Design, synthesis and antifungal/anti‐oomycete activity of pyrazolyl oxime ethers as novel potential succinate dehydrogenase inhibitors

Abstract

BACKGROUND Succinate dehydrogenase inhibitors (SDHIs) play an increasingly important role in controlling plant diseases. However, the similar structures of SDHIs result in rapid development of cross‐resistance development and a clear bottleneck of poor activity against oomycetes, therefore the need to seek new SDHI fungicides with novel structures is urgent. RESULTS Innovative pyrazolyl oxime ethers were designed by replacing amide with oxime ether based on the succinate dehydrogenase (SDH) structure, and 19 pairs of Z‐ and E‐isomers were efficiently prepared for the discovery of SDHI compounds with a novel bridge. Their biological activities against four fungi and two oomycetes were evaluated, and substantial differences were observed between the Z‐ and E‐ isomers of the title compounds. Furthermore, most of these compounds exhibited remarkable activities against Rhizoctonia solani with EC50 values of less than 10 mg L−1 in vitro, and bioassay in vivo further confirmed that E‐I‐6 exhibited good protective efficacy (76.12%) at 200 mg L−1. In addition, Z‐I‐12 provided better activity against the oomycetes Pythium aphanidermatum and Phytophthora capsici (EC50 = 1.56 and 0.93 mg L−1) than those of boscalid. Moreover, E‐I‐12 exhibited excellent SDH inhibition (IC50 = 0.21 mg L−1) thanks to its good binding ability to the SDH by hydrogen‐bonding interactions, π‐cation interaction and hydrophobic interactions. CONCLUSION Novel pyrazolyl oxime ethers have the potential as SDHI compounds for future development, and the strategy of replacing an amide bond with oxime ether may offer an alternative option in SDHI fungicide discovery.

Comprehensive Overview of Carboxamide Derivatives as Succinate Dehydrogenase Inhibitors

“…In addition, 27 showed excellent SDH inhibition (IC 50 = 1.35 mg/L), close to that of boscalid (IC 50 = 0.52 mg/L). This result indicated that oxime ethers could be a novel bridge for the development of new SDHIs fungicides …”

“…This result indicated that oxime ethers could be a novel bridge for the development of new SDHIs fungicides. 47 These results suggested that introduction of suitable Nsubstituent aryl or biphenyl group to the amide moiety of pyrazole carboxamides as hydrophobic tail could enhance their antifungal activities.…”

Design, Synthesis and Antifungal/Nematicidal Activity of Novel 1,2,4-Oxadiazole Derivatives Containing Amide Fragments

“…As a fungicide, it has not been found to be cross-resistant with other fungicides or SDHI fungicides [19,20]. Thus, the modification of the amide-bridged chain is likely to bring out a novel binding mode, further slowing down the development of resistance [14,21]. For all we have seen, the fungicides fluopimomide, florylpicoxamid, and thifluzamide and the nematicides fluazaindolizine and cyclobutrifluram all contain an amide bond (Figure 1).…”

“…A molecular docking station was built using the Ledock program according to the literature [14,51]. At present, due to the lack of reports on the tri-dimensional structures of the SDH of the fungal species, the crystal structure of SDH (PDB ID: 2FBW) [14,21,48] was downloaded from Gallus gallus on the Protein Data Bank (https://www.rcsb.org, las accessed on 18 October 2021) and was processed with Pymol. The molecular structures of F15 and fluopyram were drawn using ChemBioDraw Ultra 14.0 software and were optimized to minimize energy.…”

“…Moreover, there are few pesticide chemicals that are able to control fungi and nematodes simultaneously. Therefore, developing new, non-resistant pesticides will be of great importance to effectively control these plant diseases For the past few years, succinate dehydrogenase inhibitors (SDHI) as a key area of new compound research are experiencing fast market growth [13,14]. The SDHI mechanism of action is to inhibit the succinate dehydrogenase (SDH), which plays a crucial role as the only membrane protein in both the tricarboxylic acid cycle and mitochondrial electron transfer chain [15,16].…”