Discovery of Novel Hybrid-Type Strigolactone Mimics Derived from Cinnamic Amide.

Strigolactones (SLs) are a class of plant hormones and rhizosphere communication signals of great interest. They perform diverse biological functions including the stimulation of parasitic seed germination and phytohormonal activity. However, their practical use is limited by their low abundance and complex structure, which requires simpler SL analogues and mimics with maintained biological function. Here, new, hybrid-type SL mimics were designed, derived from Cinnamic amide, a new potential plant growth regulator with good germination and rooting-promoting activities. Bioassay results indicated that compound 6 not only displayed good germination activity against the parasitic weed O. aegyptiaca with an EC50 value of 2.36 × 10-8 M, but also exhibited significant inhibitory activity against Arabidopsis root growth and lateral root formation, as well as promoting root hair elongation, similar to the action of GR24. Further morphological experiments on Arabidopsis max2-1 mutants revealed that 6 possessed SL-like physiological functions. Furthermore, molecular docking studies indicated that the binding mode of 6 was similar to that of GR24 in the active site of OsD14. This work provides valuable clues for the discovery of novel SL mimics.

A Potential Lead for Insect Growth Regulator: Design, Synthesis, and Biological Activity Evaluation of Novel Hexacyclic Pyrazolamide Derivatives.

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.

New lead discovery of insect growth regulators based on the scaffold hopping strategy.

Insect growth regulators (IGRs), which can interrupt or inhibit pest life cycles, are low-toxicity pesticides widely used in integrated pest management (IPM). Ecdysone analogues and chitinase inhibitors are familiar IGRs that have attracted considerable attention because of their unique modes of action and low toxicity to non-target organisms. To find new and highly effective candidate IGRs with novel mechanisms, D-08 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) was chosen as a lead compound, and a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized using the scaffold hopping strategy. The bioassay showed that III-27 (N-(2-methylphenethyl)-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) had excellent activity against Plutella xylostella. Protein verification and molecular docking indicated that III-27 could act on both the ecdysone receptor (EcR) and Ostrinia furnacalis chitinase (Of ChtI) and is a promising new lead IGRs. The interaction mechanism of III-27 with EcR and Of ChtI was then studied by molecular docking. These results provide important guidance for the study of new dual-target IGRs.

Identification of sex pheromone in Macdunnoughia crassisigna Warren (Lepidoptera: Noctuidae) and field optimization of the sex attractant.

BACKGROUND: Sex pheromones have proven to be a viable tool for monitoring and controlling pests and is an important part of integrated pest management (IPM). The noctuid moth Macdunnoughia crassisigna Warren poses a significant threat as a defoliator pest, impacting soybean and cruciferous vegetable production and quality in East Asia. However, a lack of comprehensive knowledge about its sexual chemical signaling hampers the development of semiochemical-based IPM approaches for M. crassisigna. RESULTS: We first determined the mating rhythms of M. crassisigna. We then collected pheromones from the sex glands of virgin females at the mating peak and analyzed their components using gas chromatography-electroantennogram detection analysis. The results showed that three components elicited significant electrophysiological responses in male antennae. Gas chromatography-mass spectrometry analysis characterized these components as (Z)-7-dodecene acetate (Z7-12:OAc), (Z)-9-tetradecene acetate (Z9-14:OAc), and (Z)-11-hexadecen-1-ol (Z11-16:OH). Further field experiments indicated that the mixture of Z7-12:OAc and Z9-14:OAc at a ratio of 3:1 displayed significant attractivity to males, confirming its role as a putative sex pheromone of M. crassisigna. Long-term monitoring tests showed that traps baited with these pheromone lures effectively mirrored the population dynamics of M. crassisigna. CONCLUSION: This study successfully identified and validated the sex pheromone released by female M. crassisigna and formulated potent sex lures for field-based pest monitoring. These findings enriched our understanding of chemical communication in Noctuidae and laid a foundation for developing practical monitoring and control methods against M. crassisigna. © 2023 Society of Chemical Industry.

A Potential Multitarget Insect Growth Regulator Candidate: Design, Synthesis, and Biological Activity of Novel Acetamido Derivatives Containing Hexacyclic Pyrazole Carboxamides.

Insect growth regulators (IGRs) are important green insecticides that disrupt normal growth and development in insects to reduce the harm caused by pests to crops. The ecdysone receptor (EcR) and three chitinases OfChtI, OfChtII, and OfChi-h are closely associated with the molting stage of insects. Thus, they are considered promising targets for the development of novel insecticides such as IGRs. Our previous work identified a dual-target compound 6j, which could act simultaneously on both EcR and OfChtI. In the present study, 6j was first found to have inhibitory activities against OfChtII and OfChi-h, too. Subsequently, taking 6j as a lead compound, 19 novel acetamido derivatives were rationally designed and synthesized by introducing an acetamido moiety into the amide bridge based on the flexibility of the binding cavities of 6j with EcR and three chitinases. Then, their insecticidal activities against Plutella xylostella (P. xylostella), Ostrinia furnacalis (O. furnacalis), and Spodoptera frugiperda (S. frugiperda) were carried out. The bioassay results revealed that most of these acetamido derivatives possessed moderate to good larvicidal activities against three lepidopteran pests. Especially, compound I-17 displayed excellent insecticidal activities against P. xylostella (LC50, 93.32 mg/L), O. furnacalis (LC50, 114.79 mg/L), and S. frugiperda (86.1% mortality at 500 mg/L), significantly better than that of 6j. In addition, further protein validation and molecular docking demonstrated that I-17 could act simultaneously on EcR (17.7% binding activity at 8 mg/L), OfChtI (69.2% inhibitory rate at 50 µM), OfChtII (71.5% inhibitory rate at 50 µM), and OfChi-h (73.9% inhibitory rate at 50 µM), indicating that I-17 is a potential lead candidate for novel multitarget IGRs. This work provides a promising starting point for the development of novel types of IGRs as pest management agents.

Structure-Based Virtual Screening of Natural Products and Optimization for the Design and Synthesis of Novel CeCht1 Inhibitors as Nematicide Candidates.

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.

Design, Synthesis, and Biological Activity of Novel Benzo[d][1,3]dioxole-6-benzamide Derivatives: Multichitinase Inhibitors as Potential Insect Growth Regulator Candidates.

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 Ki 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.

Design, Synthesis, and Biological Activity of Novel Heptacyclic Pyrazolamide Derivatives: A New Candidate of Dual-Target Insect Growth Regulators.

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.