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One of the major mechanisms of resistance to ribosome-targeting antibiotics is the modification of ribosomal RNA (rRNA). Specific methyltransferase enzymes, for example, confer high-level resistance to aminoglycosides by selectively methylating the 16S rRNA in the ribosomal decoding center. These enzymes have been detected globally and pose a threat to the continued use of aminoglycosides. Compound 1, a dehydroamino amide inhibitor of the m¹A1408 methyltransferase NpmA, was previously disclosed and identified using high-throughput virtual screening. Here, the synthesis and biological evaluation of rationally designed analogs of 1 has been reported. Guided by molecular docking, additional putative inhibitors of NpmA, as well as the functionally related m⁷G1405 methyltransferase RmtB, varying in each region of the original scaffold are disclosed. A modular, fragment-based synthesis enables access to 17 analogs, which exhibits mixed activity against NpmA and RmtB, including several that are selective for RmtB. The structure–activity relationship determined for the dehydroamino amide series will guide continued research against this target class with the aim of developing a toolkit for selective- or pan-16S rRNA methyltransferase inhibition.

Assessing if compounds with intracellular targets reach their site of action is crucial for success in drug development. Cell type-specific uptake goes beyond permeability studies, typically mimicking crossing the gut, the lung, or the blood–brain barrier. A medium- to high-throughput cellular accumulation protocol in 96-well format is presented using six compounds, evaluating optimal conditions varying several parameters, such as incubation time, compound concentration, and extraction protocol. An optimized assay protocol for cellular accumulation of distinct chemical classes is a compromise: No one-extraction-protocol-fits-all exists; equally, some compounds need longer incubation periods to reach maximal intracellular concentration. Reliable high performance liquid chromatography with tandem mass spectrometry based quantification of cellular accumulation for all six compounds to the nM range is achieved with a short 1 h incubation. Intracellular concentrations per cell count are determined in A549^ACE+TMPRSS2 cells, taking nonspecific binding into account. Hence, this approach adds valuable information during the pre-screening of compounds with intracellular targets. Finally, optimal assay conditions are emphasized as essential for predicting activity in vitro and in vivo, based on biochemical information and intracellular concentrations. In summary, the workflow for cellular accumulation determination can serve two scenarios: 1) Pre-selection of compounds for screening purposes or 2) systematic optimization of conditions to advance compounds with intracellular targets.

Female cancers, primarily breast, cervical, and ovarian cancers, remain a major public health challenge, with rising incidence and high mortality. Cisplatin has long been a cornerstone of anticancer therapy, yet its clinical use is limited by low selectivity, severe side effects, drug resistance, and relapse. Thus, more effective and selective therapeutic strategies are needed. In this study, we evaluated the cytotoxicity and mechanisms of action of three cisplatin derivatives (C-cisplatin, D-cisplatin, and Ac-cisplatin) and their complexes with generation 2 polyamidoamine (PAMAM G2) dendrimers. All drug–dendrimer complexes were prepared at a 10:1 molar ratio and tested on two cancer cell lines—HeLa (cervical cancer) and MCF-7 (breast cancer)—and one non-cancer human microvascular endothelial cell line (HMEC-1). Complex formation was confirmed by zeta potential measurements. Cytotoxicity was assessed for both free and complexed drugs. To explore potential mechanisms of action, mitochondrial membrane potential and reactive oxygen species (ROS) levels were evaluated. Flow cytometry was then used to determine dominant cell-death pathways. The complexes demonstrated cytotoxicity comparable to or greater than cisplatin and showed improved selectivity toward cancer cells. Among them, D-cisplatin complexed with PAMAM G2 was the most promising candidate, exhibiting the highest selectivity toward HeLa cells.

Imagine a divalent metal ion (such as Zn(II)) binding to a folded ionophore such as salinomycin. The resulting complex is superacidified, shooting a proton at an unbound salinomycin molecule and cleaving it into two parts. However, when potassium ion is prebound to salinomycin, no superacidic protons are generated by this complex, whereas the protons generated by the divalent metal ion complex just bounce off. More details can be found in the Research Article by Adam Huczyński, Travis Dudding, Thomas Lectka, and co-workers (DOI: 10.1002/cmdc.202500783).

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.