Insect growth regulators (IGRs) can
cause abnormal growth and development
in insects, resulting in incomplete metamorphosis or even death of
the larvae. Ecdysone receptor (EcR) and chitinase in insects play
indispensable roles in the molting process. Ecdysone analogues and
chitinase inhibitors are considered as potential IGRs. In order to
find new and highly effective IGR candidates, based on the structure–activity
relationship and molecular docking results of the active compound 6i (3-(tert-butyl)-N-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole-5-carboxamide)
discovered in our previous work, we changed the t-butyl group on the pyrazole ring into heptacycle to enhance the
hydrophobicity. Consequently, a series of novel heptacyclic pyrazolamide
derivatives were designed and synthesized. The bioassay results demonstrated
that some compounds showed obvious insecticidal activity. Especially, D-27 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) showed good activities against Plutella xylostella (LC50, 51.50 mg·L–1) and Mythimna separata (100% mortality at 2.5 mg·L–1). Furthermore,
protein validation indicated that D-27 acts not only
on the EcR but also on chitinase Of ChtI. Molecular
docking and molecular dynamics simulation explained the vital factors
in the interaction between D-27 and receptors. D-27 may be a new lead candidate with a dual target in which Of ChtI shall be the main one. This work created a new starting
point for discovering a novel type of IGRs.
Nematode
chitinases are critical components of the nematode life
cycle, and CeCht1 is a potential target for developing
novel nematicides. Herein, lunidonine, a natural quinoline alkaloid,
was first discovered to have inhibitory activity against CeCht1, which was acquired from a library of over 16,000 natural products
using a structure-based virtual screening methodology. A pocket-based
lead optimization strategy was employed based on the predicted binding
mode of lunidonine. Subsequently, a series of benzo[d][1,3]dioxole-5-carboxylate derivatives were designed and synthesized,
and their inhibitory activities against CeCht1 as
well as in vitro nematicidal activities against Caenorhabditis
elegans were assessed. The analysis of structure–activity
relationship and inhibitory mechanisms provided insights into their
interactions with the CeCht1 active site, which could
facilitate future research in improving the potency of the inhibitory
activity. Especially, compound a12 interacted well with CeCht1 and exhibited excellent in vitro nematicidal activity
against C. elegans with a LC50 value of 41.54 mg/L, suggesting that it could be a promising candidate
for a novel chemical nematicide targeting CeCht1.
The known binding modes and structural features of these inhibitors
will contribute to the design of stronger CeCht1-based
nematicides to control nematodes in agriculture.
Ecdysone receptor (EcR) and chitinase play a critical role in the molting stage of insect pests. Each of them is considered a promising target for the development of novel insect growth regulators (IGRs). In the present paper, a total of 24 (23 novel) hexacyclic pyrazolamide derivatives were designed and synthesized by reducing the heptacycle and inserting small flexible linkers on the basis of the previously discovered dual-target compound D-27 acting simultaneously on EcR and Ostrinia furnacalis chitinase (OfChtI). Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda, and Ostrinia furnacalis larvae were evaluated. The results revealed that the insecticidal activity was not significantly enhanced when the heptacycle on the pyrazole ring was reduced to a hexacycle. However, the insertion of an additional methylene spacer between the substituted phenyl ring and the amide bond can improve the insecticidal activity. Among the derivatives, the most potent compound, 6j, exhibited promising insecticidal activities against P. xylostella and S. frugiperda. Further protein binding assays and molecular docking indicated that 6j could target both EcR and OfChtI, and is a potential lead compound for IGRs. The present work provides valuable clues for the development of new dual-target IGRs.
Insect growth regulators (IGRs) disrupt normal development
of physiological processes in insects and are recognized as green
insecticides. Insect chitinases play a crucial role in cuticle degradation
during molting, and OfChtI, OfChtII,
and OfChi-h are the prospective targets for discovering
new insecticides as IGRs. In our previous study, we identified the
lead compound a12 as a promising multitarget inhibitor.
Herein, we used the binding modes of a12 with three chitinases
to recognize the critical interactions and residues favorable to the
bioactivity. Subsequently, to improve the bioactivity of inhibitors
via enhanced the interactions with important residues, a series of
benzo[d][1,3]dioxole-6-benzamide derivatives were
rationally designed and synthesized, and their inhibitory activities
against Ostrinia furnacalis (O. furnacalis) chitinases, as well as insecticidal
activities against O. furnacalis and Plutella xylostella (P. xylostella) were investigated. Among them, compound d29 acted
simultaneously on OfChtI, OfChtII,
and OfChi-h with K
i values
of 0.8, 11.9, and 2.3 μM, respectively, a significant improvement
over the inhibitory activity of the lead compound a12. Moreover, d29 exhibited superior activity than a12 against two lepidopteran pests by interfering with normal
insect growth and molting, indicating that d29 is a potential
lead candidate for novel IGRs with a multichitinase mechanism. The
present study revealed that simultaneous inhibition on multiple chitinases
could achieve excellent insecticidal activity. The elucidation of
inhibition mechanisms and molecular conformations illustrated the
interactions with the three chitinases, as well as the discrepancy
in bioactivity, which will be beneficial for future work to improve
the potency of bioactivity as IGRs for pest control in sustainable agriculture.
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