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

A series of novel pyrazole-4-carboxamides bearing anether groupwere designed and synthesized on the basis of the structure of commercialsuccinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram viascaffold hopping and evaluated for their antifungal activities againstfive fungi. The bioassay results showed that most of the target compoundsexhibited excellent in vitro antifungal activityagainst Rhizoctonia solani and somecompounds exerted remarkable antifungal activities against Sclerotinia sclerotiorum, Botrytiscinerea, Fusarium graminearum, and Alternaria alternate. Particularly,compounds 7d and 12b displayed outstandingantifungal activity against R. solani, with an EC50 value of 0.046 mu g/mL, far superiorto that of boscalid (EC50 = 0.741 mu g/mL) and fluxapyroxad(EC50 = 0.103 mu g/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) enzymaticinhibition assay showed that compound 7d generated significantSDH inhibition, with an IC50 value of 3.293 mu M, whichwas about 2 times better than that of boscalid (IC50 =7.507 mu M) and fluxapyroxad (IC50 = 5.991 mu M).Furthermore, scanning electron microscopy (SEM) analysis indicatedthat compounds 7d and 12b significantlydestroyed the typical structure and morphology of R.solani hyphae. The molecular docking study revealedthat compounds 7d and 12b could embed intothe binding pocket of SDH and form hydrogen bond interactions withTRP173 and TRY58 at the activity site of SDH, which was in line withfluxapyroxad, indicating that they had a similar mechanism of action.These results demonstrated that compounds 7d and 12b could be promising candidates of SDHI fungicides, whichdeserved further investigation.