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

Shan Xiao; Lin Wei; Zongqin Hong; Li Rao; Yanliang Ren; Jian Wan; Lingling Feng

doi:10.1016/j.bmc.2019.01.023

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

Bioorg Med Chem. 2019 Mar 1;27(5):805-812. doi: 10.1016/j.bmc.2019.01.023. Epub 2019 Jan 24.

Authors

Shan Xiao¹, Lin Wei¹, Zongqin Hong¹, Li Rao¹, Yanliang Ren², Jian Wan³, Lingling Feng¹

Affiliations

¹ International Cooperation Base of Pesticide and Green Synthesis (Hubei), Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University, Wuhan 430079, China.
² International Cooperation Base of Pesticide and Green Synthesis (Hubei), Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: renyl@mail.ccnu.edu.cn.
³ International Cooperation Base of Pesticide and Green Synthesis (Hubei), Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: jianwan@mail.ccnu.edu.cn.

PMID: 30711311
DOI: 10.1016/j.bmc.2019.01.023

Abstract

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∼L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1∼L13). Especially, compound L14 not only shows higher CyFBA-II activity (K_i = 0.65 μM), 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).

Keywords: Aldolases; Algicides activities; De novo discovery; Fragment-based Virtual Screen; Thiourea.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fructose-Bisphosphate Aldolase / antagonists & inhibitors*
Fructose-Bisphosphate Aldolase / chemistry
Fructose-Bisphosphate Aldolase / genetics
Herbicides / chemical synthesis
Herbicides / chemistry
Herbicides / pharmacology*
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Mutation
Synechocystis / drug effects
Synechocystis / enzymology
Thiourea / analogs & derivatives*
Thiourea / chemical synthesis
Thiourea / pharmacology*

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Herbicides
Fructose-Bisphosphate Aldolase
Thiourea