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

Abstract

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.

Novel fungicidal phenylethanol derivatives linking a trifluoromethyl pyrazole pharmacophore: design, synthesis, crystal structure, and biology evaluation

“…The circular epidermises with 8 mm diameter were peeled off using a puncher, and the mycelium cakes of B. cinerea were then inoculated onto the given surface of the tomatoes. 40,41 Each treatment was repeated three times. The treated tomatoes were incubated in an incubator at 20 °C with 80% humidity for 7 days.…”

Synthesis of 4H-Pyrazolo[3,4-d]pyrimidin-4-one Hydrazine Derivatives as a Potential Inhibitor for the Self-Assembly of TMV Particles

“… ,, However, hydrazine scaffolds have yet to be explored for their potential in the treatment of plant viruses. Pyridine fragments have been identified as a unique pharmacophore, and various agrochemicals containing pyridine fragments have been described, − making it the most successful heterocycle among plant protection chemicals in the 21st century …”