Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives
作者：Zygmunt Kazimierczuk、Malgorzata Chalimoniuk、Agnieszka Ewa Laudy、Rosa Moo-Puc、Roberto Cedillo-Rivera、Bohdan Jerzy Starosciak、Stanislaw J. Chrapusta
DOI：10.1007/s12272-010-0604-8
日期：2010.6
The reaction of substituted benzylhalides, or of halomethyl derivatives of thiophene or furane, with thiourea or its derivatives yielded the respective isothioureas as hydrohalide salts. The products (a total of 17, including 16 novel compounds) were tested for activity against five Gram-positive and nine Gram-negative bacterial strains, six yeast species and two protozoan species. The most active against Gram-positive bacteria were S-(2,4-dinitrobenzyl)isothiourea hydrochloride (MIC range for four out of five strains tested: 12.5–25 μg/mL) and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide (MIC range: 12.5–50 μg/mL). The lowest MICs of novel isothioureas for yeast and Gram-negative bacteria ranged between 50 and 100 μg/mL. Nine novel isothioureas showed appreciable genotoxicity in the Bacillus subtilis ‘rec-assay’ test, the most potent being S-2-(5-nitrofuran-2-ylmethyl)isothiourea and S-(2-nitrobenzyl) isothiourea. At 10 μM concentration, S-(3,4-dichlorobenzyl)isothiourea hydrochloride and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide inhibited Ca2+/calmodulin-dependent (non-inducible) nitric oxide synthase activity in normal rat brain homogenates stronger (p < 0.05) than the reference drug 7-nitroindazole (by 78, 76 and 60%, respectively); ten other new isothiourea derivatives significantly inhibited the activity to a lower extent (by 28–60%). These results extend the list of promising isothioureas with substantial activity in vitro and suggest that an in-depth study of toxicity, antimicrobial properties in vivo and nitric oxide synthase isoform selectivity of selected novel compounds is warranted.
取代苄基卤化物或噻吩或呋喃的卤甲基衍生物与硫脲或其衍生物的反应生成相应的异硫脲盐酸盐。产品（总共17个，包括16个新颖化合物）对五种革兰氏阳性细菌、九种革兰氏阴性细菌、六种酵母菌和两种原生动物进行了活性测试。对革兰氏阳性细菌最活跃的是S-(2,4-二硝基苄基)异硫脲盐酸盐（MIC范围为四株测试菌株：12.5–25 μg/mL）和S-(2,3,4,5,6-五溴苄基)异硫脲氢溴酸盐（MIC范围：12.5–50 μg/mL）。新颖的异硫脲对酵母和革兰氏阴性细菌的最低MIC范围在50至100 μg/mL之间。九个新颖的异硫脲在枯草芽孢杆菌“rec-assay”测试中显示出显着的遗传毒性，其中最强烈的是S-2-(5-硝基呋喃-2-基甲基)异硫脲和S-(2-硝基苄基)异硫脲。在10 μM浓度下，S-(3,4-二氯苄基)异硫脲盐酸盐和S-(2,3,4,5,6-五溴苄基)异硫脲氢溴酸盐比参比药物7-硝基吲唑更强（p < 0.05），抑制正常大鼠脑匀浆中的Ca2+/钙调蛋白依赖性（非诱导性）一氧化氮合酶活性（分别抑制78%、76%和60%）；其他十个新的异硫脲衍生物显著抑制活性，但程度较低（抑制28–60%）。这些结果扩展了具有显著体外活性的有希望的异硫脲列表，并表明有必要深入研究所选新颖化合物的毒性、体内抗菌特性和一氧化氮合酶亚型选择性。
