A Rational Design, Synthesis, Biological Evaluation and Structure–Activity Relationship Study of Novel Inhibitors against Cyanobacterial Fructose-1,6-bisphosphate Aldolase

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• 作者：Xinya Han ; Xiuyun Zhu ; Shuaihua Zhu ; Lin Wei ; Zongqin Hong ; Li Guo ; Haifeng Chen ; Bo Chi ; Yan Liu ; Lingling Feng ; Yanliang Ren ; Jian Wan
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2016
• 出版时间：January 25, 2016
• 年：2016
• 卷：56
• 期：1
• 页码：73-81
• 全文大小：433K
• ISSN：1549-960X

文摘

In the present study, a series of novel maleimide derivatives were rationally designed and optimized, and their inhibitory activities against cyanobacteria class-II fructose-1,6-bisphosphate aldolase (Cy-FBA-II) and Synechocystis sp. PCC 6803 were further evaluated. The experimental results showed that the introduction of a bigger group (Br, Cl, CH₃, or C₆H₃-o-F) on the pyrrole-2′,5′-dione ring resulted in a decrease in the Cy-FBA-II inhibitory activity of the hit compounds. Generally, most of the hit compounds with high Cy-FBA-II inhibitory activities could also exhibit high in vivo activities against Synechocystis sp. PCC 6803. Especially, compound 10 not only shows a high Cy-FBA-II activity (IC₅₀ = 1.7 μM) but also has the highest in vivo activity against Synechocystis sp. PCC 6803 (EC₅₀ = 0.6 ppm). Thus, compound 10 was selected as a representative molecule, and its probable interactions with the surrounding important residues in the active site of Cy-FBA-II were elucidated by the joint use of molecular docking, molecular dynamics simulations, ONIOM calculations, and enzymatic assays to provide new insight into the binding mode of the inhibitors and Cy-FBA-II. The positive results indicate that the design strategy used in the present study is very likely to be a promising way to find novel lead compounds with high inhibitory activities against Cy-FBA-II in the future. The enzymatic and algal inhibition assays suggest that Cy-FBA-II is very likely to be a promising target for the design, synthesis, and development of novel specific algicides to solve cyanobacterial harmful algal blooms.