Target-Based Design, Synthesis, and Biological Evaluation of Novel 1,2,4-Triazolone Derivatives as Potential nAChR Modulators.

Novel agrochemicals have been successfully developed using target-based drug design (TBDD). To discover a novel, efficient, and highly selective nicotinic insecticide candidate, we developed a unified pharmacological model using TBDD by studying the binding modes of 11 nicotinic acetylcholine receptor (nAChR) modulators with acetylcholine binding protein (AChBP) targets for the first time. This model was used to design and develop a series of 1,2,4-triazolone derivatives. Bioassays demonstrated excellent insecticidal activities against Aphis glycines of compounds 4k (LC50 = 4.95 mg/L) and 4q (LC50 = 3.17 mg/L), and low toxicities to Apis mellifera. Additionally, compound 4q was stably bound to Aplysia californica AChBP, which was consistent with the pharmacological model obtained via molecular docking and molecular dynamics simulations. Therefore, compound 4q could be a potential lead candidate targeting nAChR. The explicit pharmacological model of nAChR modulators with Ac-AChBP in this study may facilitate the future rational design of eco-friendly nicotinic insecticides.

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.

Rational design and identification of novel thiosemicarbazide derivatives as laccase inhibitors.

BACKGROUND: Laccase is a key enzyme in the fungal 1,8-dihydroxynaphthalene (DHN) melanin biosynthesis pathway, which is a potential target for the control of pathogenic fungi. In our previous work, compound a2 was found with higher inhibition activity against laccase and antifungal activity than laccase inhibitor PMDD-5Y. The introduction of hydrogen-bonded receptors in the amino part was found to be beneficial in improving laccase inhibitory activity by target-based-biological rational design. In this work, the hydrogen-bonded receptors morpholine and piperazine were introduced for structure optimization to enhancing biological activity. RESULTS: Enzyme activity tests indicated that all target compounds had inhibitory activity against laccase, and some compounds exhibited better activity against laccase than a2, it was further verified that the introduction of hydrogen-bonded receptors in the amino portion could enhance the laccase inhibitory activity of target compounds. Most compounds showed excellent antifungal activities in vitro. Compound m14 displayed good activity against Magnaporthe oryzae both in vitro and in vivo. The scanning electron microscopy (SEM) analysis showed that the mycelium of M. oryzae treated with m14 were destroyed. Molecular docking revealed the binding mode between laccase and target compounds. CONCLUSION: Thirty-eight compounds were synthesized and showed good inhibitory activity against laccase, the introduction of morpholine and piperazine in the amino part was beneficial to improve antifungal activity and laccase activity. Further validation of laccase as a potential target for rice blast control, while m14 can be used as a candidate compound for the control of rice blast. © 2023 Society of Chemical Industry.

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 Laccase Inhibitors as Fungicides against Rice Blast.

Laccase is a potential target for novel agricultural fungicide discovery. PMDD-5Y was the first agent reported with high activity against laccase to control phytopathogenic fungi. Thirty-two novel agents containing cinnamaldehyde thiosemicarbazide were synthesized with PMDD-5Y as the lead compound, with most of the target compounds exhibiting excellent activity in vitro. Compound a2 (EC50 = 9.71 µg/mL) exhibited greater potency against Magnaporthe oryzae than the commercial fungicide isoprothiolane (EC50 = 18.62 µg/mL). The curative and protective effects of a2 against M. oryzae on rice were more than those of PMDD-5Y. Scanning electron microscopy indicated that a2 could cause mycelial growth atrophy and malformation. Furthermore, a2 (IC50 = 0.18 mmol/L) showed higher activity against laccase than PMDD-5Y (IC50 = 0.33 mmol/L) and cysteine (IC50 = 0.30 mmol/L). Molecular docking analysis revealed the nature of interaction between these compounds and laccase. This research identified a novel laccase inhibitor a2 as a fungicide candidate to control rice blast in agriculture.

Design, Synthesis and Bioactivity of Novel Low Bee-Toxicity Compounds Based on Flupyrimin.

Neonicotinoids are important insecticides for controlling aphids in agriculture. Growing research suggested that neonicotinoid insecticides are a key factor causing the decline of global pollinator insects, such as bees. Flupyrimin (FLP) is a novel nicotinic insecticide with unique biological properties and no cross-resistance, and is safe for pollinators. Using FLP as the lead compound, a series of novel compounds were designed and synthesized by replacing the amide fragment with a sulfonamideone. Their structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Bioassay results showed that compound 2j had good insecticidal activity against Aphis glycines with an LC50 value of 20.93 mg/L. Meanwhile, compound 2j showed significantly lower acute oral and contact toxicity to Apis mellifera. In addition, compound 2j interacted well with the protein in insect acetylcholine binding protein (AChBP). The molecular docking on honeybee nicotinic acetylcholine receptor (nAChR) indicated that the sulfonamide group of compound 2j did not form a hydrogen bond with Arg173 of the ß subunit, which conforms to the reported low bee-toxicity conformation. In general, target compound 2j can be regarded as a bee-friendly insecticide candidate.

Synthesis, Antifungal Activity, and 3D-QASR of Novel 1,2,3,4-Tetrahydroquinoline Derivatives Containing a Pyrimidine Ether Scaffold as Chitin Synthase Inhibitors.

The introduction of active groups of natural products into the framework of pesticide molecules is an effective approach for discovering active lead compounds, and thus has been widely used in the development of new agrochemicals. In this work, a novel series of 1,2,3,4-tetrahydroquinoline derivatives containing a pyrimidine ether scaffold were designed and synthesized by the active substructure splicing method. The new compounds showed good antifungal activities against several fungi. Especially, compound 4fh displayed excellent in vitro activity against Valsa mali and Sclerotinia sclerotiorum with EC50 values of 0.71 and 2.47 µg/mL, respectively. 4fh had slightly stronger inhibitory activity (68.08% at 50 µM) against chitin synthase (CHS) than that of polyoxin D (63.84% at 50 µM) and exhibited obvious curative and protective effects on S. sclerotiorum in vivo. Thus, 4fh can be considered as a new candidate fungicide as a chitin synthase inhibitor. An accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model presented a useful direction for the further excogitation of more highly active fungicides. Molecular docking revealed that the conventional hydrogen bond mainly affected the binding affinity of 4fh with chitin synthase. The present results will provide a guidance to discover potential CHS-based fungicides for plant disease control in agriculture.

Design, Synthesis, and Biological Activity of Novel Fungicides Containing a 1,2,3,4-Tetrahydroquinoline Scaffold and Acting as Laccase Inhibitors.

Laccase is a novel target for fungicides. We previously developed a new fungicide, 4-chlorocinnamaldehyde thiosemicarbazide (PMDD-5Y), as a laccase inhibitor. The introduction of active groups of natural products into the framework of a pesticide molecular structure is an effective method for discovering active lead compounds, and it has applications in the discovery of new pesticides. In this work, PMDD-5Y was selected as a lead compound, and we designed and synthesized a series of novel sulfonyl hydrazide derivatives containing the natural product scaffold 1,2,3,4-tetrahydroquinoline. The new compounds had antifungal activities against several fungi, especially Valsa mali and Sclerotinia sclerotiorum. One compound (4bl) displayed very good in vitro activity against S. sclerotiorum and V. mali, with EC50 values of 3.32 and 2.78 µg/mL, respectively. The results of an enzyme activity assay showed that 4bh had the best inhibitory activity against laccase, with an EC50 value of 14.85 µg/mL. This was more active than the lead compound PMDD-5Y and the positive control cysteine. Using a molecular docking method, we studied the binding mode of the title compounds with laccase. The structural features of these new laccase inhibitors as fungicides will advance research and impact the field of discovering more potent fungicides to control diseases in agriculture.

Design, Synthesis, and Fungicidal Activity of Novel Thiosemicarbazide Derivatives Containing Piperidine Fragments.

In order to discover novel eco-friendly lead compounds for plant pathogenic fungi control, a series of benzaldehyde thiosemicarbazide derivatives with a piperidine moiety have been designed and synthesized. Fungicidal activities of all the synthesized compounds were evaluated in vitro. The results indicated that all the title compounds exhibited moderate to good fungicidal activities. Compound 3b displayed excellent activities against Pythium aphanidermatum, Rhizoctonia solani, Valsa mali, and Gaeu-mannomyces graminsis, with EC50 values lower than 10 µg/mL. Especially, in the case of Pythium aphanidermatum, its activity (EC50 = 1.6 µg/mL) is superior to the commercial azoxystrobin (EC50 = 16.9 µg/mL) and close to fluopicolide (EC50 = 1.0 µg/mL). Initial structure-activity relationship (SAR) analysis showed that the heterocyclic piperidine group can influence the biological activities of the title compounds significantly. The fungicidal activity of compounds with piperidine is better than that of compounds without piperidine. The highly-active compound 3b, with its simple structure and easy synthetic route, is worthy to be further studied as a new lead fungicide.