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

Abstract

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 4b, 4g, 4h, 4i, and 5j showed remarkable antifungal activity against Sclerotinia sclerotiorum, affording EC50 values ranging from 0.1∼1.1 mg/L. In particular, compound 4i displayed the most potent activity against S. sclerotiorum (EC50 = 0.140 ± 0.034 mg/L), which was superior to that of boscalid (EC50 = 0.645 ± 0.023 mg/L). A further morphological investigation revealed the abnormal mycelia and damaged cell structures of compound 4i-treated S. sclerotiorum by scanning electron microscopy. Furthermore, the in vivo antifungal assay against S. sclerotiorum revealed that compounds 4g and 4i were effective for suppressing rape Sclerotinia rot at a dosage of 200 mg/L. In the SDH inhibition assay, compounds 4g and 4i also presented significant inhibitory activity with IC50 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 4g with SDH revealed that compound 4g 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.