To find new lead compounds with high biological activity, a series of novel 4-methyl-1,2,3-thiadiazole-5-carboxaldehyde benzoyl hydrazone derivatives were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, IR spectrum and elemental analysis. Preliminary bioassay indicated that the title compounds exhibited moderate to strong fungicidal activity against six fungi in vitro at 50 μg/mL. Moreover, some of the title compounds exhibited good curative activity against TMV in vivo at 500 μg/mL. The structure-activity relationship analysis of compounds against Valsa mali showed that compounds containing halogen at the para position on phenyl exhibited the best activity. Especially compound 8k showed broad spectrum fungicidal activities against Valsa mali, Botrytis cinerea, Pythium aphanidermatum, Rhizoctonia solani, Fusarium moniliforme and Alternaria solani with the EC50 values of 8.20, 24.42, 15.80, 40.53, 41.48, and 34.16 μg/mL, respectively.Download high-res image (156KB)Download full-size imageA series of novel 4-methyl-1,2,3-thiadiazole-5-carboxaldehyde benzoyl hydrazone derivatives designed and synthesized. They were exhibited moderate to strong fungicidal activity against six fungi in vitro at 50 μg/mL, and some of them presented good curative activity against TMV in vivo at 500 μg/mL.

Insect growth regulators play an important role in integrated pest management strategies. The FGLa–allatostatins (ASTs) are a family of neuropeptides that can inhibit juvenile hormone (JH) biosynthesis by the corpora allata (CA) of Diploptera punctata in vitro, are regarded as insect growth regulator candidates. In the search for new potential mimics and to explore the effect of linker length on inhibiting JH biosynthesis, a series of AST analogs were synthesized by modifying the linker of K24, which was found to have a significant effect on JH biosynthesis in vitro in our previous study. Functional evaluation demonstrated that all the target compounds can activate the Dippu-AstR, albeit with different potencies. Analog L6 with the longest linker (n = 5), exhibited not only a promising effect on inhibition of JH biosynthesis both in vitro and in vivo, but also good activity in inhibiting basal oocyte growth. Structure–activity relationships (SAR) studies showed that longer linkers provided greater contribution to activity.A series of AST analogs were synthesized by modifying the linker of K24. The bioassay results showed that all target analogs exhibited different potencies in inhibiting JH biosynthesis and activating Dippu-AstR as a consequence of vary linker length. Analog L6, with the longest linker (n = 5), had outstanding effect on inhibiting JH biosynthesis in vitro and in vivo, as well as good activity in inhibiting basal oocyte growth.

In order to discover highly active ecdysone analogs, a series of new substituted pyrazole amide derivatives were obtained using structure-guided optimization method and further screened for their insecticidal activities, in the basis of the core structures of the two active compounds N-(3-methoxyphenyl)-3-(tert-butyl)-1-phenyl-1H-pyrazole-5-carboxamide (6e) and N-(4-(tert-butyl)phenyl)-3-(tert-butyl)-1-phenyl-1H-pyrazole-5-carboxamide (6i), previously presented by us. The chemical structures of the title compounds were identified by spectral analyses. The preliminary bioassay results indicated that one among the synthesized pyrazole derivatives, compound 34, endowed with good activity against Mythimna Separata at 10 mg/L, which was equal to that displayed by the positive control tebufenozide. In addition, examples of molecular docking and molecular dynamics studies demonstrated that 34 may be the potential inhibitor to EcR and its docking conformation was similar to that of tebufenozide. In addition, increasing the hydrophobic effect and considering the suitable bulk effect on pyrazole ring are beneficial to the inhibiting activity to EcR and activity in vivo.In the basis of core structures of two active compounds 6e and 6i, a series of novel substituted pyrazole amides was obtained and further screened for their insecticidal activities. One target compound 34 displayed excellent activities against lepidopteran pests, and its binding conformation to EcR was studied using molecular docking and molecular dynamics methods, which showed 34 might be the potential inhibitor to EcR and its binding model was similar to that of tebufenozide.

Based on the similarities in the conformation of VS008 (N-(4-methylphenyl)-3-(tert-butyl)-1-(phenylmethyl)-1H-pyrazole-5-carboxamide) and BYIO6830 (N′-(3,5-dimethylbenzoyl)-N′-tert-butyl-5-methyl-2,3-dihydro-1,4-benzodioxine-6-carbohydrazide) bound to the active site of the EcR subunit of the ecdysone receptor (EcR)-ultraspiracle protein (USP) heterodimeric receptor, a series of new pyrazole amide derivatives were designed and synthesized. Their structures were confirmed by IR, 1H NMR, 13C NMR and elemental analysis. Results from a preliminary bioassay revealed that two of the pyrazole derivatives exhibited promising insecticidal activity. Specifically, compounds 6e and 6i exhibited good activity against Helicoverpa armigera (cotton bollworm) at low concentration. Symptoms displayed by tebufenozide-treated H. armigera were identical with those displayed by its treated counterpart. 6i showed the same poisoning symptoms as those of tebufenozide. In addition, results from molecular docking result indicated that the binding modes of 6e and 6i at the active site of the EcR subunit of the heterodimeric receptor were similar to that of the bound tebufenozide.Based on the binding conformation of ligands with the ecdysone receptors (EcRs), a series of new pyrazole amide derivatives were designed and prepared. Several compounds, for example 6e and 6i, had good insecticidal activity. Helicoverpa armigera treated with 6i showed the same poisoning symptoms as those of tebufenozide. Furthermore, molecular docking and molecular dynamics studies revealed that the binding modes of 6e or 6i with the EcR subunit were similar to that of tebufenozide. These results gave the useful guide to discover new IGRs.

Insect kinin neuropeptides are pleiotropic peptides that are involved in the regulation of hindgut contraction, diuresis, and digestive enzyme release. They share a common C-terminal pentapeptide sequence of Phe1-Xaa2-Yaa3-Trp4-Gly5-NH2 (where Xaa2 = His, Asn, Phe, Ser, or Tyr; Yaa3 = Pro, Ser, or Ala). Recently, the aphicidal activity of insect kinin analogues has attracted the attention of researchers. Our previous work demonstrated that the sequence-simplified insect kinin pentapeptide analogue Phe-Phe-[Aib]-Trp-Gly-NH2 could retain good aphicidal activity and be the lead compound for the further discovery of eco-friendly insecticides which encompassed a broad array of biochemicals derived from micro-organisms and other natural sources. Using the peptidomimetics strategy, we chose Phe-Phe-[Aib]-Trp-Gly-NH2 as the lead compound, and we designed and synthesized three series, including 31 novel insect kinin analogues. The aphicidal activity of the new analogues against soybean aphid was determined. The results showed that all of the analogues exhibited aphicidal activity. Of particular interest was the analogue II-1, which exhibited improved aphicidal activity with an LC50 of 0.019 mmol/L compared with the lead compound (LC50 = 0.045 mmol/L) or the commercial insecticide pymetrozine (LC50 = 0.034 mmol/L). This suggests that the analogue II-1 could be used as a new lead for the discovery of potential eco-friendly insecticides.

An allatostatin (AST) neuropeptide mimic (H17) is a potential insect growth regulator, which inhibits the production of juvenile hormone (JH) by the corpora allata. To determine the effect of conformation of novel AST analogues and their ability to inhibit JH biosynthesis, eight insect AST analogues were synthesized using H17 as the lead compound by N-methylation scanning, which is a common strategy for improving the biological properties of peptides. A bioassay using JH production by corpora allata of the cockroach Diploptera punctata indicated that single N-methylation mimics (analogues 1–4) showed more activity than double N-methylation mimics (analogues 5–8). Especially, analogues 1 and 4 showed roughly equivalent activity to that of H17, with IC50 values of 5.17 × 10–8 and 6.44 × 10–8 M, respectively. Molecular modeling based on nuclear magnetic resonance data showed that the conformation of analogues 1 and 4 seems to be flexible, whereas analogues 2 and 3 showed a type IV β-turn. This flexible linear conformation was hypothesized to be a new important and indispensable structural element beneficial to the activity of AST mimics.

Two series of novel 2,4-diphenyl-1,3-oxazolines containing an oxime ether moiety were designed and synthesized via the key intermediate N-(2-chloro-1-(p-tolyl)ethyl)-2,6-difluorobenzamide. The bioassay results showed that the target compounds with an oxime ether substituent at the para position of 4-phenyl exhibited excellent acaricidal activity against Tetranychus cinnabarinus in the laboratory. Moreover, all of the target compounds had much higher activities than etoxazole, as the ovicidal and larvicidal activities of the target compounds I-a–I-l and II-a–II-n against T. cinnabarinus were all over 90% at 0.001 mg L–1, but etoxazole gave only 30% and 40% respectively at the same concentration. The activity order of compounds with regard to acaricidal activity in vivo was almost consistent with their affinity activity with sulfonylurea receptor (SUR) of Blattella germanica in vitro, hence, it was supposed that the acaricidal mechanism of action of the target compounds was that they can bind with the site of SUR and therefore inhibit chitin synthesis. Moreover, the eminent effect of the compound II-l, [2-(trifluoromethyl)benzaldehyde O-(4-(2-(2,6-difluorophenyl)-4,5-dihydrooxazol-4-yl)benzyl) oxime], against Panonychus citri and T. cinnabarinus in the field indicated that II-l exhibited a promising application prospect as a new candicate for controlling spider mites in the field.

A series of novel neonicotinoid analogues were designed and synthesized by introducing a hydrazide group into clothianidin. Their structures were confirmed by IR, 1H NMR, and HRMS (ESI). Preliminary bioassay showed that some compounds, 5b and 5g, exhibited good activity against soybean aphids (Aphis glycines) at 100 mg L−1. In addition, molecular docking with receptor was carried out to explain their different activity from clothianidin.In order to find novel neonicotinoids insecticide with good selectivity and activity, a new series of clothianidin analogues with hydrazide group were designed and synthesized. Bioassay result indicated that some compounds showed good insecticidal activity against soybean aphids at 100 mg L−1. Molecular docking study was carried out to explain their different activity from clothianidin.

A novel series of 1,3,4-oxadiazole derivatives containing a 5-phenyl-2-furan moiety were synthesized from the intermediates diacylhydrazine 3 and acylhydrazone 5 via an efficient approach under microwave irradiation in good yields. Their structures were characterized by IR, 1H NMR, and elemental analysis. The antifungal tests indicated that the title compounds showed in vivo fungicidal activity against Botrytis cinerea and Rhizoctonia solanii at 500 μg/mL obviously. Some tested compounds even had a superiority effect over the commercial fungicides 40% Pyrimethanil SC and 3% Validamycin AS. The activity between the title compound and their precursors diacylhydrazine 3 and acylhydrazone 5 was also compared and discussed.

Cockroach-type allatostatins (ASTs) were discovered in cockroaches through their capacity to inhibit the production of juvenile hormone by the corpora allata (CA). ASTs were considered as potential insect growth regulator (IGR) candidates, but several disadvantages, including the absence of the effect in vivo and rapid degradation in vivo, precluded their application in pest management. The CA were selected as the target, and the core pentapeptide region (YDFGL) was chosen as the lead sequence in the search for new IGRs based on the allatostatins. We designed and synthesized 24 analogues, which mimicked each amino acid of the core region, to determine structure−activity relationships and the possibility of shortening the ASTs in the core region while retaining activity. The results suggest that the sequence FGLa is more important than Y/FX because Y/FX mimics show strong effects in vitro and in vivo. In particular, compound I3 was synthesized by substitution of Y/FX with 6-phenylhexnoic acid and exhibits higher activity in vitro than the complete core region. Furthermore, compound I3 has a clear effect in vivo on juvenile hormone (JH) biosynthesis of Diploptera punctata females, providing a possible application for cockroach management. On the basis of the structure−activity relationship of pentapeptide analogues, a general structure of potential potent AST analogues is proposed here. A new approach using peptidomimetics in the discovery of IGRs is demonstrated in our study.

(E)-β-Farnesene is a strong and efficient alarm pheromone in most aphid species. However, applications in agriculture are prevented by its relatively high volatility, its susceptibility to oxidation and its complex and expensive synthesis. To develop novel compounds for aphid control, we have designed and synthesized analogues of (E)-β-farnesene, containing a pyrazole moiety present in several insecticides. Their structures have been confirmed by 1H NMR, elemental analysis, high-resolution mass spectroscopy and IR. Binding activities to three odorant-binding proteins (OBPs) of the pea aphid Acythosiphon pisum have been evaluated and correlated with their structures with reference to (E)-β-farnesene. Several derivatives were shown both to bind to A. pisum OBPs with a specificity similar to that of (E)-β-farnesene and to have aphicidal activity comparable to that of thiacloprid, a commercial insecticide. The compounds synthesized in this work represent new potential agents for aphid population control and provide guidelines to design analogues of (E)-β-farnesene endowed with both insecticidal and repellent activity for aphids.

A pair of chemical isomeric structures of N-acylhydrazone compounds I and II were designed and synthesized. The reaction was carried out with high diastereoselectivity to obtain one configurational isomer in excellent yields. The exact configuration and conformation of IIa and IIe were confirmed by the X-ray single crystal diffraction. The antitumor bioassay revealed that some compounds exhibited excellent activity against the selected cancer cell lines. In particular, IIf (IC50 = 16.4 μM) was better than doxorubicin (IC50 = 53.3 μM) against human promyelocytic leukemic cells (HL-60). Their toxicities were predicted in silico. The results showed that compounds II were safe and eligible to be development candidates. IIf showed great promise as a novel lead compound for further anticancer discovery.A pair of N-acylhydrazones I and II were synthesized in excellent yields. The antitumor bioassay revealed some compounds exhibited excellent activity. Their toxicities were predicted by in silico methods.

Chitin, a major structural component of insect cuticle and fungus cell wall but absent in plants and vertebrates, is regarded as a safe and selective target for pest control agents. Chitin synthesis inhibitors (CSIs) have been well-known as insect growth regulators (IGRs) but rarely found as fungicides in agriculture. To find novel CSIs with good activity, benzoylphenylurea, a typical kind of CSIs, was chosen as the lead compound and 26 novel aryl carbamic acid-5-aryl-2-furanmethyl esters were designed by converting the urea linkages of benzoylphenylureas to carbamic acid esters and changing the aniline parts into furanmethyl groups. The title compounds were synthesized and their structures confirmed by IR, 1H NMR, and elemental analysis. Preliminary insecticidal and fungicidal bioassays were carried out. The results indicated that the title compounds had no insecticidal effect on Culex pipiens pallens and Plutella xylostella Linnaeus, but most compounds exhibited good fungicidal activities against Corynespora cassiicola, Thanatephorus cucumeris, Botrytis cinerea, and Fusarium oxysporum. In particular, compounds V-4, V-6, V-7, and V-8 showed better activities against the four strains than those of the commercialized fungicides. The morphologic result suggested that compound V-21 had disturbed the cell wall formation of C. cassiicola. The results indicated that modification on the urea linkage of benzoylphenylurea was an effective way to discover new candidates for fungicides.

Cockroach-type allatostatins (FGLamides) (ASTs) can inhibit the production of juvenile hormone in vitro, and they therefore are regarded as possible insect growth regulator (IGR) candidates for pest control. However, several shortcomings, such as the absence of in vivo effects, rapid degradation, and high production costs, preclude their practical use in pest management. To discover new IGRs, 25 novel analogues of pentapeptide (Y/FXFGLa) were designed and synthesized with different aromatic acids, fatty acids, and dicarboxylic acids as the Y/FX region replacements on the basis of previous results. Their bioactivities in vitro were determined, and the results showed that eight analogues (K14, K15, K17, K18, K19, K23, K24, and K25) were more active than the lead, core region pentapeptide. The IC50 values of K15 and K24 (IC50 = 1.79 and 5.32 nM, respectively) were even lower than that of the natural AST, Dippu-AST 1(IC50 = 8 nM), which indicated both analogues have better activity than Dippu-AST 1; particularly, K15 has better activity than most natural Dippu-ASTs. A predictable and statistically meaningful hologram quantitative structure−activity relationship (HQSAR) model of 32 AST analogues (28 as training sets and 4 as test sets) was obtained. The final model suggested that a potent AST analogue should contain an aromatic group, a linker of appropriate length, and the FGLa portion. These results will be useful in the design of new AST analogues that are structurally related to the training set compounds.

QSAR studies of 27 diacyl-hydrazine derivatives containing furan rings were conducted and compared with the DFT method and AM1-MOPAC method. q2 values of 0.61 and 0.40 validated the predictability and reliability of eq. (5) from the DFT method were higher than those of eq. (6) from the AM1-MOPAC method. The DFT-optimized conformations and ESP-fitting charges of the target compounds were also used for 3D-QSAR analysis, including CoMFA and CoMSIA. The leave-one-out cross-validation correlation coefficient and the good correlation between the predicted and experimental activities of excluded test compounds revealed that CoMFA and CoMSIA models were robust. The QSAR results were consistent with the 3D-QSAR results, indicating that the electrostatic and hydrophobic properties of the target compounds were significant to the biological activity. These models are useful tools for predicting the larvicidal activities of new compounds and designing new specific insect growth regulators.

Allatostatins (ASTs) comprise a family of insect neuropeptides isolated from cockroaches and found to inhibit the production of juvenile hormone (JH) by the corpora allata (CA). For this reason, the ASTs can be regarded as possible IGR candidates for pest control. Six peptidomimetic analogs according to the C-terminal pentapeptide of ASTs were prepared by solid-phase organic synthetic methods in an attempt to obtain new simple substitution agents. Assays of inhibition of JH biosynthesis in vitro by corpora allata from the cockroach Diploptera punctata showed that the activity of analog I (IC50: 0.09 μM) was more active than that of the C-terminal pentapeptide (Tyr–Xaa–Phe–Gly–Leu–NH2, IC50: 0.13 μM) it mimicked and the activity of the analog II (IC50: 0.13 μM) proved roughly equivalent to the C-terminal pentapeptide. The results indicate that a new simple mimicry for Tyr–Xaa–Phe–Gly has been discovered; analog I may be a novel compound candidate for potential IGRs. This study will be useful for the design of new AST analogs for insect management.

•The conformations of the pentapeptide and four N-terminal modifications of AST analogs were investigated using NMR spectroscopy and molecular modeling.•A type IV β-turn and a γ turn were found in K23 and K9 in DMSO, respectively.•A flexible conformation was formed in the pentapeptide, H17 and K10 in DMSO.•This flexible conformation could be an important and indispensable structural element for activity.The FGLamide allatostatins (ASTs) can inhibit the production of juvenile hormone in vitro, and they therefore are regarded as possible insect growth regulator candidates for pest control. To understand the structural features of the ASTs that cause the differences in their activity the pentapeptide and four N-terminal modifications of AST analogs (H17, K9, K10 and K23) were selected to investigate their conformations. From NMR spectroscopy and molecular modeling, it is clear that K23 and K9 have a type IV β-turn and a γ turn in DMSO, respectively. The pentapeptide, H17 and K10 form a flexible conformation. Our study indicates that this flexible conformation could be an important and indispensable structural element for activity, whereas the turn structure may not be especially significant for biological activity.

•We design and synthesize a series of novel insect kinin analogs.•We evaluate the aphicidal activity and assess the role of the N-terminal protective group.•Structure-simplified analog X showed higher activity and could be a new lead for further insecticide discovery.•The ‘leaf-dipping method’ is closer to the aphids’ living environment compared with artificial diet.The insect kinins are a class of multifunctional insect neuropeptides present in a diverse variety of insects. Insect kinin analogs showed multiple bioactivities, especially, the aphicidal activity. To find a biostable and bioactive insecticide candidate with simplified structure, a series of N-terminal modified insect kinin analogs was designed and synthesized based on the lead compound [Aib]-Phe-Phe-[Aib]-Trp-Gly-NH2. Their aphicidal activity against the soybean aphid Aphis glycines was evaluated. The results showed that all the analogs maintained the aphicidal activity. In particular, the aphicidal activity of the pentapeptide analog X Phe-Phe-[Aib]-Trp-Gly-NH2 (LC50 = 0.045 mmol/L) was similar to the lead compound (LC50 = 0.048 mmol/L). This indicated that the N-terminal protective group may not play an important role in the activity and the analogs structure could be simplified to pentapeptide analogs while retaining good aphicidal activity. The core pentapeptide analog X can be used as the lead compound for further chemical modifications to discover potential insecticides.A series of N-terminal modified insect kinin analogs were designed and synthesized based on the lead compound [Aib]-Phe-Phe-[Aib]-Trp-Gly-NH2. All the analogs showed aphicidal activity against Aphis glycines. In particular, the pentapeptide analog X (LC50 = 0.045 mmol/L) has similar activity to the lead (LC50 = 0.048 mmol/L). This indicated that the N-terminal protective group may not play an important role in activity and the structure might be further simplified.Download full-size image

In order to discover novel compounds with high-activity to control aphid, a series of novel (E)-β-farnesene analogues containing 1,2,3-thiadiazole were designed and synthesized, and their structures were confirmed by IR, 1H NMR, 13C NMR, and HRMS (ESI). The stability of representative compounds was studied by HPLC and 1H NMR techniques. Repellent activity results indicated that compounds 8h and 8j displayed 60.3% and 62.0% repellent rates, respectively. The aphicidal bioassay results showed that most analogues exhibited considerable aphicidal activity against Myzus persicae. Especially, analogues 8l, 8s and 8t exhibited high activity with LC50 values of 33.4 μg/mL, 50.2 μg/mL and 61.8 μg/mL, respectively, which were higher than the lead compound (E)-β-farnesene, but lower than commercial insecticide pymetrozine with a LC50 of 7.1 μg/mL.A series of novel (E)-β-farnesene analogues containing 1,2,3-thiadiazole were designed and synthesized by replacing unstable conjugated double bond of (E)-β-farnesene with1,2,3-thiadiazole ring. They are not only exhibited good stability but also showed strong repellent effects and aphicidal activities compared to the lead (E)-β-farnesene.