Reversible Regulation of Succinate Dehydrogenase by Tools of Photopharmacology

A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis of the structure of commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping and evaluated for their antifungal activities against five fungi. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activity against Rhizoctonia solani and some compounds exerted remarkable antifungal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Alternaria alternate. Particularly, compounds 7d and 12b displayed outstanding antifungal activity against R. solani, with an EC 50 value of 0.046 μg/mL, far superior to that of boscalid (EC 50 = 0.741 μg/mL) and fluxapyroxad (EC 50 = 0.103 μg/mL). Meanwhile, compound 12b also presented a broader fungicidal spectrum than other compounds. Moreover, in vivo anti-R. solani results showed that compounds 7d and 12b could significantly inhibit the growth of R. solani in rice leaves with excellent protective and curative efficacies. In addition, the results of the succinate dehydrogenase (SDH) enzymatic inhibition assay showed that compound 7d generated significant SDH inhibition, with an IC 50 value of 3.293 μM, which was about 2 times better than that of boscalid (IC 50 = 7.507 μM) and fluxapyroxad (IC 50 = 5.991 μM). Furthermore, scanning electron microscopy (SEM) analysis indicated that compounds 7d and 12b significantly destroyed the typical structure and morphology of R. solani hyphae. The molecular docking study revealed that compounds 7d and 12b could embed into the binding pocket of SDH and form hydrogen bond interactions with TRP173 and TRY58 at the activity site of SDH, which was in line with fluxapyroxad, indicating that they had a similar mechanism of action. These results demonstrated that compounds 7d and 12b could be promising candidates of SDHI fungicides, which deserved further investigation.

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

Luo

Zhao

Zhang

et al. 2023

“…Among commercial SDH inhibitors, the representative molecules generally contain core amide bonds and hydrophobic and polar moieties. 18 According to the investigation, as many as half of 24 commercialized SDH inhibitors contain pyrazole-4carboxamides skeleton. 19 Over the past few years, many research groups have optimized the pyrazole-4-carboxamides scaffold, such as the modification of the pyrazole ring, introducing a skeleton containing diphenyl ether 20 and diarylamine 21 into that amine part, replacing amides with urea/thiourea, 22 hydrazides, 23 and oxime ethers , 24 and hopping and inversing the amide groups.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Among commercial SDH inhibitors, the representative molecules generally contain core amide bonds and hydrophobic and polar moieties . According to the investigation, as many as half of 24 commercialized SDH inhibitors contain pyrazole-4-carboxamides skeleton .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Pyrazol-5-yl-benzamide Derivatives Containing Oxazole Group as Potential Succinate Dehydrogenase Inhibitors

Cheng

Luo

et al. 2022

A series of pyrazol-5-yl-benzamide derivatives containing the oxazole group were designed and synthesized as potential SDH inhibitors. According to the results of the bioassays, most target compounds displayed moderate-to-excellent in vitro antifungal activities against Valsa mali, Sclerotinia scleotiorum, Alternaria alternata, and Botrytis cinerea. Among them, compounds C13, C14, and C16 exhibited more excellently inhibitory activities against S. sclerotiorum than boscalid (EC50 = 0.96 mg/L), with EC50 values of 0.69, 0.26, and 0.95 mg/L, respectively. In vivo experiments on rape leaves and cucumber leaves showed that compounds C13 and C14 exhibited considerable protective effects against S. sclerotiorum than boscalid. SEM analysis indicated that compounds C13 and C14 significantly destroyed the typical structure and morphology of S. scleotiorum hyphae. In the respiratory inhibition effect assays, compounds C13 (28.0%) and C14 (33.9%) exhibited a strong inhibitory effect on the respiration rate of S. sclerotiorum mycelia, which was close to boscalid (30.6%). The results of molecular docking indicated that compounds C13 and C14 could form strong interactions with the key residues TRP O:173, ARG P:43, TYR Q:58, and MET P:43 of the SDH. Furthermore, the antifungal mechanism of these derivatives was demonstrated by the SDH enzymatic inhibition assay. These results demonstrate that compounds C13 and C14 can be developed into novel SDH inhibitors for crop protection.

“…For common herbicides, only a small amount of them entered the plant body, but most would adhere to plant leaves, soil, and so forth . The residual active herbicides can cause a series of environmental problems. − Compared with common herbicides, the activity of the photosensitive herbicide molecules can be regulated by light, which is of significance for the safe application of herbicide molecules and the reduction of resistance. − However, photosensitive herbicides have been rarely reported.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of (E)/(Z)-Verbenone Oxime Ethers and Photoresponsive Behavior to Herbicidal Activity

Cui

Wang

Lin

et al. 2022

The accumulation of residual active herbicides in the environment can cause a series of problems. It is thus meaningful to explore a photoresponsive herbicide, whose activity can be weakened under the action of light to reduce the negative effect. To this purpose, a series of (E)/(Z)-verbenone oxime ethers were designed, synthesized, and characterized. Oxime ether groups were adopted as the trigger switches. The preliminary screening for herbicidal activity showed that some of them exhibited better or comparable effects than that of the commercial herbicide flumioxazin against Brassica campestris and Echinochloa crusgalli. Meanwhile, five pairs of the target compounds with significantly different herbicidal effects between E- and Z-forms were further investigated for their reversible isomerization reaction and the accompanying variation of herbicidal activity. As a result, the maximum conversion rates were around 50%, and the herbicidal effect of the resulting mixture of E- and Z-isomers decreased outstandingly. The phototransformation mechanism of a pair of isomers (E)-4a and (Z)-4a was preliminarily explored. Besides, a reasonable and effective 3D-quantitative structure–activity relationship model (r 2 = 0.984 and q 2 = 0.571) was established and the binding mode was also investigated by molecular docking.