MedChemComm最新文献

A novel series of procaine derivatives incorporating 1,2,3-triazole and isoxazoline scaffolds were developed and evaluated for their anticancer potential, particularly against esophageal cancer. Initially, the synthesized compounds were screened for their kinase inhibitory activity against PI3K, mTOR, CDK1, CDK4, EGFR, and VEGFR2, where they exhibited excellent inhibitory potency against PI3K and mTOR. Among the synthesized compounds, 8e, 8f, and 8g emerged as the top-performing kinase inhibitors. These three candidates were subsequently tested against a panel of human cancer cell lines, including breast, cervical, lung, liver, and esophageal cancer cells. Notably, they demonstrated superior cytotoxic activity against esophageal cancer cells. Of these, compound 8e was identified as the most potent and was further evaluated against six esophageal cancer cell lines (Eca109, TE1, TE13, KYSE30, KYSE70, and KYSE150) with diverse genotypic backgrounds. Compound 8e exhibited the highest activity against Eca109 cells. Further investigations revealed that compound 8e significantly inhibited Eca109 cell viability, as confirmed by the MTT assay, and induced apoptosis, as evidenced by annexin V/PI dual staining and DAPI nuclear staining. It also caused G0/G1 cell cycle arrest, decreased mitochondrial membrane potential, and demonstrated marked telomerase inhibitory activity. In addition, wound healing and transwell assays confirmed its ability to suppress the migration and invasion of Eca109 cells. Western blot analysis revealed that compound 8e modulated the expression of key apoptotic regulators (Bcl-2, Bax, and p53) and downregulated the PI3K/Akt/mTOR signaling pathway. In an orthotopic xenograft mouse model, compound 8e significantly reduced tumor volume and increased body weight in a dose-dependent manner, indicating potent in vivo efficacy with favorable tolerability. Biochemical analyses showed that compound 8e mitigated oxidative stress by regulating MDA, SOD, and GSH levels and suppressed pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. Immunohistochemical staining further confirmed reduced expression of PI3K and p-Akt (Ser473) in tumor tissues. Pharmacokinetic evaluation via both intravenous and oral administration demonstrated that compound 8e possesses excellent bioavailability, highlighting its potential as a promising therapeutic candidate for the treatment of esophageal cancer.

Tissue fibrosis is a common consequence of many different acute and chronic injuries, which severely impairs the function of affected organs. A significant challenge is the lack of effective strategies to treat fibrotic disorders. The metabolic dysregulation underlying fibrosis may be reversed by the small molecule caffeic acid phenethyl ester (CAPE), but there are limitations which prevent its clinical use. Following the identification of caffeic acid derivative 1 from an in-house library screen, we performed structure–activity relationship studies which led to the discovery of novel small molecule inhibitors of extracellular matrix (ECM) collagen secretion. The small molecules increased PPARG and CD36 expression (markers of fatty acid metabolism), suggesting a mechanism of action involving a metabolic shift from fibrotic-to-normal state. The compounds identified in this study provide a foundation for further development towards a novel, first-in-class therapeutic agent for fibrosis.

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.