesis of a novel 1‐(2‐(4‐isobutylphenyl)propanoyl)‐3‐arylthioureas (4a–j) as jack bean urease inhibitors has been described. Freshly prepared 2‐(4‐isobutylphenyl) propanoyl isothiocyanate was treated with substituted aromatic anilines in one pot using anhydrous acetone. The compounds 4e, 4h, and 4j showed IC50 values 0.0086 nm, 0.0081 nm, and 0.0094 nm, respectively. The enzyme inhibitory kinetics results showed that compound 4h inhibit the enzyme competitively while derivatives 4e and 4j are the mixed type inhibitors. The compound 4h reversibly binds the urease enzyme showing Ki value 0.0012 nm. The Ki values for 4e and 4j are 0.0025 nm and 0.003 nm, respectively. The antioxidant activity results reflected that compounds 4b, 4i, and 4j showed excellent radical scavenging activity. Moreover, the cytotoxic activity of the target compounds was evaluated using brine shrimp assay and it was found that all of the synthesized compounds exhibited no cytotoxic effects to brine shrimps. The computational molecular docking and molecular dynamic simulation of title compounds were also performed, and results showed that the wet laboratory findings are in good agreement to the dry laboratory results. Based upon our results, it is proposed that compound 4h may act as a lead candidate to design the clinically useful urease inhibitors.
中文翻译：
新型1-（2-（4-（4-异丁基苯基）丙酰基）-3-芳基硫脲）作为Jack bean脲酶抑制剂的合成，酶抑制动力学和计算研究
在本文中，已描述了一种新型的1-（2-（4-异丁基苯基）丙酰基）-3-芳基硫脲（4a-j）的合成，作为杰克豆脲酶抑制剂。将新鲜制备的2-（4-异丁基苯基）丙酰基异硫氰酸酯在一个锅中用无水丙酮用取代的芳族苯胺处理。化合物4E，4H，和4J显示IC 50个值0.0086Ñ米，0.0081Ñ米，和0.0094Ñ米分别。酶抑制动力学结果表明，化合物4h具有竞争性抑制酶的作用，而衍生物4e和4j是混合型抑制剂。化合物4h可逆地结合尿素酶，显示出K i值为0.0012 n m。4e和4j的K i值分别为0.0025 n m和0.003 n m。抗氧化活性结果反映出化合物4b，4i和4j表现出优异的自由基清除活性。此外，使用盐水虾测定法评估了目标化合物的细胞毒性活性，发现所有合成的化合物均对盐水虾没有细胞毒性作用。还进行了标题化合物的计算分子对接和分子动力学模拟，结果表明，湿实验室的结果与干实验室的结果非常吻合。根据我们的结果，建议化合物4h可作为设计临床上有用的脲酶抑制剂的主要候选药物。
更新日期：2017-11-07
中文翻译：
新型1-（2-（4-（4-异丁基苯基）丙酰基）-3-芳基硫脲）作为Jack bean脲酶抑制剂的合成，酶抑制动力学和计算研究
在本文中，已描述了一种新型的1-（2-（4-异丁基苯基）丙酰基）-3-芳基硫脲（4a-j）的合成，作为杰克豆脲酶抑制剂。将新鲜制备的2-（4-异丁基苯基）丙酰基异硫氰酸酯在一个锅中用无水丙酮用取代的芳族苯胺处理。化合物4E，4H，和4J显示IC 50个值0.0086Ñ米，0.0081Ñ米，和0.0094Ñ米分别。酶抑制动力学结果表明，化合物4h具有竞争性抑制酶的作用，而衍生物4e和4j是混合型抑制剂。化合物4h可逆地结合尿素酶，显示出K i值为0.0012 n m。4e和4j的K i值分别为0.0025 n m和0.003 n m。抗氧化活性结果反映出化合物4b，4i和4j表现出优异的自由基清除活性。此外，使用盐水虾测定法评估了目标化合物的细胞毒性活性，发现所有合成的化合物均对盐水虾没有细胞毒性作用。还进行了标题化合物的计算分子对接和分子动力学模拟，结果表明，湿实验室的结果与干实验室的结果非常吻合。根据我们的结果，建议化合物4h可作为设计临床上有用的脲酶抑制剂的主要候选药物。
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