title: A Rational Design, Synthesis, Biological Evaluation and Structure--Activity Relationship Study of Novel Inhibitors against Cyanobacterial Fructose-1,6-bisphosphate Aldolase.
abstract: 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.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Xinya
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Shuaihua
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Zongqin
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Hubei Environmental Monitoring Central Station , Wuhan, Hubei 430072, China.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chi
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Feng
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University , Wuhan, Hubei 430079, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wan
mesh_terms: D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D046939:Synechocystis / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D011758:Pyrroles; D005634:Fructose-Bisphosphate Aldolase