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 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.