The ongoing evolution of SARS-CoV-2 and its immune-evading variants underscores an urgent requirement for broad-spectrum antiviral drugs. In this study, a series of lycorine derivatives was synthesized. This led to the identification of compound 7 as a promising antiviral candidate. Compound 7 exhibited potent inhibitory activity against SARS-CoV-2 and its variants, including Alpha, Beta, Delta, and Omicron, in vitro. The antiviral efficacy of compound 7 was then validated in vivo. Treatment with compound 7 significantly reduced viral loads and alleviated lung pathologies in SARS-CoV-2-infected hamsters. Mechanistically, compound 7 directly targeted the short isoform of the zinc-finger antiviral protein (ZAP-S) and bound to specific residues (E111, E115, and F549). This result was confirmed using cellular thermal shift assays, bio-layer interferometry, and mutagenesis studies. This interaction enhanced the ZAP-S stability and disrupted -1 programmed ribosomal frameshifting (-1PRF), a critical process for viral polyprotein synthesis. The antiviral activity of compound 7 was ZAP-S-dependent, as ZAP-S knockdown abolished its efficacy while overexpression enhanced it. These results established compound 7 as a novel antiviral candidate that can combat SARS-CoV-2 and its variants by targeting ZAP to inhibit -1PRF. This compound, therefore, represents a promising therapeutic strategy.

Dysfunction of the voltage-gated sodium channel NaV1.7 underlies multiple pain-sensitivity disorders, making NaV1.7 inhibition an attractive therapeutic strategy. However, currently available NaV1.7 inhibitors, frequently suffer from limited structural diversity and moderate selectivity. We previously identified a novel indole-based hit that demonstrated modest selectivity toward other sodium channels. Herein, systematic structure-activity relationship studies of 1H-indole-3-propionamide derivatives led to the discovery of compound 56, a potent and subtype-selective NaV1.7 inhibitor. The analgesic mechanism of 56 was elucidated through an electrophysiological evaluation in mouse dorsal root ganglion neurons. Moreover, 56 reduced the risk of human ether-à-go-go-related gene (hERG)-related cardiotoxicity and demonstrated a favorable motor function profile in mice. With acceptable pharmacokinetic properties, oral administration of 56 displayed robust analgesic efficacy across various murine models of acute, chronic inflammatory, and neuropathic pain. The findings of the study highlight a highly promising, orally available lead compound for pain treatment.

Chemical reactions, which transform one set of substances to another, drive research in chemistry and biology. Recently, computer-aided chemical reaction prediction has spurred rapidly growing interest, and various deep learning-based algorithms have been proposed. However, current efforts primarily focus on developing models that support specific applications, with less emphasis on building unified frameworks that predict chemical reactions. Here, we developed Bidirectional Chemical Intelligent Net (BiCINet), a prediction framework based on Bidirectional and Auto-Regressive Transformers (BARTs), for predicting chemical reactions in various tasks, including the bidirectional prediction of organic synthesis and enzyme-mediated chemical reactions. This versatile framework was trained using general chemical reactions and achieved top-1 forward and backward accuracies of 80.7 % and 48.6 %, respectively, for the public benchmark dataset USPTO_50K. By multitask transfer learning and integrating various task prompts into the model, BiCINet enables retrosynthetic planning and metabolic prediction for small molecules, as well as retrosynthetic analysis and enzyme-catalyzed product prediction for natural products. These results demonstrate the superiority of our multifunctional framework for comprehensively understanding chemical reactions. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action. However, conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive. Fortunately, deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties. Herein, we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs. Through wet-lab validation, WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells. Furthermore, the R-(−)-WJ0909 (WJ0909B), demonstrated optimal antitumor efficacy in vitro and ex vivo patient-derived organoids (PDOs). Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis. Moreover, WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models. This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 mu M. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.

A series of novel substituted uracil-1'(N)-acetic acid esters (5-9) and 4-pyridone-1'(N)-acetic acid esters (10-11) of 20(S)-camptothecins (CPTs) have been synthesized by the acylation method. All of these new esters were assayed for in vitro cytotoxicity against five human cancer cell lines A549, Bel7402, BGC-823, HCT-8 and A2780. The in vitro bioassay results showed that all the synthesized compounds 5-11 had cytotoxities that were higher than TPT and comparable to CPT on these five tumor cell lines, some of them even showed comparable or superior cytotoxic activity to CPT. The in vitro data exhibited the cytotoxicity of the ester depended on that of its parent compound. The ester 5, 6, 8, 10, 11 even possessed the cytotoxity activity comparable to or even a little better than CPT on A549, HCT-8 and A2780. The compound 11 had the same level of cytoxity on Bel7402 as that of CPT. Here the synthesis and the in vitro antitumor evaluation of a series of novel 20-O-linked substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters derivatives of CPTs are reported.

Stimulator of interferon genes (STING) is a crucial adaptor protein that can regulate the innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, the activation of STING pathway is expected to be an efficacious immunotherapeutic tactic to treat cancer. In this study, we performed a structure-activity relationship study of amidobenzimidazole monomer, led to a series of ABZI STING agonist derivatives with potent STING-activating effects. Among them, compound 72, as a representative compound, markedly activated the STING-TBK1-IRF3 signaling pathway and significantly increased the mRNA and protein levels of IFN-β, CXCL10 and IL-6 in both WT THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). In addition, it was confirmed that compound 72 was highly selective for human STING, specifically targeting human STING signaling and showing no activation of m-STING.

In the search for potent bioactive compounds, a series of tetrahydro-2H-1,3,5-thiadiazine-2-thiones (1–13) were synthesized in good yield and characterized by means of 1H NMR, 13C NMR, and mass spectral data. The anticancer activity of the compounds was evaluated against HeLa cell line and anti-inflammatory potential via nitric oxide (NO) inhibition. Among the screened compounds, 2-(5-(3-methoxypropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (3), 2-(5-cyclopropyl-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid (5), 2-(5-cyclopropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (6), and 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid (9) were the most potent against HeLa cell line with IC50 values <4 µM, whereas the rest of the series exhibited moderate-to-good activities. All the compounds were potent NO inhibitors with IC50 values ranging from <0.4 to 14.9 µM. Docking studies, binding orientations, and interaction plots showed strong interaction of the studied compounds with the inducible NO synthase enzyme via strong hydrogen bonds and hydrophobic interactions, which authenticate the in vitro results. These newly synthesized compounds could lead to the discovery of anticancer drugs.

A series of new thiadiazine derivatives including 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (a) and 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) pentanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS2, followed by reaction with formaldehyde and amino acids. The chemical structures of synthesized compounds were confirmed by 13C-NMR and 1H-NMR techniques. The inhibitory potential of major inflammatory enzymes, COX-2 and 5-LOX was examined. Moreover, antinociceptive and anti-inflammatory activities were evaluated in the in vivo thermally induced nociceptive, and carrageenan induced paw edema models in mice. The in-vitro results reflect that these compounds exhibited concentration dependent inhibition of COX-2 and 5-LOX. The tested compounds at 50 mg/kg showed significant effect on thermally induced pain, and reduced latency time (seconds) as compared to the vehicle treated animals. Moreover, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice. Furthermore, the binding modes of the most active COX-2 and 5-LOX inhibitors were determined through computational methods. The computational study reflects that the docked compounds have high binding affinities for COX-2 and 5-LOX enzymes, which leads to inhibition of these enzymes.

A series of alkyl/aryl/aralkylamines or amino acids appended tetrahydro-2H-1,3,5-thiadiazine-2-thiones (4a-i, 5a-g, 6 and 7) were synthesized via one pot domino synthesis. The synthesis involved reacting alkyl/aryl/aralkylamines or amino acids with carbon disulfide employing basic aqueous medium and further cyclization with formaldehyde and alkyl/aryl/aralkylamines or amino acids. In addition, the carboxy-functionalized 1,3,5-thiadiazine-2-thione 6 was further subjected to esterification. All the structures were confirmed through spectral techniques i.e IR, H-1 NMR, C-13 NMR, and MS analysis. Furthermore, the newly synthesized compounds were biologically assessed via in vitro COX-2 and 5-LOX assays, in vivo anti-nociceptive and anti-inflammatory activities. Among the screened compounds, 6, 5f, and 7 exhibited highest inhibitory potency against COX-2 with IC50 values of 11.96, 13.54, and 13.93 mu M, respectively. Moreover, compounds 6 and 7 exhibited excellent inhibitory potential against 5-LOX with IC50 values of 14.01 and 14.13 mu M. The in-vivo anti-inflammatory bioassay studies showed that compounds 6, 7 and 5f dramatically reduced the paw edema size at 1 h and 3 h time intervals. In the anti-nociceptive activity, compound 6 showed pain protection comparative to Tramadol in all tested time intervals. In addition, studies of molecular docking revealed the compounds binding modes in the allosteric site of COX-2 and active site of 5-LOX, where these compounds exhibited higher binding scores and good binding interactions.

A series of the new 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl)pentanoic acids (a) and 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS 2 , followed by reaction with formaldehyde and aminoacids. Structures of synthesized compounds were confirmed through 13 C- NMR and 1 H- NMR spectra and also their molecular mass was determined. To predict the binding mode of these compounds with COX-1, COX-2, and 5-LOX, docking study was performed. Furthermore, in vitro COX-2 and 5-LOX inhibition assays were carried out. Moreover, anti-nociceptive and anti-inflammatory activities were evaluated in in-vivo thermal induced nociceptive and carrageenan induced paw edema models in mice. The finding of the computational study shows that the tested compounds have binding affinities for COX-1, COX-2, and 5-LOX enzymes, which leads to inhibition of these enzymes. The results of the in vitro study revealed that the tested compounds exhibited concentration dependent COX-2 and 5-LOX inhibition property. The tested compounds at dose of 50 mg/kg have a significant effect on thermally induced pain, reduced latency time (seconds) compared to the vehicle treated animals. Also, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice.

白三烯B4(leukotriene B4,LTB4)是一种促炎调节因子,多数炎症细胞均可产生.LTB4与其受体BLT1(leukotriene B4 receptor 1)结合后可通过趋化作用和黏附分子上调将嗜中性粒细胞和巨噬细胞迁移至炎症部位.大量研究表明LTB4-BLT1轴与自身免疫性疾病及炎症的发生有关.因此,LTB4受体拮抗剂对治疗这类疾病具有重要作用.本文简略描述了 LTB4的作用,综述了目前处于临床或临床前研究的LTB4受体拮抗剂的研究进展.

In this review, an effort towards presenting an all-around account of the recent progress on the natural product, aloperine, is made, and the antivirus structure-activity relationship of its derivatives is also summarized comprehensively. In addition, the principal pharmacological effects and corresponding molecular mechanisms of aloperine are discussed. Some new structural modifications of aloperine are also given, which might provide brief guidance for further investigations on the natural product aloperine.

石蒜碱是药用石蒜科植物的有效成分之一,是重要的异喹啉类生物碱.石蒜碱拥有刚性的环系骨架、连续的手性中心、三级胺等独特的化学结构特征.同时其药理活性丰富多样,近年来,针对其抗癌、抗病毒、抗炎、抗寄生虫、抑制乙酰胆碱酯酶活性的研究越来越多,尤其在抗癌、抗病毒方面石蒜碱表现出较大潜力,特别是新型冠状病毒SARS-CoV-2研究.石蒜碱各种药理活性的作用机制复杂且新颖,是当前的研究热点.为了更好地梳理有关石蒜碱的研究进展,为其机制探讨和结构修饰提供思路,本文着眼于石蒜碱的药理活性和构效关系进行了系统的总结.

Parthenolide and micheliolide have attracted great attention in anticancer research due to their unique activities. In this study, thirteen parthenolide derivatives and twenty-three micheliolide derivatives were synthesized. Most synthesized compounds showed higher cytotoxicity than parthenolide or micheliolide. The in vivo anticancer activity of several representative compounds was evaluated in mice. One micheliolide derivative, 9-oxomicheliolide (43), showed promising in vivo antitumor activity compared with clinical drugs cyclophosphamide or temozolomide. Compound 43 was particularly effective against glioblastoma, with its tumor inhibition rate in mice comparable to the drug temozolomide. The discovery of compound 43 also demonstrates the feasibility of developing anticancer micheliolide derivatives by modification at C-9 position. Anticancer mechanism studies revealed that 9-oxomicheliolide exhibited inhibition effect against NF-κB and STAT3 signaling pathways, as well as induction effects of cell apoptosis. It is postulated that 9-oxomicheliolide is likely to be a modulator of the immune system, which regulates the anticancer immune responses.

含笑内酯是来自天然植物的愈创木烷型倍半萜内酯,具有多重药理作用.近年来,为了提高含笑内酯的生物活性和血药浓度,对其结构进行了大量修饰与改造,发现了一系列活性优于含笑内酯以及更具成药性研究的含笑内酯衍生物.本文总结了含笑内酯作用机制、结构修饰、生物活性及构效关系的相关研究进展.

Objective: Parthenolide (PTL) induces anti-tumor effects via the nuclear factor kappa B (NF-κB) signaling pathway. MCL3, a PTL derivative, is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation of PTL. The aim of this study was to elucidate the antitumor activity and mechanism of action of MCL3 in glioblastoma (GBM). Materials and Methods: The effects of MCL3 on G422 cell proliferation, apoptosis, invasion, and angiogenesis in vitro were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, the cell invasion, and tube formation assays. The subcutaneously transplanted G422 xenograft model was used to detect the effect of MCL3 on tumor growth in vivo. Pathological changes were analyzed by immunohistochemical staining. The effects of MCL3 on NF-κB and Stat3 transcriptional activities were examined using a dual-luciferase reporter assay. Protein levels related to the NF-κB/ interleukin (IL)-6/Stat3 signaling pathway were determined using western blot analysis. Results: MCL3 inhibited GBM cell proliferation, invasion, and angiogenesis in a concentration-dependent manner. Moreover, MCL3 decreased the transcriptional activities of NF-κB and Stat3. MCL3 suppressed tumor growth in the subcutaneously transplanted G422 xenograft model, while the inhibition rate was 79% in tumor weight at 40.0 mg/kg. MCL3 blocked the NF-κB/IL-6/Stat3 signaling pathway in G422 cells and tumor tissues, resulting in the downregulation of Stat3 target genes related to apoptosis, invasion, etc., Conclusion: The results show that MCL3 might inhibit G422 GBM growth partly due to the inhibition of the NF-κB/IL-6/Stat3 signaling pathway.

There are no effective antiviral drugs to treat hand, foot, and mouth disease. In this study, a series of lycorine derivatives were synthesized and evaluated against enterovirus 71 and coxsackievirus A16 in vitro. Derivatives 7c-m with the phenoxyacyl group at the C-1 position showed higher efficacy and lower toxicity than lycorine. In addition, derivative 7e enhanced the survival rate to 40% in the mouse model of the lethal EV71 infection.

An efficient and mild method has been developed for the amination of β-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,β-unsaturated intermediates followed by the Michael addition of amines.

AbstractBackgroundAlzheimer's disease (AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APPswe/PS1△E9 mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.MethodsEvodiamine and its derivatives were effectively synthesized by EDCI‐mediated condensation at room temperature. These target compounds contained 1 thio‐ and 21 oxo‐evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H2O2‐induced cell loss in SH‐SY5Y cells were investigated using the WST‐8 assay. The Morris water‐maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APPswe/PS1△E9 mice.ResultsIn this study, a series of oxo‐ and thio‐evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APPswe/PS1△E9 mice.ConclusionOur study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.