Structure-Based Design and Synthesis of Novel Dual-Target Inhibitors against Cyanobacterial Fructose-1,6-Bisphosphate Aldolase and Fructose-1,6-Bisphosphatase

摘要

Cyanobacteria class II fructose-l,6-bisphoshate aldolase (Cy-FBA-II) and cyanobacteria fructose-1,6-bi-sphosphatase (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 (IC_(50) = 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 (IC_(50) = 2.3-16,9 μM) and moderate Cy-FBPase inhibitory activities (IC_(50) = 31.5— 141.2 μM); however, compounds L20e—L20h could potently inhibit both Cy-FBA-II and Cy-FBPase with IC_(50) values less than 30 μM, which demonstrated more or less dual-target inhibitor's feature. Moreover, most of them exhibited potent algicide activity (EC_(50) = 0.8—22.3 ppm) against cyanobacteria Synechocystis sp. PCC 6803.