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

Abstract

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.

Design, Synthesis, and Antifungal Activities of Novel Carboxamides Derivatives Bearing a Chalcone Scaffold as Potential SDHIs

“…The in vivo protective activities and curative activities of compound 5 k and Boscalid were determined on rice leaves by the detached leaf assay according to literature [8,32,33] …”

“…The in vivo protective activities and curative activities of compound 5 k and Boscalid were determined on rice leaves by the detached leaf assay according to literature. [8,32,33] In Vitro SDH Inhibition Assay SDH enzyme activity of 5 k and Boscalid were measured using a succinate dehydrogenase assay kit (Mlbio, ml076573). [34][35][36] The detailed experimental method was shown in the Supporting Information.…”

“…Therefore, there is an increasing and urgent need for development of safe and environment friendly chemical fungicides to effectively control fungal diseases. Succinate dehydrogenase inhibitors (SDHIs), which represent the 4th generation of chemical fungicides, are the fastest‐growing fungicides in the market recently [8] . They can block the electron transfer of mitochondrial electron transport chain and disrupt the tricarboxylic acid cycle via inhibiting succinate dehydrogenase (SDH), resulting in fungal death [9–11] .…”

“…Succinate dehydrogenase inhibitors (SDHIs), which represent the 4th generation of chemical fungicides, are the fastest-growing fungicides in the market recently. [8] They can block the electron transfer of mitochondrial electron transport chain and disrupt the tricarboxylic acid cycle via inhibiting succinate dehydrogenase (SDH), resulting in fungal death. [9][10][11] This unique mechanism, which is different from the former three generations of fungicides and not prone to cross-resistance, making SDHIs excellent candidates for overcoming fungicide resistance.…”

Discovery of Highly Efficient Novel Antifungal Lead Compounds Targeting Succinate Dehydrogenase: Pyrazole-4-carboxamide Derivatives with an N-Phenyl Substituted Amide Fragment

“…Currently, the use of fungicides is the most common method of plant protection. − Succinate dehydrogenase (SDH), also known as succinate ubiquinone oxidoreductase (SQR) or mitochondrial complex II, , plays a crucial role in electron transport chains and oxidative phosphorylation, converting succinic acid into fumarate and reducing ubiquinone to ubiquinone alcohol, making it an ideal target for studying new types of fungicides. Therefore, in pesticides, succinate dehydrogenase inhibitor (SDHI) fungicides are widely used. − …”