ChemMedChem最新文献

Novel tetrahydroindolone dihydropyrimidinone hybrid compounds exhibited significant antibiofilm activity against resistant bacterial Staphylococcus aureus and Pseudomonas aeruginosa strains, indicating molecular hybridization played crucial role to this performance. Toxicity studies using Caenorhabditis elegans model revealed no observable toxicity, even at elevated concentrations. Combination of strong antibiofilm activity with non-toxic behavior underlines the antivirulence potential, positioning the hybrid compounds as promising adjuvants in the fight against chronic bacterial infections. More details can be found in the Research Article by Karine R. Zimmer, Dennis Russowsky, and co-workers (DOI: 10.1002/cmdc.202500716).

In the present study, eight novel substituted 4-cyano-N-(4-cyano-1,3-oxazol-5-yl)-N-alkyl-1,3-oxazole-5-sulfonylamides have been synthesized. Compounds are characterized by IR, ¹H, ¹³C NMR spectroscopy, elemental analysis, and chromato-mass-spectrometry. The anticancer activities of six compounds are evaluated against the NCI-60 human tumor cell line panel. The tested compounds exhibit the strongest antiproliferative (TGI) and cytotoxic (LC₅₀) activities within the leukemia, non-small-cell lung cancer, melanoma, and colon cancer subpanels. Overall, the mean activity parameters (GI₅₀, TGI, and LC₅₀) calculated for three compounds do not differ significantly and are within the range of 1-100 µM, and for some lines, it reaches the value 10^-8 mol L^-1. Structure-activity relationship analysis reveals markedly higher activity for bisoxazole derivatives bearing 4-MeC₆H₄ or 4-FC₆H₄ at the second position of the oxazole rings (compounds 2, 3, and 7), whereas derivatives with diphenyl, di-tolyl substituents (compounds 1 and 6), or 4-ClC₆H₄ (compound 8) exhibit substantially lower anticancer activity. In addition, the potential molecular mechanisms of anticancer action of these compounds are investigated using molecular docking methods. Derivatives show the highest affinity for tubulin and cyclin-dependent kinases. Docking of 4-cyano-N-[4-cyano-2-(4-fluorophenyl)-1,3-oxazol-5-yl]-N-methyl-2-(4-methylphenyl)-1,3-oxazole-5-sulfonamide into the colchicine-binding site of αβ-tubulin reveals a binding affinity of -10.9 kcal mol^-1, with the ligand located at the subunit interface.

Efficient and tumor-targeted drug delivery systems can significantly enhance therapeutic efficacy while reducing adverse effects. Herein, a one-pot encapsulation method is employed to load the hydrophobic drug aesculetin (AE) into zeolitic imidazolate framework-8 (ZIF-8) nanocarriers (denoted as AE@ZIF-8), followed by surface modification with hyaluronic acid (HA) to construct the AE@ZIF-8/HA composite system. Due to the introduction of HA, the surface of AE@ZIF-8/HA carries a negative charge, which helps prolong its circulation time in the body and exhibits good blood compatibility and biological safety. Studies have shown that HA can specifically bind to the highly expressed CD44 receptor on the surface of tumor cells, promoting the selective enrichment of the drug at the tumor site. In the tumor microenvironment, HA can be degraded by hyaluronidase, while the ZIF-8 carrier decomposes under acidic conditions, enabling controlled release of AE. Compared with free AE, AE@ZIF-8/HA exhibits significantly enhanced antitumor activity both in vitro and in vivo. Therefore, this drug delivery system effectively addresses the poor water solubility and low bioavailability of free AE while achieving dual functions of tumor-targeting and stimuli-responsive drug release.

Cell division cycle 37 (CDC37) is a kinase-specific HSP90 cochaperone that stabilizes oncogenic kinases and is frequently overexpressed in malignancies, making it a compelling therapeutic target. Herein, we systematically delineate therapeutic strategies aimed at inhibiting CDC37, including modulating its Ser13 phosphorylation switch through CK2 inhibition or PP5 activation, disrupting the CDC37-HSP90 complex, and blocking its interaction with kinase clients. These approaches culminate in the concerted degradation of multiple kinase client proteins. CDC37 inhibitors induce cell cycle arrest and apoptosis in models of colon cancer, prostate cancer, and others. Critically, by disrupting the thermal stability of kinases, CDC37-targeting agents can resensitize resistant tumors to kinase inhibitors. In summary, targeting CDC37 is not only a novel anticancer strategy but also a paradigm-shifting approach to address the persistent challenge of kinase inhibitor resistance.

The COVID-19 pandemic highlighted the urgent need for effective antiviral treatments targeting SARS-CoV-2. TMPRSS2, a serine protease essential for viral entry into host cells, represents a promising therapeutic target, and this study explores guanidino diaryl thioureas as potential TMPRSS2 inhibitors. Initial screening identified a “hit-compound” (1) with reversible inhibitory activity against TMPRSS2. Computational studies, including docking and molecular dynamics simulations, were conducted to optimize derivatives of compound 1. Twenty-five derivatives were synthesized, and their pharmacokinetic properties and cytotoxicity assessments indicated favorable drug-likeness and minimal toxicity. However, biochemical studies revealed that none of the derivatives improved TMPRSS2 inhibitory activity compared to the original “hit-compound”. The findings suggest that reversible inhibitors may be suboptimal for TMPRSS2 targeting, as camostat and nafamostat exert their effects through irreversible covalent binding. Future efforts should focus on developing irreversible TMPRSS2 inhibitors to enhance antiviral efficacy against SARS-CoV-2.

Myelocytomatosis oncogene (MYC) inhibitors are not available for clinical applications because the MYC protein is not part of a receptor-ligand pair and lacks a defined binding site for small molecules. GD-07, drug-like small molecule identified throughcheminformatics that selectively binds to the G-quadruplex (G4) in the c-MYC promoter with high binding affinity and selectivity over dsDNA. NMR analysis reveals that GD-07 binds to the upper tetrad of c-MYC G4. It exhibits a favorable pharmacokinetic profile and high cytotoxicity in ovarian cancer (OC) cells (A2780) compared to the standard drug carboplatin. Normal cells show no sensitivity to GD-07, indicating a broad therapeutic window. GD-07 suppresses MYC expression, curbing glucose metabolism, and glycolysis while promoting p53 and proapoptotic markers in OC cells. In patient-derived OC organoids, GD-07 shows greater activity than carboplatin with promising clinical translatability.

Herein, the synthesis and biological evaluation of hypofuran B and a series of analogs against Trypanosoma cruzi and Plasmodium falciparum is described. The compounds are obtained through crossed aldol condensation between phenylacetaldehyde and furfural derivatives, using reaction conditions optimized according to the aromatic substituents. Yields ranged from 20% to 83%, with E/Z ratios between 89:11 and 98:2. Three compounds are isolated as single crystals suitable for X-ray diffraction, and their crystal structures are determined. The most active analogs showed IC₅₀ values of 5.35–10.35 µg mL⁻¹ and are further evaluated for cytotoxicity in L929 cells. For P. falciparum, a clear structure–activity–toxicity relationship is observed. The most promising compound displayed a CC₅₀ value above 400 µg mL⁻¹, indicating lower cytotoxicity than chloroquine. In silico predictions also supported favorable drug-like profiles. Overall, the moderate antiparasitic activity, low cytotoxicity, and consistent structure–activity trends highlight hypofuran B and related drynaran derivatives as promising antimalarial leads.

The activation of the receptor for advanced glycation end-products (RAGE) induces a chronic, low-noise inflammation responsible for the aging process, known as inflammaging. Associated with numerous pathologies such as Alzheimer's, insulin-resistant diabetes, cardiovascular diseases, and certain cancers, RAGE has become an interesting therapeutic target in the context of aging well. To this end, we identified new benzo[b]thiophene-2-carboxamide derivatives as potential RAGE ligands. Herein, we developed an alternative approach to easily synthesize benzo[b]thiophene-2-carboxamide analogs from 5-arylidene-2,4-thiazolidinedione intermediates based on the Ullmann–Goldberg coupling conditions. In light of LCMS, NMR, X-ray, and DFT studies, a mechanism for this reaction was proposed. This novel strategy enabled us to synthesize analogs whose best molecule 3t′, with an IC₅₀ of 13.2 µM, shows similar interactions with RAGE as the reference molecule Azeliragon (13.0 µM).

Impaired endoplasmic reticulum (ER) Ca²⁺ homeostasis contributes to β-cell dysfunction under diabetic stressors such as methylglyoxal (MGX), a reactive byproduct that induces oxidative protein modifications and advanced glycation end-products. The calcium pump sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), essential for ER Ca²⁺ regulation, is inhibited by MGX-mediated carbonylation and thiol oxidation. Pharmacological SERCA activation has emerged as a promising strategy to restore ER Ca²⁺ balance, but whether protection results from direct allosteric modulation, indirect antioxidant effects, or both has remained unclear. Herein, it is shown that novel, potent synthetic activators directly stimulate SERCA and restore its activity following MGX-induced inhibition. While some compounds display antioxidant activity, recovery of SERCA function correlated with activation potency rather than radical scavenging or lipid peroxidation inhibition. It is demonstrated for the first time that direct SERCA activation alone is sufficient to significantly reverse oxidative damage, revealing a mechanistically distinct therapeutic approach to preserve ER Ca²⁺ homeostasis in diabetes.

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. In this study, three hydroxamic acids derived from L–cysteine are synthesized to explore their biological dual effect as Glyoxalase 1 (Glo-1) inhibitors and ferroptosis inducers. Among the synthesized derivates, compound 2 exhibited the highest inhibitory potency against Glo-1 and is the most potent compound against nonsmall cell lung cancer cell lines. For this compound, an increase in intracellular reactive oxygen species (ROS), depletion of intracellular reduced glutathione (GSH) levels, and induced morphological changes is observed that correspond to ferroptosis. Furthermore, these effects are reversed by Liproxstatin-1, a potent and selective ferroptosis inhibitor. Acute and subacute toxicological assays in mice showed mild toxicity (LD₅₀ > 2000 mg kg⁻¹) and moderate organ damage. These in vitro and in vivo findings suggest that ferroptosis induction may serve as a side effect of Glo-1 inhibition, making compound 2 a promising lead for further development and optimization.