Design, Synthesis, and Bioassay for the Thiadiazole-Bridged Thioacetamide Compound as Cy-FBP/SBPase Inhibitors Based on Catalytic Mechanism Virtual Screening

Authors：Zuo, Lingzi; Huang, Shi; He, Yanlin; Zhang, Liexiong; Cheng, Guonian; Feng, Yu; Han, Qiang; Ge, Li; Feng, Lingling^*

Source：Journal of Agricultural and Food Chemistry, 2023, 71(31): 11834-11846.

DOI：10.1021/acs.jafc.3c01913

• cyanobacterial blooms
• Cy-FBP
• SBPase
• pharmacophore
• thiadiazole-bridged thioacetamide
• photosynthesis mechanism

Cyanobacterialfructose-1,6-/sedoheptulose-1,7-bisphosphatase (Cy-FBP/SBPase)was an important regulatory enzyme in cyanobacterial photosynthesisand was a potential target enzyme for screening to obtain novel inhibitorsagainst cyanobacterial blooms. In this study, we developed a novelpharmacophore screening model based on the catalytic mechanism andsubstrate structure of Cy-FBP/SBPase and screened 26 S series compounds with different structures and pharmacophore characteristicsfrom the Specs database by computer-assisted drug screening. Thesecompounds exhibited moderate inhibitory activity against Cy-FBP/SBPase,with 9 compounds inhibiting >50% at 100 & mu;M. Among them, compound S5 showed excellent inhibitory activity against both Cy-FBP/SBPaseand Synechocystis sp. PCC6803 (IC50 = 6.7 & PLUSMN; 0.7 & mu;M and EC50 = 7.7 & PLUSMN;1.4 & mu;M). The binding mode of compound S5 to Cy-FBP/SBPasewas predicted using the molecular docking theory and validated bysentinel mutation and enzyme activity analysis. Physiochemical, genetranscription level, and metabolomic analyses showed that compound S5 significantly reduced the quantum yield of photosystemII and the maximum electron transfer rate, downregulated transcriptlevels of related genes encoding the Calvin cycle and photosystem,reduced the photosynthetic efficiency of cyanobacteria, thus inhibitedmetabolic pathways, such as the Calvin cycle and tricarboxylic acidcycle, and eventually achieved an efficient algicide. In addition,compound S5 had a high safety profile for human-derivedcells and zebrafish. In summary, the novel pharmacophore screeningmodel obtained from the current work provides an effective solutionto the cyanobacterial bloom problem.