1,2,3-三唑氨基嘧啶类抗蓝藻作为PDHc-E1竞争性抑制剂的合成及活性,Journal of Agricultural and Food Chemistry

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1,2,3-三唑氨基嘧啶类抗蓝藻作为PDHc-E1竞争性抑制剂的合成及活性
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2019-10-29 , DOI: 10.1021/acs.jafc.9b02878
Yuan Zhou ₁ , Jiangtao Feng ₁ , Lingling Feng ₁ , Dan Xie ₁ , Hao Peng ₁ , Meng Cai ₁ , Hongwu He ₁

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蓝藻有害藻华是全球关注的问题，但是市场上目前所有可用的杀藻剂都是非选择性的，并且对非目标物种具有潜在的副作用。在目前的工作中，合理设计并合成了包含16个新的1,2,3-三唑氨基嘧啶的两类化合物（4和6）作为蓝细菌的防治剂。我们的设计重点是通过抑制丙酮酸脱氢酶复合物E1（PDHc-E1）来抑制蓝细菌。化合物4和6显示出对强效抑制大肠杆菌PDHC-E1（IC ₅₀ = 4.13-23.76μM）和对也强杀藻活动集胞藻。PCC 6803（EC₅₀ = 1.7–8.1μM）和微囊藻。FACHB905（EC ₅₀ = 2.1–11.8μM）。特别是6d对4种藻类的杀藻活性不仅高于prometricn。它们也与硫酸铜相当或更高。类似物4c，4d，6d和6e显示出强效的杀藻活性和对大肠杆菌PDHc-E1的抑制作用，但对猪PDHc-E1的抑制作用却可以忽略不计。如分子对接，定点诱变，酶促测定和抑制动力学分析所揭示，分别为4c和6d竞争性抑制PDHc-E1。我们的结果表明，可以通过合理设计竞争性PDHc-E1抑制剂来开发高选择性，有效的杀藻剂。

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Synthesis and Activity of 1,2,3-Triazole Aminopyrimidines against Cyanobacteria as PDHc-E1 Competitive Inhibitors

Cyanobacteria harmful algal blooms are of global concern, but all currently available algicides in the market are nonselective and have potential side effects on nontarget species. In the present work, two series of compounds (4 and 6) comprising 16 novel 1,2,3-triazole aminopyrimidines were rationally designed and synthesized as control agent for cyanobacteria. Our design focus was the inhibiting cyanobacteria by inhibition against pyruvate dehydrogenase complex E1 (PDHc-E1). Compounds 4 and 6 showed potent inhibition against Escherichia coli PDHc-E1 (IC₅₀ = 4.13–23.76 μM) and also strong algicidal activities against Synechocystis sp. PCC 6803 (EC₅₀ = 1.7–8.1 μM) and Microcystis sp. FACHB905 (EC₅₀ = 2.1–11.8 μM). In particular, the algicidal activities of 6d against four algal species were not only higher than that of prometryn; they were also comparable to or higher than that of copper sulfate. The analogues 4c, 4d, 6d, and 6e displayed potent algicidal activities and inhibition of E. coli PDHc-E1 but exhibited negligible inhibition of porcine PDHc-E1. As revealed by molecular docking, site-directed mutagenesis, enzymatic assays, and an inhibition kinetic analysis, 4c and 6d inhibited PDHc-E1 in a competitive manner. Our results suggest that highly selective, effective algicides can be developed by rationally designing competitive PDHc-E1 inhibitors.

更新日期：2019-10-29

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