MedChemComm最新文献

Antimicrobial resistance threatens global health, with multidrug-resistant pathogens causing millions of deaths annually. Conventional antibiotics face limitations due to bacterial biofilms, resistance mechanisms, and host toxicity. Bacteriophages, due to their high specificity, hold great potential in antimicrobial therapy, targeted drug delivery. In recent years, advances in chemical biology and nanomaterials science have led to the continuous refinement of surface chemical modification strategies for bacteriophage capsids, providing robust support for their functional expansion. This review summarizes commonly employed bacteriophage surface modification techniques, including both covalent and non-covalent approaches, and categorizes various types of photosensitizers along with their recent progress in antimicrobial applications. Furthermore, it highlights recent studies on bacteriophage–photodynamic synergistic therapy systems in treating bacterial infections and discusses their application prospects and future directions in the field of precision antimicrobial therapy.

Naegleria fowleri (N.f.), commonly referred to as the “brain-eating amoeba”, is a free-living amoeboflagellate excavate capable to cause primary amoebic meningoencephalitis (PAM)—a rapidly progressing and typically fatal brain infection. Current treatment options are limited, poorly effective, and highly toxic, underscoring the urgent need for novel therapeutics. In this study, we explore the potential of repurposing FDA-approved microtubule-targeting agents (MTAs) for anti-N.f. therapy. By performing a comparative analysis of two large-scale drug screens—one assessing anti-amoebic activity and the other evaluating effects on tubulin polymerization—we identify strong correlations between microtubule disruption and amoebic growth inhibition. Notably, we highlight three major drug families (triphenylethylene, phenothiazine, and miconazole derivatives) and describe how their anti-amoebic effects relate to their MTA activity. In particular, triphenylethylene and phenothiazine compounds demonstrate a high positive correlation between tubulin polymerization inhibition and N.f. suppression, suggesting a shared molecular mechanism. Furthermore, we identify potent MTAs such as ebselen and auranofin—both capable of crossing the blood–brain barrier—as promising candidates for repurposing. These findings demonstrate the value of MTA-based screening in anti-amoebic drug discovery and point toward new therapeutic avenues for treating this devastating disease.

Antimicrobial resistance challenges the effectiveness of carbapenem antibiotics as last-line therapy, due to the production of both serine and metallo-β-lactamase enzymes. β-Lactamase inhibitors currently available on the market include clavulanic acid, sulbactam, tazobactam, avibactam, relebactam and vaborbactam but, while they are active against serine β-lactamases, they are inactive against the zinc-containing metallo-β-lactamases. This review aims to discuss the distinctive structural qualities of β-lactamase enzymes and to summarise the efficacy of clinically approved and emerging β-lactamase inhibitors against clinically significant carbapenemases.

This study aims to develop a green and effective magnetic catalyst, biochar/Fe₃O₄@APTMS, for the one-pot synthesis of bioactive hexahydroquinolines derivatives. Following synthesis, some biological activities were assessed including antibacterial activity and antidiabetic potential through polyol inhibition assays. The reaction involved four-component condensation of ammonium acetate, malononitrile or ethylcyanoacetate, dimedone (5,5-dimethyl-1,3-cyclohexanedione) and some aromatic aldehydes by refluxing in ethanol to afford products in high yields (91–97%) in a short time (10 minutes). Additionally, heterogeneous catalyst provides several advantages, including operational simplicity, rapid reaction times, easy product isolation, and recyclability of unreacted starting materials. The nano catalyst was fully characterized with Fourier Transform Infrared Spectroscopy (FT-IR), Raman, Field Emission Scanning Electron Microscopy (FE-SEM), and energy dispersive X-ray mapping (EDX-Map) while the characterization of the products with Nuclear magnetic resonance spectroscopy (¹³C NMR and ¹H NMR) confirmed their structure. Some of the compounds tested showed moderate but significant antidiabetic activity against aldose reductase (IC₅₀ values 4.03 to 18.29 μg mL⁻¹) and antibacterial activity against Gram-positive strains of bacteria, Staphylococcus aureus and Enterococcus faecalis, with inhibition zones up to 15.5 mm. These results showed promise for the compounds being used as dual-function therapeutic agents for diabetic complications and microbial infection.

Background: the urgent need for effective prevention and treatment strategies for hepatitis B virus (HBV) has driven extensive research into natural compounds. This study aims to explore the therapeutic potential of matairesinol monoglucoside (MMG) in the treatment of HBV infection. Methods: primary hepatocytes and Kupffer cells were isolated from wild-type (WT) or stimulator of interferon genes (STING) knockout mice and subsequently infected with AAV-HBV to establish an in vitro anti-HBV assay model. The anti-HBV effects of MMG were assessed by measuring HBV DNA, HBsAg, and HBeAg levels, as well as using qRT-PCR and ELISA to evaluate type I interferon markers (IFN-α and IFN-β), and a luciferase assay. In vivo anti-HBV effects were determined by pre-treating mice with MMG prior to AAV-HBV infection. Results: MMG treatment significantly reduced the expression of HBV DNA, HBsAg, and HBeAg in both primary hepatocytes and Kupffer cells. Additionally, MMG enhanced the production of type I interferons (IFN-α and IFN-β) in both cell types. The knockout of STING diminished the effects of MMG on type I interferon production. Mechanistically, MMG was shown to modulate the STING-TBK1-IRF3 signaling axis, leading to increased IFN production. Conclusions: MMG shows promise as a potential therapeutic agent against HBV by targeting the STING signaling pathway.

Porphyrins are well-known photosensitizers (PSs), a few of which are clinically approved drugs for use in photodynamic therapy (PDT). Porphyrin derivatives including tetra-cationic porphyrins, e.g.TMPyP4, are also well-studied binders for G-quadruplex (G4) DNA. Since G4 DNAs are known to play a role in malignant transformation of cells, a variety of G4 binders have been used in cancer therapy by regulating the function of G4 DNA. In this study, two water-soluble porphyrins (1 and 2), with four terminal cationic moieties connected with alkyl linkers were synthesized as bifunctional molecules for simultaneous G4 binding and PDT-PS. Photoinduced singlet oxygen (¹O₂) generation and DNA cleavage were tested under visible light irradiation revealing the efficient generation of ¹O₂ in line with photoinduced DNA cleavages. Studies in a cancer cell line (HeLa) and a normal fibroblast (NHDF) cells revealed significantly stronger photocytotoxicities of these porphyrins (1 and 2) in comparison to TMPyP4, presumably due to better cellular internalization – as observed by flow cytometry. Interestingly, enhanced photocytotoxicity of 1 and 2 was observed in HeLa in comparison to NHDF. This may be related to the fact that more G4 DNAs are present in the nuclei of cancer cell lines to allow binding of porphyrins 1 and 2, as observed by fluorescence microscopy. The interactions of porphyrins 1 or 2 with a G4-forming telomeric DNA were evaluated by a FRET assay and spectroscopic methods (fluorescence, UV-vis, and CD) and showed selective binding to G4 DNA. The results show the potential of porphyrins 1 and 2 as PDT-PSs targeting cancer cells with higher G4-forming domains.

Despite recent advances, Alzheimer's disease (AD) remains largely a mystery more than a century after its discovery. Protein kinases are among the new targets under investigation, which is not surprising given their crucial role in maintaining cellular homeostasis and in the development of various diseases. Several protein kinase inhibitors have shown remarkable therapeutic efficacy in the context of AD, although none of them have yet received approval by regulatory agencies. Alongside the use of classic inhibitors, a new therapeutic approach has emerged in recent years, shifting the focus from modulation to targeted degradation of the protein. The purpose of this review is to highlight and discuss novel series of proteolysis-targeting chimeras (PROTACs) directed against protein kinases relevant to the development of AD.

The SLIT2/ROBO1 signaling axis plays a critical role in neural development, immune regulation, and tumor progression, including glioblastoma. However, small molecule inhibitors targeting this protein–protein interaction remain unexplored. Herein, we report the discovery and validation of DEL-S1, a first-in-class small molecule that binds to SLIT2 and disrupts its interaction with ROBO1. Using a DNA-encoded library (DEL) screen of 4.2 billion compounds, DEL-S1 was identified and confirmed to bind SLIT2 via temperature-related intensity change (TRIC) assay. Functional inhibition of the SLIT2/ROBO1 complex by DEL-S1 was demonstrated using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, yielding an IC₅₀ of 68.8 ± 12.5 μM. Molecular docking and molecular dynamics (MD) simulations revealed key interaction hotspots at the SLIT2 binding interface and confirmed that DEL-S1 impairs SLIT2/ROBO1 complex formation by inducing conformational rearrangements. DEL-S1 exhibited favorable ADME properties, including satisfactory plasma and microsomal stability, low cytotoxicity, and minimal hERG liability. To facilitate structure–activity relationship (SAR) exploration, we designed and implemented a modular, one-pot synthetic route leveraging cyanuric chloride reactivity, enabling rapid derivatization of the triazine scaffold of DEL-S1. This strategy yielded structurally diverse analogs, including water-soluble carboxylate derivatives with preserved SLIT2/ROBO1 inhibitory activity. Together, this work establishes a novel chemical scaffold targeting SLIT2 and introduces a flexible synthetic platform to support further optimization toward therapeutic development.

Serine/arginine protein kinase 1 (SRPK1) plays a pivotal role in the phosphorylation of SR/RS domain-containing proteins, which are involved in various cellular processes. Its overexpression has been associated with the progression of various malignancies, positioning SRPK1 as a promising target for cancer treatment. In this study, we report the design, synthesis, and preliminary biological evaluation of two hybrid molecules, geo15 and geo140, which combine known SRPK1 inhibitors with the antimetabolites gemcitabine and 5-fluorouracil (5-FU), respectively. These conjugates were synthesized to assess whether hybridization enhances potency compared to the parent compounds, and to investigate potential novel mechanisms of action. In vitro assays were performed to evaluate SRPK1 inhibition and antiproliferative activity in selected cancer cell lines. Among the tested compounds, the JH-VII-139-1-based hybrid geo140 exhibited notable SRPK1 inhibitory potency and cytotoxic effects, demonstrating a favorable profile for further optimization. Interestingly, treatment with geo140 did not appear to alter the overall SRPK1 distribution in interphase cells but resulted in a notable increase of mitotic cells that displayed a substantial accumulation of SRPK1, thus suggesting that the hybrid compound may have an impact on cell cycle progression. This work supports the potential of molecular hybridization as a strategy for the development of novel SRPK1-targeting anticancer agents.

HMOX1 has gained increasing recognition across multiple malignancies; however, its precise oncogenic or tumor-suppressive roles remain incompletely defined. In this study, we comprehensively investigated HMOX1 across diverse tumor types utilizing the cancer genome atlas (TCGA). We further integrated data from multiple bioinformatics platforms, including TIMER2, UALCAN, GEPIA2, cBioPortal, R, GSCA, and LinkedOmics. Western blotting and quantitative real-time PCR (qRT-PCR) confirmed differential HMOX1 expression between normal renal epithelial cells and KIRC cells. Functional assays in vitro and in vivo demonstrated that HMOX1 regulates proliferation, migration, and cell-cycle progression in 786-O and Caki-1 cells. Pan-cancer analyses revealed that HMOX1 is aberrantly expressed across multiple malignancies with significant associations with the tumor stage. Survival analyses indicated that elevated HMOX1 expression predicted poor overall survival (OS) in LGG (P = 0.025) but favorable OS and disease-free survival (DFS) in KIRC (OS: P = 0.00062; DFS: P = 9 × 10⁻⁴). Moreover, mutations were the predominant genetic alteration affecting HMOX1, while promoter methylation was broadly reduced across cancers. HMOX1 expression positively correlated with immune infiltration by CD8⁺ T cells (KIRC: Spearman ρ = 0.26, FDR = 2.56 × 10⁻⁸) and macrophages (KIRC: Spearman ρ = 0.32, FDR = 2.77 × 10⁻¹³). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses in KIRC implicated HMOX1 in the chemokine and NF-κB signaling pathways. Both in vitro and in vivo experiments demonstrated that HMOX1 knockdown accelerates cell-cycle progression and enhances proliferation and migration in 786-O and Caki-1 cells. Collectively, our findings establish HMOX1 as a promising prognostic biomarker and potential immunotherapeutic target across multiple cancers.