title: Structure-based design and synthesis of novel dual-target inhibitors against cyanobacterial fructose-1,6-bisphosphate aldolase and fructose-1,6-bisphosphatase.
abstract: Cyanobacteria class II fructose-1,6-bisphoshate aldolase (Cy-FBA-II) and cyanobacteria fructose-1,6-bisphosphatase (Cy-FBPase) are two neighboring key regulatory enzymes in the Calvin cycle of the cyanobacteria photosynthesis system. Each of them might be taken as a potential target for designing novel inhibitors to chemically control harmful algal blooms (HABs). In the present paper, a series of novel inhibitors were rationally designed, synthesized, and optimized based upon the structural and interactional information of both Cy-FBA-II and Cy-FBPase, and their inhibitory activities were examined in vitro and in vivo. The experimental results showed that compounds L19e-L19g exhibited moderate inhibitory activities (IC50 = 28.1-103.2 μM) against both Cy-FBA-II and Cy-FBPase; compounds L19a-L19d, L19h, L20a-L20d exhibited high Cy-FBA-II inhibitory activities (IC50 = 2.3-16.9 μM) and moderate Cy-FBPase inhibitory activities (IC50 = 31.5-141.2 μM); however, compounds L20e-L20h could potently inhibit both Cy-FBA-II and Cy-FBPase with IC50 values less than 30 μM, which demonstrated more or less dual-target inhibitor's feature. Moreover, most of them exhibited potent algicide activity (EC50 = 0.8-22.3 ppm) against cyanobacteria Synechocystis sp. PCC 6803.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Xinya
authors.initials: X
authors.lastname: Han
authors.forename: Qidong
authors.initials: Q
authors.lastname: Tu
authors.forename: Lingling
authors.initials: L
authors.lastname: Feng
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Li
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Ren
authors.forename: Jian
authors.initials: J
authors.lastname: Wan
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000458:Cyanobacteria / Q000737:chemistry / Q000201:enzymology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006597:Fructose-Bisphosphatase; D005634:Fructose-Bisphosphate Aldolase