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 <b>4b</b>, <b>4g</b>, <b>4h</b>, <b>4i</b>, and <b>5j</b> showed remarkable antifungal activity against <i>Sclerotinia sclerotiorum</i>, affording EC50 values ranging from 0.1∼1.1 mg/L. In particular, compound <b>4i</b> displayed the most potent activity against <i>S. sclerotiorum</i> (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 <b>4i</b><i>-</i>treated <i>S. sclerotiorum</i> by scanning electron microscopy. Furthermore, the in vivo antifungal assay against <i>S. sclerotiorum</i> revealed that compounds <b>4g</b> and <b>4i</b> were effective for suppressing rape Sclerotinia rot at a dosage of 200 mg/L. In the SDH inhibition assay, compounds <b>4g</b> and <b>4i</b> 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 <b>4g</b> with SDH revealed that compound <b>4g</b> 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.