The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera, Noctuidae), is a highly polyphagous invasive pest that damages various crops. Pesticide control is the most common and effective strategy to control FAW. In this study, we evaluated the toxicity of metaflumizone and indoxacarb against third-instar FAW larvae using the insecticide-incorporated artificial diet method under laboratory conditions. Both metaflumizone and indoxacarb exhibited substantial toxicity against FAW, with LC50 values of 2.43 and 14.66 mg/L at 72 h, respectively. The sublethal effects of metaflumizone and indoxacarb on parental and F1 generation FAW were investigated by exposing third-instar larvae to LC10 and LC30 concentrations of these insecticides. Sublethal exposure to these two insecticides significantly shortened adult longevity, extended pupal developmental times and led to reduced pupal weight, pupation rates, and adult fecundity in the treated parental generation and F1 generation at LC10 or LC30 concentrations, in comparison to the control group. The larval developmental times were shortened in the parental generation but prolonged in the F1 generation, after being treated with sublethal concentrations of metaflumizone. Furthermore, larvae exposed to LC10 or LC30 concentrations of indoxacarb exhibited elevated activity levels of cytochrome P450 monooxygenase and glutathione S-transferase, which coincides with the observed synergistic effect of piperonyl butoxide and diethyl maleate. In conclusion, the high toxicity and negative impact of metaflumizone and indoxacarb on FAW provided significant implications for the rational utilization of insecticides against this pest.

Polypeptide materials offer scalability, biocompatibility, and biodegradability, rendering them an ideal platform for biomedical applications. However, the preparation of polypeptides with specific functional groups, such as semicarbazide moieties, remains challenging. This work reports, for the first time, the straightforward synthesis of well-defined methoxy-terminated poly(ethylene glycol)-b-polypeptide hybrid block copolymers (HBCPs) containing semicarbazide moieties. This synthesis involves implementing the direct polymerization of environment-stable N-phenoxycarbonyl-functionalized α-amino acid (NPCA) precursors, thereby avoiding the handling of labile N-carboxyanhydride (NCA) monomers. The resulting HBCPs containing semicarbazide moieties enable facile functionalization with aldehyde/ketone derivatives, forming pH-cleavable semicarbazone linkages for tailored drug release. Particularly, the intracellular pH-triggered hydrolysis of semicarbazone moieties restores the initial semicarbazide residues, facilitating endo-lysosomal escape and thus improving therapeutic outcomes. Furthermore, the integration of the hypoxic probe (Ir(btpna)(bpy)2 ) into the pH-responsive nanomedicines allows sequential responses to acidic and hypoxic tumor microenvironments, enabling precise detection of metastatic tumors. The innovative approach for designing bespoke functional polypeptides holds promise for advanced drug delivery and precision therapeutics.

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kβ, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.

Photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. The application of photopharmacology in the research of invertebrate sodium channels has not been investigated. Here we report several photochromic ligands of metaflumizone. One ligand, termed ABM04, underwent reversible trans-cis isomerization under ultraviolet or blue light irradiation. cis-ABM04 had excellent larvicidal activity against mosquito larvae with an LC50 value of 4.39 μM and showed insecticidal activity against Mythimna separata with an LC50 value of 7.19 μM. However, trans-ABM04 was not found to have biological activity. ABM04 (10 μM) can induce depolarization of dorsal unpaired median neurons and enable the real-time photoregulation of mosquito larval behavior. The precise regulation of invertebrate sodium channels is realized for the first time, which provides a new strategy for the basic and accurate research of invertebrate sodium channels.

Ryanodine receptors (RyRs) are important ligand-gated Ca2+ channels; their excessive activation leads to Ca2+ leakage in the sarcoplasmic reticulum that may cause neurological diseases. In this study, three series of novel potent RyR1 inhibitors based on dantrolene and bearing semicarbazone and imidazolyl moieties were designed and synthesized, and their biological activity was evaluated. Using a single-cell calcium imaging method, the calcium overload inhibitory activities of 26 target compounds were tested in the R614C cell line, using dantrolene as a positive control. The preliminary investigation showed that compound 12a suppressed Ca2+ release as evidenced by store overload-induced Ca2+release (SOICR) (31.5 ± 0.1%, 77.2 ± 0.1%, 93.7 ± 0.2%) at 0.1 μM, 3 μM and 10 μM, respectively. Docking simulation results showed that compound 12a could bind at the active site of the RyR1 protein. The Morris water-maze test showed that compound 12a significantly improved the cognitive behavior of AD-model mice. Further studies on the structural optimization of this series of derivatives are currently underway in our laboratory.

Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects on immune systems. The cell apoptosis and cell cycle distribution of compound 4d were also studied. Molecular docking studies revealed multiple interactions between 4d and NF-κB. Our findings demonstrate the potential of semicarbazones as a promising type of compounds with anticancer activity.

Thirty semicarbazone and thiosemicarbazone derivatives (2a-w and 4a-g) from chalcones containing furan and thiophene ring were designed and synthesized. They were characterized by IR, 1H NMR, 13C NMR and HRMS. The crystal structure of compound 2r was characterized by single crystal X-ray diffraction. It crystallizes in the monoclinic system with space group P21/c. The insecticidal activity of the synthesized compounds was screened against Leucania separata and Pieris rapae using beta-cypermethrin as the comparative standard. The results displayed that most of them had remarkable insecticidal activity. Among them, compounds 2e-g showed better activity than beta-cypermethrin against L. separata and P. rapae. Compound 2p also possessed a better activity than beta-cypermethrin against P. rapae. The insecticidal activities of these compounds have been reported for the first time.

A series of novel steroidal 5α,8α-endoperoxide derivatives bearing semicarbazone (7a-g) or thiosemicarbazone (7h-k) side chain were designed, synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, HCT-116, MCF-7, and A549) using the MTT assay in vitro. The results showed that compound 7j exhibited significant cytotoxic activity against HepG2 cells (IC50 = 3.52 μM), being more potent than ergosterol peroxide. Further cellular mechanism studies in HepG2 cells indicated that compound 7j triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential (MMP), which was associated with up-regulation of Bax, down-regulation of Bcl-2, activation levels of the caspase cascade, and formation of reactive oxygen species (ROS). The above findings indicated that compound 7j may be used as a promising skeleton for antitumor agents with improved efficacy.

The Hepatocyte Growth Factor Receptor (HGFR) c-Met is over-expressed and/or mutated in various human tumor types. Dysregulation of c-Met/HGF signaling pathway affects cell proliferation, survival and motility, leading to tumor growth, angiogenesis, and metastasis. Therefore, c-Met has become an attractive target for cancer therapy.
This study is aimed to evaluate a new series of 4-phenoxypyridine derivatives containing semicarbazones moiety for its cytotoxicity.
A series of novel 4-phenoxypyridines containing semicarbazone moieties were synthesized and evaluated for their in vitro cytotoxic activities against MKN45 and A549 cancer cell lines and some selected compounds were further examined for their inhibitory activity against c-Met kinase. In order to evaluate the mechanism of cytotoxic activity of compound 24, cell cycle analysis, Annexin V/PI staining assay, AO/EB assay, wound-healing assay and docking analysis with c-Met were performed.
The results indicated that most of the compounds showed moderate to good antitumor activity. The compound 28 showed well cytotoxic activity against MKN45 and A549 cell lines with IC50 values of 0.25μM and 0.67μM, respectively. Compound 24 showed good activity on c-Met and its IC50 value was 0.093μM.
Their preliminary Structure-Activity Relationships (SARs) studies indicated that electronwithdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Treatments of MKN45 cells with compound 24 resulted in cell cycle arrest in G2/M phase and induced apoptosis in a dose-dependent manner. In addition, AO/EB assays indicated 24 induced dose-dependent apoptosis of A549 and MKN45 cells. Wound-healing assay results indicated that compound 24 strongly inhibited A549 cell motility.

Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and 10g with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while 10g exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-β-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated 10g as an excellent anti-hepatofibrosis candidate, which reduced CCl4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs.