Phytopathogenic Fungicidal Activity and Mechanism Approach of Three Kinds of Triphenylphosphonium Salts.

The triphenylphosphonium (TPP) cation has been widely used as a carrier for mitochondria-targeting molecules. We synthesized two commonly employed targeting systems, namely, ω-triphenylphosphonium fatty acids (group 2) and ω-triphenylphosphonium fatty alcohols (group 3), to assess the impact of the TPP module on the biological efficacy of mitochondria-targeting molecules. We evaluated their fungicidal activities against nine plant pathogenic fungi in comparison to alkyl-1-triphenylphosphonium compounds (group 1). All three compound groups exhibited fungicidal activity and displayed a distinct "cut-off effect", which depended on the length of the carbon chain. Specifically, group 1 compounds showed a cut-off point at C10 (compound 1-7), while group 2 and 3 compounds exhibited cut-off points at C15 (compound 2-12) and C14 (compound 3-11), respectively. Notably, group 1 compounds displayed significantly higher fungicidal activity compared to groups 2 and 3. However, group 2 and 3 compounds showed similar activity to each other, although susceptibility may depend on the pathogen tested. Initial investigations into the mechanism of action of the most active compounds suggested that their fungicidal performance may be primarily attributed to their ability to damage the membrane, as well as uncoupling activity and inhibition of fungal respiration. Our findings suggest that the TPP module used in delivery systems as aliphatic acyl or alkoxyl derivatives with carbon chains length < 10 will contribute negligible fungicidal activity to the TPP-conjugate compared to the effect of high level of accumulation in mitochondria due to its mitochondria-targeting ability. These results provide a foundation for utilizing TPP as a promising carrier in the design and development of more effective mitochondria-targeting drugs or pesticides.

Long-Chain Molecules with Agro-Bioactivities and Their Applications.

Long-chain molecules play a vital role in agricultural production and find extensive use as fungicides, insecticides, acaricides, herbicides, and plant growth regulators. This review article specifically addresses the agricultural biological activities and applications of long-chain molecules. The utilization of long-chain molecules in the development of pesticides is an appealing avenue for designing novel pesticide compounds. By offering valuable insights, this article serves as a useful reference for the design of new long-chain molecules for pesticide applications.

Triphenylphosphonium (TPP)-Conjugated Quinolone Analogs Displayed Significantly Enhanced Fungicidal Activity Superior to Its Parent Molecule.

Although 1-hydroxy-4-quinolone derivatives, such as 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), aurachin C, and floxacrine, have been reported as effective cytochrome bc1 complex inhibitors, the bioactivity of these products is not ideal, presumably due to their low bioavailability in tissues, particularly their poor solubility and low mitochondrial accumulation. In order to overcome the drawbacks of these compounds and develop their use as agricultural fungicides acting by cytochrome bc1 inhibition, in this study, three novel mitochondria-targeting quinolone analogs (mitoQNOs) were designed and synthesized by conjugating triphenylphosphonium (TPP) with quinolone. They exhibited greatly enhanced fungicidal activity compared to the parent molecule, especially mitoQNO11, which showed high antifungal activity against Phytophthora capsici and Sclerotinia sclerotiorum with EC50 values of 7.42 and 4.43 µmol/L, respectively. In addition, mitoQNO11 could inhibit the activity of the cytochrome bc1 complex of P. capsici in a dose-dependent manner and effectively depress its respiration and ATP production. The greatly decreased mitochondrial membrane potential and massively generated reactive oxygen species (ROS) strongly suggested that the inhibition of complex III led to the leakage of free electrons, which resulted in the damage of the pathogen cell structure. The results of this study indicated that TPP-conjugated QNOs might be used as agricultural fungicides by conjugating them with TPP.

Triphenylphosphonium-Driven Targeting of Pyrimorph Fragment Derivatives Greatly Improved Its Action on Phytopathogen Mitochondria.

Pyrimorph is a carboxylic acid amide (CAA) fungicide, which shows excellent activity against oomycetes such as pepper phytophthora blight, tomato late blight, and downy mildew of cucumber. It works mainly by inhibiting the biosynthesis of cell wall of oomycetes. However, pyrimorph also shows weak activity of inhibiting mitochondrial complex III, which is the first CAA fungicide found to act on mitochondria. To improve this effect on mitochondria and develop fungicides that may have a novel mechanism of action, in this paper, by disassembling pyrimorph and conjugating the fragments with the mitochondrial-targeted delivery system (triphenylphosphonium), three series of mitochondrial-targeting analogues of pyrimorph were designed and synthesized. The results show that the pyridine-containing 1,1-diaryl is the core module of inhibition mitochondrial function of pyrimorph. Among these conjugates, compound 3b with a short linker showed the highest and broad-spectrum fungicidal activity, strong respiratory inhibition activity, and adenosine 5'-triphosphate synthesis inhibition activity, suggesting its potential as a fungicide candidate. 3b exhibited greatly improved action on mitochondria, such as by destroying the mitochondrial function of pathogens, causing mitochondrial swelling, weakening its influence on cell wall morphology, and so on. More importantly, this study provides a method to strengthen the drugs or pesticides with weak mitochondrial action, which is of special significance for developing mitochondrial bioactive molecules with the novel action mechanism.

Mitochondrion-Targeted Triphenylphosphonium-Based Kresoxim-Methyl Analogues: Synthesis, Fungicidal Activity, and Action Mechanism Approach.

ß-Methoxyacrylate fungicides as complex III Qo site inhibitors play a crucial role in the control of crop diseases. In this study, the triphenylphosphonium (TPP)-driven mitochondrion-targeting strategy was used to modify the kresoxim-methyl scaffold at the toxicophore or side chain to develop novel mitochondrion-targeted QoI fungicides. These kresoxim-methyl analogues exhibited different fungicidal activities, depending on the position of TPP conjugation and the linker length. Among them, 2A-5 and 2C-4 showed excellent characteristics superior to kresoxim-methyl as candidate fungicides, in which the activity enhancement against Phytophthora capsici was the most remarkable, with an EC50 value of about 5 µM. Notably, both hyphal and zoospore structures of the pathogens were severely damaged after treatment with them. The action mechanism approach revealed that they might cause a significant decrease in ATP synthesis and ROS outbreak in different ways. The results also provided a new insight into the contribution of targeting group TPP to the fungicidal activity in TPP-driven fungicides.

Synthesis and fungicidal activity of methyl (E)-1-(2-((E)-2-methoxy-1-(methoxyimino)-2-oxoethyl)benzyl)-2-(1-arylidene)hydrazine-1-carboxylates †‡.

To discover novel strobilurin fungicides, a series of methyl (E)-1-(2-((E)-2-methoxy-1-(methoxy-imino)-2-oxoethyl)benzyl)-2-(1-arylidene)hydrazine-1-carboxylates were designed based on the principle of biologically active splicing and the receptor target structure. The fungicidal activity results show that this class of compounds has excellent fungicidal activity, especially against S. sclerotiorum (Lib.) deBary, wheat white powder and puccinia polysora. The result of structure-activity relationship implied that the introduction of t-butyl in the side chain facilitates the hydrophobic interaction between the compound and the active site. The electrostatic effect of the substituents on the benzene ring is also a key factor affecting such activities. Among them, the compound I-1 not only showed a fungicidal effect comparable to that of kresoxim-methyl in vivo, but also had an excellent inhibitory effect on spore germination of P. oryzae Cav in vitro, which indicated that it could be used as a potential commercial fungicide for plant disease control.

The application of "plug-in molecules" method in novel strobilurin fungicides screening.

Based on the "plug-in molecular" method, a series of novel strobilurin derivatives with aryloxypyridinyl-1-ethanone oxime side chains were designed, synthesized, and screened. The biological activity experiment showed that they had an excellent fungicidal effect on plant pathogens, especially Sclerotinia sclerotiorum. Compounds 5-01 and 5-09 had significant fungicidal activity and broad fungicidal spectrum. The structure-activity relationship indicates that the cis configuration, increasing the number of pharmacophores, substitution of the 2 position of the pyridine ring, and the introduction of chlorine atom on the benzene ring were not conducive to the fungicidal activity of such compounds. The model of 3D-QSAR indicated the introduction of large electropositive groups at the 4 position of the benzene ring and the introduction of small electronegative groups at the 2 position of the benzene ring were beneficial to the fungicidal activity, and compounds 6 were designed. Compared with azoxystrobin, compound 6-02 had a more effective fungicidal effect against Sclerotinia sclerotiorum (Lib.) de Bary. Cytotoxicity test and transmission electron microscopy showed that the modification of strobilurins fungicide by the "plug-in molecular" method would not affect its toxicity and mechanism. The "plug-in molecular" method is an efficient method for screening highly active compounds, which has important guiding significance for creating new pesticide molecules.