The
carbon–silicon switch strategy has become a key technique
for structural optimization of drugs to widen the chemical space,
increase drug activity against targeted proteins, and generate novel
and patentable lead compounds. Flubeneteram, targeting succinate dehydrogenase
(SDH), is a promising fungicide candidate recently developed in China.
We describe the synthesis of novel SDH inhibitors with enhanced fungicidal
activity to enlarge the chemical space of flubeneteram by employing
the C–Si switch strategy. Several of the thus formed flubeneteram-silyl
derivatives exhibited improved fungicidal activity against porcine
SDH compared with the lead compound flubeneteram and the positive
controls. Disease control experiments conducted in a greenhouse showed
that trimethyl-silyl-substituted compound W2 showed comparable
and even higher fungicidal activities compared to benzovindiflupyr
and flubeneteram, respectively, even with a low concentration of 0.19
mg/L for soybean rust control. Furthermore, compound W2 encouragingly performed slightly better control than azoxystrobin
and was less active than benzovindiflupyr at the concentration of
100 mg/L against soybean rust in field trials. The computational results
showed that the silyl-substituted phenyl moiety in W2 could form strong van der Waals (VDW) interactions with SDH. Our
results indicate that the C–Si switch strategy is an effective
method for the development of novel SDH inhibitors.
Succinate
dehydrogenase (SDH) inhibitor is one of the research
hotspots for the development of fungicides. Herein, we describe the
design and synthesis of N-methoxy-(biphenyl-ethyl)-pyrazole-carboxamide
derivatives with enhanced fungicidal activity by employing fragment
combination strategy. The SDH enzymatic activity was evaluated for
24 title compounds, and compound 7s was identified as
the highest activity against porcine SDH with an IC50 value
of 0.014 μM, 205-fold greater than that of fluxapyroxad. Furthermore,
the greenhouse experiments showed that compound 7u exhibited
potent fungicidal activity against wheat powdery mildew with an EC50 value of 0.633 mg/L, higher activity than fluxapyroxad and
benzovindiflupyr. The computational results showed that the fluorine
atom substituted on the pyrazole ring formed an extra dipolar–dipolar
interaction with C_S42 and then increased the van der Waals interaction
between the compound and SDH. The structural and mechanistic insights
obtained from the present work will provide a valuable clue to developing
novel SDH inhibitors.
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