Abstract
Protoporphyrinogen oxidase (PPO) has been identified as one of the most promising targets for herbicide discovery. A series of novel phthalimide derivatives were designed by molecular docking studies targeting the crystal structure of mitochondrial PPO from tobacco (mtPPO, PDB: 1SEZ) by using Flumioxazin as a lead, after which the derivatives were synthesized and characterized, and their herbicidal activities were subsequently evaluated. The herbicidal bioassay results showed that compounds such as 3a (2-(4-bromo-2,6-difluorophenyl) isoindoline-1,3-dione), 3d (methyl 2-(4-chloro-1,3-dioxoisoindolin-2-yl)-5-fluorobenzoate), 3g (4-chloro-2-(5-methylisoxazol-3-yl) isoindoline-1,3-dione), 3j (4-chloro-2-(thiophen-2-ylmethyl) isoindoline-1,3-dione) and 3r (2-(4-bromo-2,6-difluorophenyl)-4-fluoroisoindoline-1,3-dione) had good herbicidal activities; among them, 3a showed excellent herbicidal efficacy against A. retroflexus and B. campestris via the small cup method and via pre-emergence and post-emergence spray treatments. The efficacy was comparable to that of the commercial herbicides Flumioxazin, Atrazine, and Chlortoluron. Further, the enzyme activity assay results suggest that the mode of action of compound 3a involves the inhibition of the PPO enzyme, and 3a showed better inhibitory activity against PPO than did Flumioxazin. These results indicate that our molecular design strategy contributes to the development of novel promising PPO inhibitors.
Highlights
Protoporphyrinogen oxidase (PPO) is the last common enzyme in both chlorophyll and haem biosynthesis [1,2,3,4], catalyzing the oxidation of protoporphyrinogen IX to protoporphyrin IX via molecular oxygen [5,6,7,8,9], and this enzyme has been identified as one of the most significant targets for herbicide research [10,11]
During the last thirty years, a number of active compounds inhibiting the enzyme PPO have been synthesized [12,13], some of which have been developed for use as low-toxicity, efficient, broad-spectrum commercial herbicides [14,15], such as Flumioxazin [16,17], sulfentrazone [18] and saflufenacil [19]
N-phenyl phthalimides, which exhibit broad structural diversity [20], have attracted considerable attention; their representative commercial products, Cinidon-ethyl, Flumiclorac-pentyl and Flumioxazin, were identified as a result of a stepwise optimization procedure from Chlorphthalim. Their common structural feature consists of two parts: An N-substituted phenyl group and tetrahydrophthalimide, which can interact with key active centre residues of the Molecules 2019, 24, 4363; doi:10.3390/molecules24234363
Summary
Protoporphyrinogen oxidase (PPO) is the last common enzyme in both chlorophyll (in plants) and haem (in animals) biosynthesis [1,2,3,4], catalyzing the oxidation of protoporphyrinogen IX to protoporphyrin IX via molecular oxygen [5,6,7,8,9], and this enzyme has been identified as one of the most significant targets for herbicide research [10,11]. MtPPO enzyme, such as Arg, Gly175, Leu372, Phe392, and FAD600, via H-bonding or π–π stacking interactions [21].PPO These findings have contributed to the development of PPOwere inhibitors. 1) [22,23], after docking using the mtPPO as a target, and by using Flumioxazin as a lead (Figure 1) [22,23], which they were synthesized and characterized by NMR and High resolution mass spectrometry after which they were synthesized and characterized by NMR and High resolution mass spectrometry (HR-MS) Their herbicidal activities were evaluated against Brassica campestris (B. campestris),.
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