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

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