Novel Evodiamine-Based Sulfonamide Derivatives as Potent Insecticide Candidates Targeting Insect Ryanodine Receptors.

Pests represent an important impediment to efficient agricultural production and pose a threat to global food security. On the basis of our prior research focused on identifying insecticidal leads targeting insect ryanodine receptors (RyRs), we aimed to identify evodiamine scaffold-based novel insecticides. Thus, a variety of evodiamine-based derivatives were designed, synthesized, and assessed for their insecticidal activity against the larvae of Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). The preliminary bioassay results revealed that more than half of the target compounds exhibited superior activity compared to evodiamine, matrine, and rotenone against M. separata. Among these, compound 21m displayed the most potent larvicidal efficiency, with a remarkable mortality rate of 93.3% at 2.5 mg/L, a substantial improvement over evodiamine (10.0% at 10 mg/L), matrine (10.0% at 200 mg/L), and rotenone (30.0% at 200 mg/L). In the case of P. xylostella, compounds 21m and 21o displayed heightened larvicidal activity, boasting LC50 values of 9.37 × 10-2 and 0.13 mg/L, respectively, surpassing that of evodiamine (13.41 mg/L), matrine (291.78 mg/L), and rotenone (18.39 mg/L). A structure-activity relationship analysis unveiled that evodiamine-based derivatives featuring a cyclopropyl sulfonyl group at the nitrogen atom of the B ring and a fluorine atom in the E ring exhibited more potent larvicidal effects. This finding was substantiated by calcium imaging experiments and molecular docking, which suggested that 21m could target insect RyRs, including resistant mutant RyRs of P. xylostella (G4946E and I4790M), with higher affinity than chlorantraniliprole (CHL). Additionally, cytotoxicity assays highlighted that the potent compounds 21i, 21m, and 21o displayed favorable selectivity and low toxicity toward nontarget organisms. Consequently, compound 21m emerges as a promising candidate for further development as an insecticide targeting insect RyRs.

Bioactivity-Guided Synthesis Accelerates the Discovery of Evodiamine Derivatives as Potent Insecticide Candidates.

Pests threaten worldwide food security by decreasing crop yields and damaging their quality. Natural product-based molecular design and structural optimization have been one of the most effective ways to innovate pesticides for integrated insect management. To continue our previous studies on the discovery of insecticidal lead, a series of evodiamine derivatives were designed, synthesized, and evaluated for their insecticidal activities. The bioassay results demonstrated that compounds Ian and Iao exhibited 90 and 80% insecticidal activities against Mythimna separata at 2.5 mg/L, respectively, which were superior to evodiamine (10% at 10 mg/L), matrine (45% at 600 mg/L), and rotenone (30% at 200 mg/L). Compounds Ian-Iap showed 90% insecticidal activities against Plutella xylostella at 1.0 mg/L, far more potent than those of evodiamine, matrine, and rotenone. Compound Ian displayed 60% insecticidal activity against Helicoverpa armigera at 5.0 mg/L, while evodiamine, matrine, and rotenone showed very poor activities. The study on the insecticidal mechanism of action by a calcium imaging experiment indicated that the insect ryanodine receptors (RyRs) could be the potential target of Ian. Furthermore, the molecular docking indicated that Ian anchored in the binding site of the RyR of P. xylostella. The above results manifested the potential of evodiamine derivatives as potent insecticide candidates.

Design, synthesis and fungicidal activity of pyrazole-thiazole carboxamide derivatives.

Twenty-one novel pyrazole-thiazole carboxamide derivatives were rationally designed and synthesized. Bioassay results indicated that 6d (EC50 = 5.11 µg/mL) and 6j (EC50 = 8.14 µg/mL) exhibited better in vitro activities than fluxapyroxad (EC50 = 11.93 µg/mL) and thifluzamide (EC50 = 22.12 µg/mL) against Rhizoctonia cerealis. Particularly, compound 6j showed promising in vivo protective activity against Rhizoctonia solani and Puccinia sorghi Schw. with 80% and 90% inhibition at 10 µg/mL, respectively. Our studies found that pyrazole-thiazole is a promising fungicide lead deserving for further derivation.

Design, synthesis and fungicidal activity of 3,4-dichloroisothiazolocoumarin-containing strobilurins.

Twenty-one novel 3,4-dichloroisothiazolocoumarin-containing strobilurins were rationally designed and synthesized. Preliminary bioassay showed that compounds 7c, 7h and 7l exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, 7c exhibited good activity against S. sclerotiorum with median effective concentration (EC50) of 4.08 µg/mL, while the positive control coumoxystrobin showed EC50 of 1.00 µg/mL. In addition, 7d showed better fungicidal activity with a lower EC50 value of 7.65 µg/mL against Botrytis cinerea than that of positive control trifloxystrobin with its EC50 value of 21.96 µg/mL. This study indicated that 3,4-dichloroisothiazolocoumarin-containing strobilurin was a promising fungicide lead deserved for further study.

Design, Synthesis, and Evaluation of Novel Isothiazole-Purines as a Pyruvate Kinase-Based Fungicidal Lead Compound.

Target identification is one of the most important bases for novel pesticide development; pyruvate kinase (PK) was discovered as a potent fungicide target in our previous studies. To continue the PK-based fungicide development, novel isothiazole-purine derivatives were rationally designed and synthesized. Bioassay results showed that compound 5ai displayed excellent in vitro activity against Rhizoctonia solani with an EC50 of 1.5 µg/mL, which was superior to those of positive controls diflumetorim with its EC50 of 19.8 µg/mL and PK-based lead YZK-C22 with its EC50 of 4.2 µg/mL. Compounds 3b (5.2 µg/mL) and 3c (4.5 µg/mL) displayed better activities against Gibberella zeae with their EC50s falling between 4.0 and 5.5 µg/mL, while YZK-C22 showed an EC50 of 6.4 µg/mL. In addition, 5ah exhibited promising in vivo activity against Erysiphe graminis and Puccinia sorghi Schw. with 100% efficacy at 10 µg/mL and 90% efficacy at 2 µg/mL against P. sorghi Schw. Compound 5ai showed good PK inhibitory activity with an IC50 of 38.8 µmol/L, and it was well docked into the active site of the target enzyme PK, which was slightly more active than YZK-C22 with its IC50 of 42.4 µmol/L. Our studies discovered that isothiazole-purines were PK-based fungicidal leads deserving of further study.

Design, synthesis and biological evaluation of pyrazole-aromatic containing carboxamides as potent SDH inhibitors.

To continue our ongoing studies on discovery of new potent antifungal leads, 43 novel pyrazole-aromatic containing carboxamides were rationally designed and synthesized. Bioassays indicated that most target compounds displayed good in vitro antifungal activities against Botrytis cinerea, Rhizoctonia cerealis and Sclerotinia sclerotiorum and in vivo antifungal activity against R. solani. Compound 11ea exhibited the most significant in vitro activity against R. cerealis (EC50 = 0.93 µg/mL) with about 2-fold more potent than a previously reported lead compound A1 (EC50 = 2.01 µg/mL), and about 11-fold more potent than the positive control/commercial succinate dehydrogenase inhibitor thifluzamide (EC50 = 23.09 µg/mL). Structure-activity relationship analysis and molecular docking simulations indicated that the presence of difluoromethyl pyrazole-(m-benzene) carboxamide scaffold obviously increased the antifungal activity. The further enzymatic bioassay showed that both thifluzamide and compound 11ea displayed excellent SDH inhibitory effects, and fluorescence quenching analysis suggested that they may share the same target SDH.

Design, synthesis and antifungal activity of (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues.

Nitrogen- or oxygen-containing organic compounds which have significant antifungal activity, twenty one novel nitrogen or oxygen-containing (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and HRMS. Preliminary bioassay showed that most of them exhibited certain-to-good antifungal activity. Compounds 5k-2, 5n, 5p and 5r exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, and 5r exhibited good antifungal activity against S. sclerotiorum with EC50 of 7.21 µg/mL. Compounds 5a and 5r also showed over 90% inhibition against Botrytis cinerea. In particular, 5r showed significant higher activity with the lowest EC50 of 7.92 µg/mL than the positive control trifloxystrobin (21.96 µg/mL) and azoxystrobin (9.43 µg/mL). Providing a practical method for the synthesis of new scaffolds 1,2-Benzoxazepinone and systematically investigate their antifungal activity.

Discovery of a polysubstituted phenyl containing novel N-phenylpyrazole scaffold as potent ryanodine receptor activator.

To develop the novel ryanodine receptors (RyRs) insecticides, encouraged by our previous research work, a series of novel N-phenylpyrazole derivatives containing a polysubstituted phenyl ring scaffold were designed and synthesized. The bioassays results indicated that some title compounds exhibited excellent insecticidal activity. For oriental armyworm (Mythimna separata), compounds 7f, 7g, 7i and 7o at 0.5 mg L-1 displayed 100% larvicidal activity, and even at 0.1 mg L-1, 7o was 30% larvicidal activity, comparable to chlorantraniliprole (30%) and better than cyantraniliprole (10%). Compounds 7f and 7o had the median lethal concentrations (LC50) of 8.83 × 10-2 and 7.12 × 10-2 mg L-1, respectively, close to chlorantraniliprole (6.79 × 10-2 mg L-1). Additionally, for diamondback moth (Plutella xylostella), the larvicidal activity of compounds 7f and 7i were 90% and 70% at 0.01 mg L-1, respectively, better than chlorantraniliprole (50%) and cyantraniliprole (40%). More impressively, the LC50 value of 7f was 4.2 × 10-3 mg L-1, slightly lower than that of chlorantraniliprole (5.0 × 10-3 mg L-1). The molecular docking between compound 7f and RyRs of diamondback moth validated our molecular designation. Furthermore, the calcium imaging experiment explored the influence of compound 7o on the calcium homeostasis in the central neurons of the third larvae of oriental armyworm. The results of this study indicated that 7o is a potent novel lead targeting at RyRs.

Design, Synthesis, and Evaluation of the Antifungal Activity of Novel Pyrazole-Thiazole Carboxamides as Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH) is regarded as a promising target for fungicide discovery. To continue our ongoing studies on the discovery of novel SDH inhibitors as fungicides, novel pyrazole-thiazole carboxamides were designed, synthesized, and evaluated for their antifungal activity. The results indicated that compounds 9ac, 9bf, and 9cb showed excellent in vitro activities against Rhizoctonia cerealis with EC50 values from 1.1 to 4.9 mg/L, superior to that of the commercial fungicide thifluzamide (EC50 = 23.1 mg/L). Compound 9cd (EC50 = 0.8 mg/L) was far more active than thifluzamide (EC50 = 4.9 mg/L) against Sclerotinia sclerotiorum. Compound 9ac exhibited promising in vivo activity against Rhizoctonia solani (90% at 10 mg/L), which was better than that of thifluzamide (80% at 10 mg/L). The field experiment showed that compound 9ac had 74.4% efficacy against Rhizoctonia solani on the 15th day after two consecutive sprayings at an application rate of 4.80 g a.i./667 m2, which was close to that of thifluzamide (83.3%). Furthermore, molecular docking explained the possible binding mode of compound 9ac in the RcSDH active site. Our studies indicated that the pyrazole-thiazole carboxamide hybrid is a new scaffold of SDH inhibitors.

[Relationship between temperament, parenting style and resilience of children aged 3-5 years].

OBJECTIVE: To investigate the developmental characteristics of resilience in children aged 3-5, and to explore the relationship between temperament, parenting style and resilience. METHODS: A total of 570 preschoolers aged 3-5 years in Hangzhou participated in this study. The children's teachers completed the assessment of the resilience scale of DECA-P2 (Devereux Early Childhood Assessment for Preschoolers Second Edition); the children's parents completed assessment of temperament questionnaire CBQ (Children's Behavior Questionnaire) and parenting style questionnaire PSDQ (Parenting Styles and Dimensions Questionnaire). RESULTS: Totally 432 valid questionnaires were retrieved with a recovery rate of 75.79%. The levels of initiative and self-regulation of 5-y children were higher than those of children aged 3 or 4 (all P<0.01); the level of attachment/relationship of 5-y children was higher than that of children aged 4 (P<0.01); the levels of initiative and self-regulation of girls were higher than those of boys (P<0.05 or P<0.01). The negative affect dimension of temperament was negatively correlated with resilience (all P<0.05), while the effortful control and authoritative parenting styles were positively correlated with resilience (all P<0.05). The negative affect and effortful control were able to partially predict resilience of children through authoritative parenting style (mediating effect were-0.0143 and 0.0363). CONCLUSIONS: Preschoolers aged 3-5 years with different age and gender show differences in resilience, and parenting styles may play a mediating effect between temperament and resilience.

Design and synthesis of thiazolylhydrazone derivatives as inhibitors of chitinolytic N-acetyl-ß-d-hexosaminidase.

N-acetyl-ß-d-hexosaminidase (Hex) is potential target for pesticide design. Here, a series of thiazolylhydrazone derivatives were designed, synthesized and evaluated as competitive inhibitors of OfHex1, a Hex from the agricultural pest Ostrinia furnacalis. The derivative 3k, with a (benzyloxy)methyl group at the N3 atom, demonstrated greater potency with a Ki of 10.2 µM. Molecular docking analysis indicated that the (benzyloxy)methyl group of 3k was bound to a previously unexplored pocket formed by Loop478-496. Then further optimization around naphthalene ring led to find the more potency substituent phenyl. The derivative 7, with phenoxyethyl group at R1 and a phenyl group at R2, demonstrated an augmented potency with a Ki of 2.1 µM. Molecular docking analysis indicated that 7 was bound to the active pocket of OfHex1 more favorably than 3k. This work suggests a novel scaffold for developing specific Hex inhibitors.