MedChemComm最新文献

A new series of quinoline-3-carboxylate derivatives 3a–k were developed as prospective dual inhibitors of EGFR and HER-2. Structural elucidation was accomplished via¹H NMR, ¹³C NMR, DEPT NMR, elemental analysis and mass spectrometry. The synthesized compounds were evaluated for antiproliferative activity against breast (MCF-7) and colon (HT-29) cancer cell lines. Compounds 3a and 3f had the highest antiproliferative efficacy, especially against HT-29 colon cancer cells (IC₅₀ = 23 and 25 nM, respectively), surpassing erlotinib (IC₅₀ = 30 nM). Kinase inhibition experiments further validated the dual action of 3a and 3f, yielding IC₅₀ values of 68 nM and 30 nM against EGFR and HER-2, respectively, for 3a and IC₅₀ values of 71 and 33 nM against the same two kinases for 3f. Compounds 3a and 3f induced apoptosis by the activation of caspases 3, 8, and 9, alongside the overexpression of Bax and the downregulation of Bcl-2. In silico molecular docking studies were performed to investigate the binding interactions of the most active compound, 3a, with EGFR and HER-2 kinase domains. The compound showed strong binding affinities, forming critical hydrogen bonds and hydrophobic interactions with key active-site residues. Additionally, SwissADME analysis of 3a revealed full compliance with major drug-likeness filters, highlighting its potential as an orally available, dual EGFR/HER-2 inhibitor with favorable pharmacokinetic properties.

The escalating prevalence of multidrug-resistant tuberculosis (MDR-TB) underscores the urgent need for new classes of antitubercular agents targeting novel pathways. Carbonic anhydrase, a ubiquitous metalloenzyme, catalyses the reversible hydration of carbon dioxide in the CO₂ + H₂O HCO₃⁻ + H⁺ reaction. Suppressing this enzymatic activity has recently been identified as a new pathway for the treatment of Mycobacterium tuberculosis. To address this, a series of isoxazole–sulphonamides was rationally designed, incorporating an isoxazole pharmacophore as the aromatic tail, amide as a linker, and sulphonamide as the zinc-binding group. These compounds were evaluated against Mycobacterium tuberculosis carbonic anhydrases (MtCA 1 and 3) and two human carbonic anhydrases (hCA I and II) to identify selective inhibitors of the bacterial enzymes. The findings indicated that molecules containing an isoxazole pharmacophore with amide-linked benzene-3-sulphonamide were significantly more selective for MtCA 3 than hCA I and II. Among these compounds, 12c, 12e, and 19b had the highest inhibition against the MtCA 3 with K_i values between 0.08–0.09 μM compared to the standard acetazolamide with a K_i value of 0.10 μM. Some of the best compounds exhibited potent and selective inhibition of MtCA 3 over hCA I and II, with the meta- and para-substituted derivatives demonstrating higher selectivity and stronger inhibition. Specifically, compound 19b proved to be 199 and 38 times more selective for MtCA 3 than hCA I and hCA II respectively, compared to the standard drug acetazolamide, which is a non-selective CA inhibitor. The potential of compound 19b as a promising antitubercular agent with a MIC value of 8 μg mL⁻¹ against mc² 6230 was further strengthened by in silico ligand–target interaction studies. Thus, compound 19b is emphasised as a promising lead in the pursuit of new, selective agents targeting MtCA 3.

Chalcone-based derivatives have shown potential anticancer activity via multiple mechanisms including protein kinase inhibition. In the current study, two series of chalcone/2-thiopyrimidine conjugates 4a–4d and 6a–6i were designed, synthesized and screened for their antiproliferative activity in a single-dose assay against NCI-60 cancer cell lines. Ten compounds, 4a–4d, 6a–6c, 6f, 6h, and 6i, were selected for a five-dose assay and their GI₅₀ values were determined. Compound 4c showed potent anticancer activity against LOX IMVI melanoma cell line with a GI₅₀ value of 0.0128 μM. Seven compounds, 4a, 4c, 4d, 6c, 6f, 6h, and 6i, were found to be non-cytotoxic against fibroblast (hFB) normal cell line. Additionally, investigation of the VEGFR-2 inhibitory activity of the ten promising compounds revealed that 4c, 4d and 6i displayed promising VEGFR-2 inhibition (IC₅₀ = 0.144, 0.105, and 0.072 μM, respectively) compared to sorafenib (IC₅₀ = 0.081 μM). Moreover, 4c inhibited BRAF_WT and BRAF_V600E kinases (IC₅₀ = 0.201 and 0.101 μM, respectively) relative to vemurafenib (IC₅₀ = 0.156 and 0.063 μM, respectively). Furthermore, 4c arrested the cell cycle progression at the G₁ phase and induced late apoptosis in LOX IMVI cells. Moreover, evaluation of the effect of 4c on apoptotic markers in the mentioned cells indicated an increase in the Bax/Bcl-2 ratio by 28.12-fold along with upregulation of caspases-3 and -9 by 7.40- and 5.63-fold, respectively, in addition to anti-migratory effect. Molecular docking study of the most promising derivatives revealed a common binding pattern in the binding site of the target kinases that extends from the hinge region through the gate area towards the allosteric back pocket interacting with the key amino acids in a type II inhibitor-like binding pattern.

Schweinfurthins (SWs) are natural products isolated from the plant genus Macaranga which display a unique cytotoxicity profile in human cancer cell lines with low nanomolar potency. Their known target is the sterol transport protein (STP) oxysterol-binding protein (OSBP), a key mediator and regulator of lipid transport between the endoplasmic reticulum (ER) and the trans-Golgi network (TGN). However, until now the underlying structure–activity relationships (SAR), as well as the cellular toxicity-target engagement relationships of SWs towards OSBP have not been well-studied. In this study, we present the first comprehensive SAR and selectivity study by characterizing 59 SW analogues utilizing our STP screening panel. Complementary detailed docking studies shine light on the SW-OSBP interactions and unravel amino acid residues critical for potent binding to OSBP. Additionally, we demonstrate cellular target engagement and correlate cancer cell cytotoxicity with Golgi fragmentation as a phenotypic consequence of OSBP inhibition by selected SW analogues. Therefore, this study will pave the way for more focused investigations and therapeutic applications of OSBP inhibitors.

In recent years, heat shock protein 90 (HSP90), a widely expressed molecular chaperone, has emerged as a promising anticancer target due to its crucial role in stabilizing and regulating the functions of numerous client proteins involved in various essential cellular processes, including protein folding, signalling pathways, and activation of tumor-associated proteins. Despite extensive developments, only one HSP90 inhibitor has gained approval, reflecting the complexity of the HSP90 chaperone machinery, associated side effects, and emergence of resistance mechanisms. To overcome these limitations, researchers have focused their attention on developing targeted protein degraders (TPDs), a revolutionary therapeutic approach that selectively eliminates specific dysregulated target proteins. TPDs exploit cellular degradation pathways, including the ubiquitin–proteasome system (UPS), lysosomal pathways, and autophagy to achieve precise protein degradation. Among these strategies, proteolysis-targeting chimeras (PROTACs) as well as HEMTAC/HIM-PROTACs have emerged as prominent UPS-based technologies. PROTACs link targets to E3 ligases for proteasomal removal, where HEMTACs exploit HSP90 to drive client ubiquitination, thereby offering significant potential for cancer therapeutics. Given HSP90's role in tumor progression and considering the potential of TPDs, researchers have designed and developed various HSP90-targeting PROTACs and HEMTAC/HIM-PROTACs, which exhibits remarkable efficacy, selectivity, antiproliferative potency, and the ability to overcome drug resistance. This review highlights the structural and biological functions of HSP90, delineates the mechanistic principles underlying its degradation, and summarizes the structure–activity relationships (SARs) inlcuding the synthetic strategies employed across different HSP90-directed TPD modalities. Furthermore, the challenges and opportunities associated with the utilization of HSP90 and their client proteins in developing TPDs-based therapeutics to tackle the unmet clinical needs in cancer have been discussed.

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.