Design, Synthesis, and Antifungal Activity of Novel Thiophene/Furan-1,3,4-Oxadiazole Carboxamides as Potent Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH) is known as an ideal target for the investigations of fungicides. To develop novel SDH inhibitors, 30 novel thiophene/furan-1,3,4-oxadiazole carboxamide derivatives were designed and synthesized. In the in vitro antifungal assay, a majority of the target compounds demonstrated fair to potent antifungal activity against seven tested phytopathogenic fungi. Compounds , , , , and showed remarkable antifungal activity against , affording EC50 values ranging from 0.1∼1.1 mg/L. In particular, compound displayed the most potent activity against (EC = 0.140 ± 0.034 mg/L), which was superior to that of boscalid (EC = 0.645 ± 0.023 mg/L). A further morphological investigation revealed the abnormal mycelia and damaged cell structures of compound treated by scanning electron microscopy. Furthermore, the in vivo antifungal assay against revealed that compounds and were effective for suppressing rape Sclerotinia rot at a dosage of 200 mg/L. In the SDH inhibition assay, compounds and also presented significant inhibitory activity with IC values of 1.01 ± 0.21 and 4.53 ± 0.19 μM, respectively, which were superior or equivalent to that of boscalid (3.51 ± 2.02 μM). Molecular docking and molecular dynamics simulation of compound with SDH revealed that compound could form strong interactions with the key residues of the SDH. These results indicated that this class of derivatives could be a promising scaffold for the discovery and development of novel SDH inhibitors.