Novel pyrazole-4-carboxamides and aromatic carboxamides derivatives containing a hydrazine moiety as potential SDHIs

Abstract

To promote the discovery and development of novel SDHIs fungicides, a series of novel pyrazole-4-carboxamides 4a-t and aromatic carboxamides 8a-i with a hydrazine scaffold were designed, synthesized, and evaluated for their antifungal activities. The results showed that compound 4i exhibited outstanding antifungal activity against R. solani with EC50 value of 0.24 μg/mL, which was about three times more potent than that of Boscalid (EC50 = 0.74 μg/mL). Moreover, compound 4i also displayed promising antifungal activities against Sclerotinia sclerotiorum, B. cinerea, Alternaria alternate, and F. graminearum (IC50 = 1.21–4.50 μg/mL), indicating a broad spectrum of antifungal activities. Additionally, in vivo antifungal activities results showed that 4i could significantly inhibit the growth of R. solani in rice leaves with good protective efficacy (55.21%) and excellent curative efficacy (73.06%) at 100 μg/mL. The results of the SDH enzymatic inhibition assay showed that compound 4i generated significant SDH inhibition with IC50 value of 6.47 μM, which was superior to Boscalid (IC50 = 7.92 μM). Furthermore, SEM analysis showed that compound 4i could remarkably disrupt the typical structure and morphology of R. solani hyphae. The molecular docking study revealed that compound 4i could form H-bonds interactions and π-π interactions with TRP173 and TRY58 at the activity site of SDH, which was similar to that of Boscalid. The DFT calculation provided crucial information regarding electron transfer, which was essential in understanding the mechanism of molecules and target enzymes. These results indicated that compound 4i showed potential as a SDHIs fungicide and warranted further investigation.