Discovery of (5-(Benzylthio)-4-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl) Methanols as Potent Phytoene Desaturase Inhibitors through Virtual Screening and Structure Optimization

Abstract

Phytoene desaturase (PDS) is not only an important enzyme in the biosynthesis of carotenoids but also a promising target for herbicide discovery. However, in recent years, no expected PDS inhibitors with new scaffolds have been reported. Hence, a solution for developing PDS inhibitors is to search for new compounds with novel chemotypes based on the PDS protein structure. In this work, we integrated structure-based virtual screening, structure-guided optimization, and biological evaluation to discover some PDS inhibitors with novel chemotypes. It is noteworthy that the highly potent compound 1b, 1-(4-chlorophenyl)-2-((5-(hydroxymethyl)-4-(3-(trifluoromethyl)­phenyl)-4H-1,2,4-triazol-3-yl)­thio)­ethan-1-one, exhibited a broader spectrum of post-emergence herbicidal activity at 375–750 g/ha against six kinds of weeds than the commercial PDS inhibitor diflufenican. Surface plasmon resonance (SPR) assay showed that the affinity of our compound 1b (K D = 65.9 μM) to PDS is slightly weaker but at the same level as diflufenican (K D = 38.3 μM). Meanwhile, determination of the phytoene content and PDS mRNA quantification suggested that 1b could induce PDS mRNA reduction and phytoene accumulation. Moreover, 1b also caused the increase of reactive oxygen species (ROS) and the change of ROS-associated enzyme activity in albino leaves. Hence, all these results indicated the feasibility of PDS protein structure-based virtual screen and structure optimization to search for highly potent PDS inhibitors with novel chemotypes for weed control.

Herbicidal Activity of Beflubutamid Analogues as PDS Inhibitors and SAR Analysis and Degradation Dynamics in Wheat

“…AutoDockTools version 1.5.6 was used to prepare the ligands and receptors and predict the binding modes. The Discovery Studio 2016 client is used to visualize simulation results on the interactions between compounds and receptors …”

“…The Discovery Studio 2016 client is used to visualize simulation results on the interactions between compounds and receptors. 28 Digestion Dynamics of (S)-BF in Wheat Plants. 29−31 The application of the pesticide was initiated at the three-leaf stage of wheat, with an application concentration of 150 g ai/ha.…”

Advancement of Phenoxypyridine as an Active Scaffold for Pesticides

“…Most compounds distinctly presented better inhibitory effects on dicotyledonous weeds than monocotyledonous weeds. Among them, the IC 50 of Compound 16a [ 41 ] (IC 50 = 0.041 mg/L), 16b [ 42 ] (IC 50 = 0.0262 mg/L), 17a [ 43 ] (IC 50 = 0.01937 mg/L), 17b [ 44 ] (IC 50 = 0.01252 mg/L), 18a [ 45 ] (IC 50 = 0.032 mg/L), and 18b [ 8 ] (IC 50 = 0.0468 μmol/L) against PPO was consistent with or better than that of oxyfluorfen. At 150 g a.i./ha, Compound 16a achieved 100% inhibition against A. theophrasti for post-emergence treatment.…”

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

“…Structure-based virtual screening (SBVS) is an effective method commonly used in TBDD to identify novel structural-specific inhibitors, enabling reliable and time-saving target design of hit compounds . In recent years, there have been many successful cases of developing novel inhibitors against different protein targets using SBVS. , …”

“…19 In recent years, there have been many successful cases of developing novel inhibitors against different protein targets using SBVS. 19,20 In the previous study, we established a pharmacophore screening model based on the protein structure of Cy-FBP/ SBPase and performed virtual screening of Cy-FBP/SBPase inhibitors. Compound 10 with high inhibitory activity against Cy-FBP/SBPase was obtained, which had a certain inhibitory effect on Cy-FBP/SBPase and Synechocystis sp.…”