Design, synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors
Design, synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors
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新型支架醛缩酶抑制剂硫脲衍生物的设计、合成及其杀藻活性
DOI：
10.1016/j.bmc.2019.01.023
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发表时间：
2019
影响因子：
3.5
通讯作者：
Feng Lingling
中科院分区：
文献类型：
--
作者：
Xiao Shan;Wei Lin;Hong Zongqin;Rao Li;Ren Yanliang;Wan Jian;Feng Lingling
采用基于片段的虚拟筛选策略，基于蓝藻果糖-1，6-二磷酸醛缩酶（CyFBA）的活性位点，首次发现了两个系列的FBA-Ⅱ抑制剂（硫脲衍生物）。相比之下，大多数N-（2-苯甲酰基肼-1-硫代甲酰基）苯甲酰胺衍生物（L14-L22）与N-（苯基硫代甲酰基）苯甲酰胺衍生物（L1-L13）相比表现出更高的CyFBA-II抑制活性。特别是化合物L14不仅表现出更高的CyFBA-II活性（Ki= 0.65 μM），而且还表现出对集胞藻属PCC 6803最强的体内活性（EC 50 = 0.09 ppm），比我们以前的抑制剂（EC 50 = 0.6 ppm）高（7倍）。结合DOX计算方案、MM-PBSA和定点突变分析进一步阐明了化合物L14与CyFBA-II的结合模式。积极的结果表明，在这项研究中采用的策略是有希望的，快速发现有效的抑制剂与新的支架。硫脲衍生物具有良好的杀藻活性，有望成为解决蓝藻水华的新型杀藻剂。
By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) werede novodiscovered based on the active site of fructose-1, 6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of theN-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14∼L22) exhibit higher CyFBA-II inhibitory activities compared toN-(phenylcarbamothioyl) benzamide derivatives (L1∼L13). Especially, compoundL14not only shows higher CyFBA-II activity (Ki= 0.65 μM), but also exhibits most potentin vivoactivity against Synechocystis sp. PCC 6803 (EC50= 0.09 ppm), higher (7-fold) than that of our previous inhibitor (EC50= 0.6 ppm). The binding modes of compoundL14and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).