Novel heterocyclic amide derivatives containing a diphenylmethyl moiety: systematic optimizations, synthesis, antifungal activity and action mechanism.

BACKGROUND: The development of fungicides with low cross resistance, high efficacy and low resistance plays a central role in protecting crops, reducing yield losses, improving quality and maintaining global food security. Based on this important role, after a systematic optimization strategy, novel heterocyclic amide derivatives bearing diphenylmethyl fragment were screened, synthesized and verified with the spectrographic and x-ray diffraction analysis. RESULTS: In this study, the aforementioned optimization obtained compound B19 that was measured for antifungal activity against Rhizoctonia solani (median effective concentration, EC50 = 1.11 µg mL-1). Meanwhile, the anti-R. solani protective effect (79.34%) of compound B19 was evaluated in vivo at 100 µg mL-1, which is comparable to that of the control agent fluxapyroxad (80.67%). Thence, morphological observations revealed that compound B19 induced mycelium disruption and shrinking, mitochondrial number reduction and apoptosis acceleration, consistent with the results of the mitochondrial membrane potential and cell membrane permeability. Further investigations found that the potential target enzyme of compound B19 was SDH, which exerted fluorescence quenching dynamic curves similar to that of the commercialized SDHI fluxapyroxad. Additionally, research by molecular docking and MD simulations demonstrated that compound B19 had a similar binding mode acting on the surrounding residues in the SDH active pocket to that offluxapyroxad. CONCLUSION: The above results demonstrated that heterocyclic amide derivatives containing a diphenylmethyl moiety are promising scaffolds for targeting SDH of fungi and provide valuable antifungal leads with the potential to develop new SDH inhibitors. © 2024 Society of Chemical Industry.

Design, synthesis and antifungal activity of novel amide derivatives containing a pyrrolidine moiety as potential succinate dehydrogenase inhibitors.

To discover new succinate dehydrogenase inhibitors (SDHI) fungicides, a series of amide derivatives containing a pyrrolidine moiety were designed and synthesized, and their antifungal activities were evaluated against Monilinia fructicola (M. fructicola), Rhizoctonia solani (R. solani), Fusarium graminearum schw (F. graminearum), Fusarium oxysporum (F. oxysporum), and Phytophthora infestans (P. infestans). Some compounds showed excellent antifungal activities against the five fungi. Among them, compound 6 showed broad-spectrum inhibitory activities. The EC50 of compound 6 against M. fructicola, R. solani, F. graminearum, F. oxysporum, and P. infestans were 2.13, 14.42, 1.69, 27.79, and 27.12 mg/L, respectively. In addition, compound 6 can effectively inhibit the spore germination of M. fructicola and has moderate damage to the cell membrane. Compound 6 can effectively inhibit succinate dehydrogenase (SDH) of M. fructicola, and can significantly increase the expression levels of SDHC and SDHD. Compound 6 can be used as a lead structure for developing new SDH inhibitors.

Design, Synthesis, Inhibitory Activity, and Molecular Modeling of Novel Pyrazole-Furan/Thiophene Carboxamide Hybrids as Potential Fungicides Targeting Succinate Dehydrogenase.

To discover new fungicides targeting succinate dehydrogenase (SDH), 36 new furan/thiophene carboxamides containing 4,5-dihydropyrazole rings were designed, synthesized, and characterized. The crystal structure of compound 5l was determined with the X-ray diffraction (XRD) of single crystals. The antifungal activity of these compounds was studied against Botrytis cinerea, Pyricularia oryzae, Erysiphe graminis, Physalospora piricola, and Penicillium digitatum. Bioassay results were that most compounds had obvious inhibitory activity at 20 µg/mL. Compounds 5j, 5k, and 5l possessed outstanding inhibitory activity against B. cinerea. Their EC50 values were 0.540, 0.676, and 0.392 µg/mL, respectively. They owned better effects than fluxapyroxad (EC50 = 0.791 µg/mL). In the meantime, the inhibitory activity of 16 compounds was evaluated against SDH. It turned out that these compounds displayed excellent activity. The IC50 values of compounds 5j, 5k, and 5l reached 0.738, 0.873, and 0.506 µg/mL, respectively, whereas the IC50 value of fluxapyroxad was 1.031 µg/mL. The results of molecular dynamics (MD) simulation showed that compound 5l possessed a stronger affinity to SDH than fluxapyroxad.

Synthesis and Anti-Fungal/Oomycete Activity of Novel Sulfonamide Derivatives Containing Camphor Scaffold.

Twelve novel camphor sulfonamide derivatives 2a-2l were synthesized and characterized by 1 H-NMR, 13 C-NMR and HRMS spectra. The anti-fungal/oomycete activity bioassay showed that some of the title compounds displayed moderate to good anti-fungal/oomycete activities against B. dothidea and P. capsici. Compound 2d exhibited the best in vitro antifungal activity toward B. dothidea. The in vivo experiment revealed that compound 2d possessed considerable anti-B. dothidea effect at 200 mg/L. Mechanism study showed that compound 2d could increase the cell membrane permeability. In addition, the in vitro enzyme inhibition assay and molecular docking results indicated that compound 2d could be a potential SDH inhibitor.

A novel ferulic acid derivative attenuates myocardial cell hypoxia reoxygenation injury through a succinate dehydrogenase dependent antioxidant mechanism.

The molecular structure optimization aimed at definite target is expected to improve its anti-myocardial ischemia reperfusion (I/R) injury. Ferulic acid derivatives could probably attenuate myocardial I/R injury when optimized on account of definite target succinate dehydrogenase (SDH). Herein, an original compound hmy-paa (3-(4-hydroxy-3-methoxyphenyl)-N-(1H-pyrazol-3-yl)acrylamide), a combination of ferulic acid and active groups of enzyme inhibitor was synthesized, myocardial cell hypoxia reoxygenation (H/R) model were built, and SDH activity of myocardial cell was detected to investigate the effect of the derivative. Intriguingly, it could selectively inhibit SDH activity, and efficiently abate myocardial cell H/R injury. SDH is located in the mitochondrial inner membrane, and fluorescent hmy-paa could be observed to accumulate in cell and mitochondria through fluorescence inversion microscopy, which allows for more efficient SDH inhibition efficacy. By inhibiting SDH activity, hmy-paa could reduce oxidative damage by preventing excess production of intracellular reactive oxygen species as well as ensure energy production through the regulation of ATP level. The computational docking simulation exhibits a tightly bound mode between hmy-paa and SDH. Consequently, ferulic acid derivative hmy-paa is a new candidate for the treatment of myocardial H/R injury that exerts its therapeutic effect through a SDH dependent antioxidant mechanism. SDH could probably be a new target for drug discovery to alleviate myocardial I/R injury.