RSC medicinal chemistry最新文献

Pyrazoline-linked thiophenes (4a-p), a novel family of compounds, were designed and synthesized, and their anticancer potential was assessed. The most effective analogues of bis-thiophene (4n and 4o) and tris-thiophene (4p) were discovered to have sub-micromolar cytotoxicity against MCF-7 breast cancer (IC₅₀ = 0.17 μM) and A549 lung cancer (IC₅₀ = 0.78 μM) cells. Using flow cytometry, compound 4p triggered apoptosis in the MCF-7 cells, and caused G1/S-phase arrest (36.74% total apoptotic cells, compared to 0.99% in the control). The intrinsic apoptotic pathway was activated, as evidenced by downregulation of Bcl-2 and upregulation of P53, Bax, PUMA, and caspases-3 and -9, as validated by RT-PCR analysis. The potency of compound 4p (IC₅₀ = 148 nM) against CDK2 was much higher than that of roscovitine (IC₅₀ = 700 nM). Molecular docking supported these results by demonstrating stable hydrogen-bond interactions with Leu83 and Lys89, as well as significant hydrophobic interactions in the ATP-binding region. In vivo, 4p significantly reduced tumor burden in the Ehrlich carcinoma model (TIR% = 32.2%), recovered hematological parameters, and demonstrated negligible systemic toxicity. ADMET projections further highlighted positive drug-like qualities. Taking together, compound 4p is a promising anticancer candidate that targets CDK2 and exhibits strong in vivo efficacy, with supporting molecular evidence.

The persistent evolution of SARS-CoV-2 underscores the need for antiviral strategies. The viral main protease (M^pro) represents a conspicuous target due to its essential role in viral replication and high conservation across SARS-CoV-2. Conventional M^pro inhibitors face challenges such as drug resistance and toxicity. Proteolysis-targeting chimeras (PROTACs) offer an event-driven mechanism to degrade rather than inhibit the target protein, overcoming key limitations of occupancy-driven pharmacology. Here, we designed a series of thalidomide-based PROTACs targeting SARS-CoV-2 M^pro and explored their effectiveness through computational simulations and experimental validation. Molecular docking revealed that PROTACs A, B, and C exhibit favorable binding free energies (ΔG < -8.0 kcal mol^-1). These findings were further supported by molecular dynamics simulations, which demonstrated consistently stable binding over 10 ns, with backbone RMSD values maintained within the range of 0.18-0.30 Å. Cell experiments indicated that PROTACs A, B, and C effectively induced dose-dependent M^pro degradation in HEK293 stable cells, with DC₅₀ values ranging from 0.530 to 0.985 μM and exhibited high selectivity indices (CC₅₀/DC₅₀ > 10). Mechanistically, PROTACs-induced degradation of M^pro via the ubiquitin-proteasome system was evidenced by enhanced K48-linked polyubiquitination and suppression of degradation upon proteasome inhibition. The PROTACs (A, B and C) exhibit comparable effects and share similar mechanisms in degrading M^pro. Our work develops effective degraders targeting SARS-CoV-2 M^pro and highlights the therapeutic potential of PROTACs in combating drug-resistant viral targets via a catalytic degradation mechanism.

Natural products are valuable starting points for drug discovery, although individual modes of action are often difficult to pin down. Ursanes such as madecassic acid have been shown to have antibacterial properties, but a variety of mechanisms have been proposed. In this paper, we report previously uninvestigated activity against cytochrome bd oxidases which are only found in prokaryotes and are therefore promising new targets, using madecassic acid and a set of synthetically modified derivatives. Our work shows that madecassic acid and its derivatives can block activity of these enzymes, while phenotypic effects in membrane and whole organism assays are more complex, consistent with modulation of multiple pathways depending upon molecular structure. This provides a new route to ursane-based antibacterial action while highlighting the importance of chemical modifications in fine-tuning biological activity of natural products.

We report a straightforward method for direct determination of log P by slice-selective ¹⁹F NMR spectroscopy utilising a single NMR sample. Our technique uses a partitioned NMR sample of n-octanol/water containing the compound of interest, a modern NMR spectrometer equipped with ¹⁹F-observation and Z-axis pulsed-field gradient capabilities in addition to automation programs to measure solute distribution between solvent layers. The approach is validated using a range of fluorinated compounds with known experimental log P values. Details of our experimental method development and implementation processes are reported in supporting data and the benefits of using this approach for experimental log P determination are highlighted.

The escalating threat of antimicrobial resistance (AMR) compels the development of novel antibiotics with broad spectrum activity and environmentally responsible degradation profiles. Chalcones, naturally occurring 1,3-diaryl-2-propen-1-ones, have emerged as promising scaffolds due to their pleiotropic bioactivity and structural tunability. In this study, we explored the synthesis and functionalization of oxyprenylated chalcones as potential antibacterial compounds and explored their functionalization with protonatable moieties to enhance their affinity for bacterial membranes and their solubility properties. Starting from hydroxycordoin 1a, we synthesized a series of isomeric and hydroxy derivatives, with the aim of studying their structure-activity relationships, and based on the initial results we further modified their structure by including protonatable side chains. A key synthetic step was optimized using a design of experiments (DoE) approach, promoting resource efficiency in line with Green Chemistry principles. The antibacterial properties of the synthesized compounds were evaluated in vitro against Gram-positive and Gram-negative strains, their toxicological profiles and predicted environmental biodegradability were also assessed. These multifunctional chalcone derivatives demonstrate potential as effective and sustainable antimicrobial agents and the benzofuran derivative 20, the most potent compound of the series, could represent an interesting compound for further optmization.

Background : Vacuolar protein sorting 35 (VPS35) is a key subunit of the retromer complex, and several previous studies have shown that VPS35 plays an important role in the progression of hepatocellular carcinoma (LIHC). However, the comprehensive value of VPS35 in LIHC in prognostic assessment, immunotherapy and chemotherapy has not been systematically reported. Methods : To characterize the comprehensive value of VPS35 in LIHC, we performed a comprehensive multi-omics analysis. Based on multiple databases such as The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Human Protein Atlas (HPA), the relevant analyses were accomplished using R software and websites such as TIMER2, STRING, and TISIDB. We primarily evaluated the correlation of VPS35 expression in LIHC with prognosis, immune microenvironment infiltration, immunotherapy and chemotherapy. Western blotting (WB), quantitative real-time PCR (RT-qPCR), CCK8, colony-formation assay, Transwell, and in vivo experiments were also performed to verify the function of VPS35 in LIHC. Results : Compared with normal tissues, VPS35 was highly expressed in a variety of tumor tissues such as LIHC. VPS35 has a good diagnostic value in a variety of tumors. In a variety of tumors such as LIHC, upregulation of VPS35 expression levels is associated with poor prognosis. In LIHC, VPS35 expression levels were significantly correlated with clinicopathological features such as the T stage, pathological stage, histological grade, vascular invasion, and residual tumor. Pan-cancer analysis showed that VPS35 expression was positively correlated with tumor mutation burden (TMB) in 14 cancer types and microsatellite instability (MSI) in 15 cancer types. GO, KEGG and gene set enrichment analysis (GSEA) revealed that VPS35 was positively correlated with the immunoglobulin complex, pro-iso-cellular adhesion via plasma membrane adhesion molecules, and immunoglobulin receptor binding. Multiple related genes of VPS35 also had strong prognostic value in LIHC. Immune infiltration analysis showed that VPS35 expression levels were associated with multiple immune cell infiltrations. Further analysis showed that VPS35 expression levels were higher in proliferating T cells (Tproif) and monocyte-derived macrophages in LIHC. Downregulation of VPS35 expression levels may enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Knockdown of VPS35 significantly reduced the proliferation, invasion, migration of tumor cells and inhibited subcutaneous tumor formation. Conclusion : VPS35 is highly expressed in LIHC and exhibits significant diagnostic and prognostic value. Targeted knockdown of VPS35 may inhibit LIHC progression and enhance the efficacy of immunotherapy and chemotherapy.

Alzheimer's disease (AD) is a complex neurodegenerative disorder, with unmet clinical challenges due to the lack of early diagnosis and an efficient treatment. Theranostics, an integrated approach that combines diagnosis and therapy, has emerged as a viable option, particularly with the use of near-infrared fluorescence probes (NIRFPs), which allow real-time in vivo imaging and therapeutic monitoring. This review article discusses recent breakthroughs in the rational design of alkene-bridged donor-π-acceptor (D-π-A) NIRFPs that target AD hallmarks such as amyloid-β (Aβ) aggregation and cholinergic dysfunction. We specifically focused on multifunctional probes like THK-565 (fluorescent compound), and a dihydrotetramethyl-indocyanine theranostic near-infrared probe (DTNP), which exhibit high blood-brain barrier (BBB) permeability, target selectivity, and dual imaging/therapeutic capabilities. Furthermore, emerging probes can distinguish between Aβ and cholinesterase (ChEs) with high resolution and low toxicity. Together, these molecular imaging technologies provide a game-changing platform for detection of early-stage AD and multiple intervention approaches. We explore structure-activity connections, molecular processes, and future directions for the clinical translation of NIRFP-based theranostic agents in AD.

The alarming rise of drug resistance has created an urgent need for novel antifungal agents. On the other hand, growing environmental concerns necessitate the development of sustainable alternatives to conventional synthetic methods for active pharmaceutical ingredients (APIs). β-Aminosulfones represent a potent yet underexplored functionality in biologically active compounds. In this work, a series of β-aminosulfone derivatives, designed as potential antifungal agents, were synthesized via a one-step, reagent-free, catalyst-free double aza-Michael addition of 2-aminobenzothiazoles, biogenic amines, or aromatic amines with different vinyl sulfones. The reactions were carried out in water under microwave irradiation (150 °C, 10 min), affording β-aminosulfones in excellent yields by simple filtration, without the need for further work-up or purification. This cost-effective process makes the production cost comparable to raw materials (e.g., compound 3d at $3.43 per g). Molecular docking, performed using the Glide module of the Schrödinger suite, revealed potential inhibitory activity against the fungal target CYP51 (PDB ID: 5V5Z), with reasonably good docking scores ranging from -5.69 to -8.25 kcal mol^-1 for benzothiazole derivatives and -5.73 to -7.05 kcal mol^-1 for biogenic amines. In silico ADMET profiling of selected compounds indicated promising drug-like attributes, satisfying Lipinski's rule. β-Aminosulfones were screened for their in vitro antifungal activity against various Candida species, and they exhibited MIC values ranging from 16 to 64 μg mL^-1. Notably, one compound (3d, 0.051 μM) showed comparable potency to fluconazole (0.052 μM) against Candida glabrata. Through ergosterol depletion assays, the mechanism of antifungal activity could be linked to the CYP51 inhibition pathway. Although these compounds exhibited moderate docking scores against 1KZN for antibacterial activity (-3.96 to -5.63 kcal mol^-1), the spot test revealed insignificant inhibition. Cytotoxicity studies with selected molecules revealed that these aza-sulfones are non-toxic to human cells, encouraging further studies with β-aminosulfone scaffolds.

Tuberculosis (TB) remains a major global health threat, exacerbated by the emergence of drug-resistant strains. The mycobacterial enzyme Pks13 has emerged as a promising drug target for novel anti-TB agents. We herein report the design, synthesis, and biological evaluation of a series of pyrimido[1,2-a]imidazole derivatives as potent Pks13-TE inhibitors. An integrated virtual and biological screening of 10.5 million commercially available compounds identified TJA-31 as a hit compound, which showed moderate Pks13-TE inhibitory activity (IC₅₀ = 1.34 μM). The systematic optimization of TJA-31 based on its physicochemical properties, docking scores, and MM/GBSA binding free energy estimates led to the synthesis of 50 analogues, among which 20 compounds exhibited submicromolar inhibition. The most promising derivative, compound 34, demonstrated significantly enhanced potency with an IC₅₀ value of 0.23 μM, representing a sixfold improvement over the hit. Molecular docking studies indicated that the high activity of compound 34 could be attributed to a halogen bond between its bromine substituent and the nitrogen atom of residue His1664, a water-mediated hydrogen bond between the Ala1564 nitrogen and the 3-methoxy oxygen, and π-π stacking interactions with residues within the Pks13-TE binding pocket. These results underscore the pyrimido[1,2-a]imidazole scaffold as a promising lead series for the development of Pks13-TE inhibitors.

Medicinal chemistry has driven the evolution of oncology drug discovery, transitioning from early cytotoxic agents to modern precision-guided therapies. This opinion article traces the historical trajectory of medicinal chemistry practices, beginning with the era of conventional chemotherapy and moving through the development of targeted therapies utilizing various precision oncology strategies. It then explores the recent wave of innovations-such as proximity inducers and drug conjugates-that have significantly redefined the druggable proteome. While these emerging modalities promise transformative benefits for patients, they also introduce unique challenges related to delivery, selectivity, and acquired resistance. We conclude with a perspective on the future of oncology that the integration of these novel strategies with computational design, advanced proteomics, and biomarker-driven approaches will be essential to accelerate the development of next-generation personalized cancer therapies.