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.

New synthesis of a stereoisomeric mixture of methyl 12-trishomofarnesoate, a juvenile hormone mimic useful in sericulture by increasing silk production.

A mixture of (E,Z)-isomers of methyl 12-trishomofarnesoate (methyl 3,7,11-trimethyl-2,6,10-pentadecatrienoate), a juvenile hormone mimic, was synthesized in nine steps (32.6% overall yield) by starting from only four commercially available materials: 2-hexanone, vinylmagnesium bromide, methyl acetoacetate and trimethyl phosphonoacetate. The mimic is useful in increasing the yield of silk by elongating the larval period of the silkworm, Bombyx mori (L.).

Design and development of novel insect growth regulators: synthesis, characterization and effect of benzoyl thymyl thioureas and ureas on total haemocyte count of Dysdercus koenigii.

Insect-growth regulators (IGRs) have been receiving foremost attention as potential means of selective insect control. Benzoyl phenyl urea (BPU) is a well-known IGR having chitin synthesis inhibitor activity. Mimics of BPU have been synthesized by suitable derivatization of a naturally occurring monoterpenoid, thymol (2-isopropyl-5-methyl phenol) to form a = series of substituted benzoyl thymyl thioureas (BTTUs) [IVa-f] and benzoyl thymyl ureas (BTUs) [Va-f]. The synthesized compounds have been characterized by (1)H and (13)C NMR, LC-MS and elemental analysis. These derivatives have been screened for their effect on total haemocyte count of Dysdercus koenigii. It has been observed that the introduction of substituted benzoyl thiourea and urea linkage into a thymol ring via an amino group results in higher activity than the parent compound thymol and a comparable pattern of results with the standard insect-growth regulators, Penfluron. Urea [Va-f] compounds exhibited greater effect on Total Haemocyte Count (THC) than thiourea [IVa-f]. Fluoro substitution enhanced the effect on THC more than chloro substituted compounds, while ortho-substitution resulted in a better effect than para-substitution. The results described in this paper are promising and provide new array of synthetic chemicals that may be utilized as insect growth regulators.

Steroid conjugates: Synthesis and preliminary biological testing of pro-juvenoids.

A series of 10 new pro-juvenoids (juvenogens, insect hormonogenic compounds, pro-drug-like agents) was synthesized using isomeric synthetic juvenoids (insect juvenile hormone analogs) and steroid molecules as patterns modifying parts of the complex hormonogenic molecules. In addition, several new synthons were prepared, which were required by the designed synthetic protocol to achieve the target molecules. These pro-juvenoids were subjected to the topical screening tests and to the drinking assays on the red firebug (Pyrrhocoris apterus), a convenient model laboratory phytophagous insect. Simple and efficient synthetic procedures for the preparation of the target pro-juvenoids and their synthons are presented. Furthermore, the biological activity of the pro-juvenoids in comparison with the activity of their parent juvenoids and that of several commercially available agents is demonstrated. Juvenoids and pro-juvenoids may replace toxic insecticides persistent in the insect pest control because they have no adverse effects on non-target organisms and/or human.

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.

New synthetic precocenoids as potential insect control agents.

Ageratochromes or precocenes are known for their insect growth regulating (IGR) activity. The present investigation was taken up with an objective to look for the lead structure in these compounds which can be elaborated synthetically to obtain useful growth regulators for practical purposes. With this in mind, some variants of precocenes were synthesized in the laboratory and tested for their toxicity and growth regulating activity using red cotton bug Dysdercus koenigii as the test insect. Most of the precocenoids showed toxicity of various degree and metamorphic derangements to different extents. Adults emerging from treated nymphs could not complete the normal life span. Among the compounds tested 8-acetyl-7-hydroxy-5-methoxy-dimethylchromene (alloevodinol) was more toxic and also showed developmental defects at very low dose such as 0.5 mg l(-1)/nymph. Precocene II (6, 7-dimethoxy-2, 2-dimethylchromene) was used as the standard compound. It was the least toxic and showed effects at 30 mg l(-1)/nymph.

A potential insect growth regulator for cockroach control: design, synthesis and bioactivity of N-terminal-modified allatostatin analogues.

BACKGROUND: The FGLa-allatostatins (ASTs) are a family of neuropeptides that can inhibit juvenile hormone biosynthesis by the corpora allata (CA) in vitro, and therefore they are regarded as insect growth regulator (IGR) candidates for pest control. In our previous studies, an AST mimic, H17, was found to have a significant effect on JH biosynthesis by cockroach CA, both in vitro and in vivo. To discover new potential mimics and explore the substituent effect on the inhibition of JH biosynthesis, 30 analogues, modified with various substituents on the benzene ring at the N-terminus of lead compound H17, were designed and synthesised. Their bioactivity in inhibiting JH biosynthesis by the CA of Diploptera punctata and the potency of M9, M10 and M11 in activation of Dippu-AstR were evaluated. RESULTS: All the analogues showed an effect on JH biosynthesis by CA in vitro. M9, M10 and M11 can activate the Dippu-AstR, albeit with much lower potency than that of AST 1. M11 also exhibited improved in vitro activity (IC50 6.98 nm) in comparison with the lead compound H17 (IC50 29.5 nm). In particular, M11 displayed good in vivo activity in inhibiting JH biosynthesis and basal oocyte growth. CONCLUSION: The structure-activity relationship studies suggest that different positions of substituents on the benzene ring of the cinnamic acid can lead to different activities. The para-substitution on the benzene ring plays an important role in inhibiting JH biosynthesis in vitro. Moreover, M11 is considered to be a potential IGR for cockroach control. © 2016 Society of Chemical Industry.

Synthesis and Larvicidal Activity of Novel Thenoylhydrazide Derivatives.

A pair of chemical isomeric structures of novel N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized. Their structures were characterized by MS, IR, (1)H NMR, elemental analysis and X-ray single crystal diffraction. The regioselectivity of the Meerwein arylation reaction and the electrophilic substitution reaction of N-tert-butyl hydrazine were studied by density functional theory (DFT) quantum chemical method. The larvicidal tests revealed that some compounds I had excellent larvicidal activity against Culex pipiens pallens. As the candidates of insect growth regulators (IGRs), the larval growth inhibition and regulation against Culex pipiens pallens were examined for some compounds, especially I1 and I7. Compounds I1 and I7 were further indicated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). Finally, a molecular docking study of compound I7 was conducted, which was not only beneficial to understand the structure-activity relationship, but also useful for development of new IGRs for the control of mosquitos.

Quantitative structure-activity relationship of insect juvenile hormone mimetic compounds.

Juvenile hormone mimetic activities on Aedes aegypti (yellow-fever mosquito) and Tenebrio molitor (yellow mealworm) of compounds having (2E,4E)-3,7,11-trimethyl-2,4-dodecadienone structures were comparatively and quantitatively analyzed in terms of their physiochemical structural parameters and by regression analysis. They were structurally composed of three classes, ester and thiol ester derivatives, amides, and ketones, depending on the C1 substituents. The results indicated that the steric dimensions and the hydrophobicity of the whole molecule are important factors in governing the activity through these classes as well as through both insect species. The effects of the structure of the C1 and C11 substituents, the two ends of the chain molecule, are specific to the insect. The length along the bond axis of the C1 substituents is significant and the hydroxy and alkoxy functions attached to the C11 atom favor the activity on A. aegypti, whereas with T. molitor the width of the C1 substituents in the direction perpendicular to the bond axis is significant and the position-specific hydrophobicity of the C1 moiety enhances the activity. The activity is also affected differently by the compound types. The amide and ketone series of compounds are more active than the corresponding ester type of compounds on T. molitor, while the favorable types on A. aegypti are the ester and ketone derivatives. Correlation equations formulated for 85 active compounds on A. aegypti and 84 compounds on T. molitor led us to draw a hypothetical "mode of action" model for each species, which visualizes the overall similarity as well as the species differences of the interaction site or the receptor and may show the structural conditions necessary for activity.

Insect growth regulators. XXV. Chemical approach to the correlation of dynamic structure and biological activity of juvenile hormone analogues.

On the basis of flexibility of the carbon skeleton of a juvenoid molecule, an analysis of its steric properties required to induce a biological effect in insects Dysdercus cingulatus and Tenebrio molitor, is presented. Steric analyses of "branched" juvenoids and some derivatives of farnesoic acid differing in position of the double bonds, are also described.

Juvenile hormone analogs active on mosquitoes: synthesis and juvenile hormonal activity of newly synthesized long chain alkoxy alkyl phenyl ethers.

Different 2-(8,12 dimethyl-5-oxa-7(E), 11-tridecadienyl)-alkyl phenyl ethers, their mono oxirane and thirane derivatives were synthesized and tested on Culex pipiens quinquefasciatus Say for their juvenile hormone activity.

Evaluation of two new insect growth regulators against mosquitoes in the laboratory.

Biological activity of two new IGRs was studied under laboratory conditions against 2nd- and 4th-instar larvae and pupae of Anopheles quadrimaculatus, Aedes aegypti and Culex tarsalis. The IGR S-21149, an oxime [0-(2-(4'-Phenoxyphenoxy)ethyl propionaldoxime], produced an overall mortality or inhibition of emergence of 95% (when 4th instar treated) at 0.0047, 0.0013 and 0.00041 mg/liter in the three species, respectively. The EI95 values for the second IGR S-31183, a pyridine compound, [1-(4'-Phenoxyphenoxy)-2-(2'pyridyloxy) propane] were 0.017, 0.0026 and 0.00032 mg/liter for the three species, respectively. Both materials in general were less active against 2nd than 4th-instar larvae, except that the 2nd- and 4th instars of An. quadrimaculatus were equally susceptible. Pupae treated at up to 0.1 mg/liter showed no mortality in the pupal or the ensuing adult stages.

Synthesis, biological activities and SAR studies of novel 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid based diacyl and sulfonyl acyl hydrazines.

BACKGROUND: Diacyl hydrazines have attracted significant interest in medicine, pesticide chemistry and material science. It is an important class of insect growth regulators. In this study, acyl hydrazine, the essential active group was incorporated in to nalidixic acid with the aim of combining the active groups to generate more potent agrochemical. RESULTS: Various nalidixic acid based diacyl and sulphonyl acyl hydrazines derivatives were synthesized and characterized by spectral techniques. These compounds were screened for the antifungal activity against five pathogenic fungi, nitrification inhibitory activity and insect growth regulator (IGR) activity against Spodoptera litura. The fungicidal activity was screened against R. bataticola, S. rolfsii, R. solani, F. oxysporum and A. porri. Most of the compounds showed moderate to good antifungal activity against A. porri (ED50 = 29.6-495.9 µg/mL). All the compounds showed significant nitrification inhibitory activity at 5% level. IGR activity was examined by feeding method against S. litura. CONCLUSION: The study revealed that a few compounds possessed good activity against three different pests namely certain fungus, soil bacteria and insect, among which, compound 37 (R' = 4-chlorophenyl) behaved the best.

Peptidomimetics in the discovery of new insect growth regulators: studies on the structure-activity relationships of the core pentapeptide region of allatostatins.

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.

Design and synthesis of benzoylphenylureas with fluorinated substituents on the aniline ring as insect growth regulators.

Enormous numbers of synthetic fluorine-containing compounds have been widely used in a variety of fields, especially in drug and pesticide design. To find novel insect growth regulators, a series of benzoylphenylureas with fluorinated substituents were designed and synthesized. The results of larvicidal activities of those novel fluoro-substituted benzoylphenylureas against oriental armyworm and mosquito revealed that most compounds exhibited excellent activities. It is worth mentioning that compounds 3 and 6 exhibited higher activities against oriental armyworm and mosquito than commercial Hexaflumuron. It can be further seen that the insecticidal activities would increase significantly by introducing fluorinated substituents into the structure of the designed benzoylphenylureas.

Bioassays of compounds with potential juvenoid activity on Drosophila melanogaster: juvenile hormone III, bisepoxide juvenile hormone III and methyl farnesoates.

Metabolites of the 6,7,10,11 bisepoxide juvenile hormone III (JHB(3)), and other potential juvenoids, were tested for juvenile hormone activity using early instar or early stage pupae of Drosophila melanogaster. Importantly, methyl farnesoates were tested as they might have JH-like activity on Dipteran juveniles. Larvae were exposed to compounds in medium, or the compounds were applied to white puparia. In the assays employed in the present study, there was no indication for JH activity associated with the metabolites of JHB(3). The activity of methyl farnesoate (MF) was higher than that of JH III and far greater than bisepoxide JH III. As opposed to the two endogenous juvenile hormones, methyl farnesoate has weak activity in the white puparial bioassay. When fluorinated forms of methyl farnesoate, which is unlikely to be converted to JH, were applied to Drosophila medium to which fly eggs were introduced, there was a high degree of larval mortality, but no evidence of subsequent mortality at the pupal stage. One possible explanation for the results is that methyl farnesoate is active as a hormone in larval stages, but has little activity at the pupal stage where only juvenile hormone has a major effect.