Discovery of Highly Efficient Novel Antifungal Lead
Compounds Targeting Succinate Dehydrogenase: Pyrazole-4-carboxamide
Derivatives with an N‑Phenyl Substituted Amide
Fragment
posted on 2023-11-29, 08:44authored byXin-Peng Sun, Chen-Sheng Yu, Li-Jing Min, Charles L. Cantrell, Xuewen Hua, Na-Bo Sun, Xing-Hai Liu
Developing
environmentally friendly fungicides is crucial to tackle
the issue of rising pesticide resistance. In this study, a series
of novel pyrazole-4-carboxamide derivatives containing N-phenyl substituted amide fragments were designed and synthesized.
The structures of target compounds were confirmed by 1H
NMR, 13C NMR, and HRMS, and the crystal structure of the
most active compound N-(1-(4-(4-(tert-butyl)benzamido)phenyl)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide (U22) was further determined by X-ray single-crystal diffraction.
The bioassay results indicated that the 26 target compounds possessed
good in vitro antifungal activity against Sclerotinia
sclerotiorum with EC50 values for compounds U12, U13, U15, U16, U18, U22, and U23 being 4.17 ±
0.46, 8.04 ± 0.71, 7.01 ± 0.71, 12.77 ± 1.00, 8.11
± 0.70, 0.94 ± 0.11, and 9.48 ± 0.83 μg·mL–1, respectively, which were the similar to controls
bixafen (6.70 ± 0.47 μg·mL–1), fluxapyroxad
(0.71 ± 0.14 μg·mL–1), and pydiflumetofen
(0.06 ± 0.01 μg·mL–1). Furthermore,
in vivo antifungal activity results against S. sclerotiorum indicated that compounds U12 (80.6%) and U22 (89.9%) possessed excellent preventative efficacy at 200 μg·mL–1, which was the same as the control pydiflumetofen
(82.4%). Scanning electron microscopy and transmission electron microscopy
studies found that the compound U22 could destroy the
hyphal morphology and damage mitochondria, cell membranes, and vacuoles.
The results of molecular docking of compound U22 and
pydiflumetofen with succinate dehydrogenase (SDH) indicated they interact
well with the active site of SDH. This study validated our approach
and design strategy to produce compounds with an enhanced biological
activity as compared to the parent structure.