In Silico Structure-Guided Optimization and Molecular Simulation Studies of 3-Phenoxy-4-(3-trifluoromethylphenyl)pyridazines as Potent Phytoene Desaturase Inhibitors

In this work, a series of beflubutamid (BF) analogues' postemergent herbicidal activity was evaluated, and the structure−activity relationship (SAR) was discussed. At a dosage of 300 g ai/ha, compounds (Rac)-6h and (Rac)-6q showed excellent herbicidal activity against Amaranthus retroflexus, Abutilon theophrasti, and Medicago sativa, with inhibition rates of 90, 100, and 80% and 100, 100, and 100%, respectively, comparable to that of commercial herbicide BF, which showed inhibition rates of 90, 100, and 100%, respectively. Notably, at dosages of 150 and 300 g ai/ha, the chiral compounds (S)-6h and (S)-6q exhibited higher herbicidal activities than their racemates. Molecular docking results indicated that compounds (S)-BF and (S)-6h have stronger binding affinities with Oryza sativa phytoene desaturase (OsPDS), resulting in a higher herbicidal activity. Additionally, the degradation dynamics half-life of (S)-BF in wheat was determined to be 77.02 h. Consequently, compounds (S)-6h and (S)-6q are promising lead candidates for the development of highly effective herbicides.

Section: Resultsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…9 (q, J = 272.4 Hz), 122.4 (d, J = 8.3 Hz), 118.8 (d, J = 22.2 Hz), 117.3 (dd, J = 32.4, 13.9 Hz), 113.8 (q, J = 5.0 Hz), 80 3,. 26.6, 24.6, 18.4, 14.9, 10.1.…”

mentioning

confidence: 99%

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

Zhang,

Cai,

Ling

et al. 2023

“…The overexpression and purification methods were similar to those in our previous reports . BL21(DE3) chemically competent cells transformed with plasmid DNA (pET-15b- Synechococcus PDS) were cultured in 500 mL of 2×YT medium containing 100 μg/mL ampicillin until the cell culture density was 0.6 at OD 600 .…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Zhou

Yang

et al. 2022

Self Cite

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.

Discovery of Novel Pyridazine Herbicides Targeting Phytoene Desaturase with Scaffold Hopping

Chen,

Lei,

Geng

et al. 2024

Phytoene desaturase (PDS) is a critical functional enzyme in blocking ζ-carotene biosynthesis and is one of the bleaching herbicide targets. At present, norflurazon (NRF) is the only commercial pyridazine herbicide targeting PDS. Therefore, developing new and diverse pyridazine herbicides targeting PDS is urgently required. In this study, diflufenican (BF) was used as the lead compound, and a scaffold-hopping strategy was employed to design and synthesize some pyridazine derivatives based on the action mode of BF and PDS. The preemergence herbicidal activity tests revealed that compound 6-chloro-N-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenoxy)pyridazine-4-carboxamide (B1) with 2,4-diF substitution in the benzeneamino ring showed 100% inhibition rates against the roots and stems of Echinochloa crus-galli and Portulaca oleracea at 100 μg/mL, superior to the inhibition rates of BF. Meanwhile, compound B1 demonstrated excellent postemergence herbicidal activity against broadleaf weeds, which was similar to that of BF (inhibition rate of 100%) but superior to that of NRF. This indicated that 6-Cl in the pyridazine ring is the key group for postemergence herbicidal activity. In addition, compound B1 could induce downregulation of PDS gene expression, 15-cis-phytoene accumulation, and Y(II) deficiency and prevent photosynthesis. Therefore, B1 can be considered as a promising candidate for developing high-efficiency PDS inhibitors.