Design, synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors

作者：Xiao, Shan; Wei, Lin; Hong, Zongqin; Rao, Li; Ren, Yanliang^*; Wan, Jian^*; Feng, Lingling

来源：Bioorganic & Medicinal Chemistry, 2019, 27(5): 805-812.

DOI：10.1016/j.bmc.2019.01.023

• Aldolases
• Fragment-based Virtual Screen
• Thiourea
• Algicides activities
• De novo discovery

By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) were de novo discovered based on the active site of fructose-1,6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of the N-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14 similar to L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1 similar to L13). Especially, compound L14 not only shows higher CyFBA-II activity (K-i= 0.65 mu M), but also exhibits most potent in vivo activity against Synechocystis sp. PCC 6803 (EC50 = 0.09 ppm), higher (7-fold) than that of our previous inhibitor (EC50 = 0.6 ppm). The binding modes of compound L14 and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).

• 出版日期2019-3-1
• 单位华中师范大学