RSC medicinal chemistry最新文献

Glioblastoma multiforme (GBM) is an aggressive and treatment-resistant brain tumor. The expansion of a phenolic Mannich base library via the Petasis reaction unexpectedly led to the unsymmetrical tetrahydroquinoline-derived triarylmethanes, confirmed by single-crystal X-ray diffraction. Optimization of reaction conditions revealed the influence of solvent, temperature, and substituent patterns on product yield and regioselectivity. Several of the newly synthesized triarylmethanes demonstrated potent cytotoxicity against human GBM cell lines LN229 and SNB19, with compound 8a′ exhibiting IC₅₀ values (35.3 μM and 23.5 μM, respectively) significantly lower than those of the standard chemotherapeutic agent temozolomide (309.7 μM and 344.4 μM, respectively). In addition to inhibiting cell proliferation, 8a′ disrupted GBM cell migration in scratch assays, suggesting a strong link between cytotoxicity and impaired motility. The SiRNA experiment confirmed that the specific interaction of 8a′ with EGFR modulates intracellular calcium levels in GBM. These findings highlight the therapeutic potential of triarylmethane scaffolds in GBM treatment via EGFR interaction and underscore the importance of fine-tuning multicomponent reactions to discover biologically active chemotypes.

Pyridine carbothioamides (PCAs) are recognized for their gastric mucosal protective effects and low in vivo toxicity, making them attractive scaffolds for anticancer drug development. In this study, a series of N-phenyl 4-substituted and 2,4-disubstituted PCAs (1–8) incorporating a sulfonamide pharmacophore were synthesized, fully characterized, and evaluated as tubulin polymerization inhibitors. The compounds were tested against four cancer cell lines (A549, MCF-7, PC-3, HepG2) with colchicine and doxorubicin as reference drugs. Among them, compounds 3 and 5 exhibited potent cytotoxicity, being 2–6-fold more active than colchicine and up to 2.5-fold stronger than doxorubicin in PC-3 cells. Importantly, both showed ∼4-fold lower toxicity toward normal HLMEC cells and displayed higher selectivity towards tested cancer cells than doxorubicin. Tubulin polymerization assays confirmed their activity, with IC₅₀ values of 1.1 μM (3) and 1.4 μM (5), outperforming colchicine (10.6 μM) and CA-4 (2.96 μM). Molecular docking revealed strong binding at the colchicine site, supported by favorable inhibition constants and free binding energies. In silico ADME predictions indicated that the most lipophilic compounds 3 and 5 demonstrated favorable drug-likeness, as expected from computational studies, along with excellent gastrointestinal absorption, favorable bioavailability, and low hemolytic activity. Collectively, these findings highlight compounds 3 and 5 as promising lead candidates for the development of orally active anticancer and antimitotic agents.

Disruption of protein homeostasis (proteostasis), whether by acute proteotoxic stress or chronic expression of mutant proteins, can lead to the accumulation of toxic protein aggregates. Such aggregation is a hallmark of numerous diseases and is often associated with impaired protein clearance mechanisms. The transcription factor nuclear factor erythroid 2-related factor 1 (encoded by NFE2L1, also known as Nrf1) plays a central role in restoring proteostasis by increasing proteasome synthesis. Therefore, pharmacological activation of NFE2L1 under non-stress conditions represents a promising therapeutic strategy for neurodegenerative and other proteostasis-related diseases. In our previous study, we identified bis(phenylmethylene)cycloalkanone derivatives as NFE2L1 activators capable of inducing proteasome subunit expression, increasing heat shock protein levels, and stimulating autophagy. Building upon these findings, we have now developed a new library of structurally related compounds to identify novel more potent NFE2L1 activators. By systematically examining how specific chemical substitutions affect NFE2L1 activation, this work advances our understanding of the structure–activity relationships within this pathway.

Quite frequently, it is the progression of initial crystallographic fragment screening hits into more potent binders to their target, which constitutes the major bottleneck in many academic compound or drug development projects. While high quality starting points are critical to the success of a drug development project, it is equally important to have accessible pathways for further compound development. Here, we present two crystallographic fragment screening campaigns using a 96 fragment sub-selection of the European Fragment Screening Library (EFSL) provided by EU-OPENSCREEN. The two campaigns against the targets endothiapepsin and the NS2B–NS3 Zika protease, yielded hit rates of 31% and 18%, respectively. Further, we present how within the framework of the EU-OPENSCREEN European Research Infrastructure Consortium (ERIC) fast identification of follow-up compounds can be realized. With just one round of testing related compounds from the European Chemical Biology Library, two follow-up binders for each of the two targets could be identified proving the feasibility of this approach.

The Design-Make-Test-Analyse (DMTA) cycle relies on efficient compound synthesis, yet the synthesis (“Make”) process remains a significant bottleneck, especially for complex molecules. This opinion letter explores how digitalisation and automation are accelerating the entire synthesis process. It details their current integration, from AI-powered synthesis planning and streamlined sourcing to automated reaction setup, monitoring, purification, and characterisation. FAIR data principles are emphasised as crucial for building robust predictive models and enabling interconnected workflows. Finally, the future of fully integrated, data-driven synthesis with tools like “Chemical ChatBots” and the evolving skill set required for medicinal chemists in this increasingly digital and automated landscape are discussed.

Clathrin-mediated endocytosis (CME) is a critical pathway for cellular uptake of metabolites, hormones, and pathogens, including viruses. Recent advances in understanding CME mechanisms and developing inhibitors targeting key components (clathrin, dynamin, and HSC70) have opened therapeutic avenues for diseases, such as viral infections, cancer, and neurological disorders. This review comprehensively summarizes current CME inhibitors, including Pitstop, Dynasore, and Dyngo-4a, highlighting their mechanisms, structure–activity relationships (SARs), and limitations. Small molecules like Pitstop 2 disrupt clathrin-terminal domain (TD) interactions, while dynamin inhibitors (e.g., pthaladyns and quinodyns) target GTPase or pleckstrin homology (PH) domains to block vesicle fission. Despite progress, challenges remain: many inhibitors lack specificity, exhibit cytotoxicity, or possess unclear mechanisms. Novel strategies, such as peptide-based inhibitors (e.g., Wbox2) and non-protonophoric analogs (e.g., ES9-17), demonstrate improved precision. Future research must prioritize optimizing pharmacokinetics, reducing off-target effects, and exploiting emerging targets like endocytic accessory proteins (EAPs) to advance CME inhibitors toward clinical applications.

Human tissue transglutaminase (hTG2) is a multifunctional enzyme with both protein cross-linking and G-protein activity. Dysregulation of these functions has been implicated in diseases such as celiac disease and cancer, prompting the development of hTG2 inhibitors, many of which act covalently via a pendant electrophilic warhead. Most small molecule hTG2 inhibitors to date feature terminal, sterically minimal warheads, based on the assumption that bulkier electrophiles impair binding and reactivity. Here, we report structure–activity relationships (SAR) of a novel internal alkynyl warhead scaffold for irreversible inhibition of hTG2. This series includes one of the most potent non-peptidic hTG2 inhibitors reported to date. We demonstrate that this scaffold not only inhibits transamidase activity but also abolishes GTP binding, while exhibiting excellent isozyme selectivity. In addition, we investigate the tunability and stability of this warhead, providing insights into its broader applicability. Through detailed kinetic analysis, this study establishes a new scaffold for irreversible hTG2 inhibition and expands the design principles for covalent warheads beyond traditional terminal systems.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds HA-2l and HA-2c showed a superior IC₅₀ of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives HA-1e, HA-2g, and HA-3d exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds HA-2g, HA-2l, and HA-3d showed sub-micromolar inhibition, in the range of 0.610–0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.

Given the growing resistance to traditional quaternary ammonium compounds (QACs) – long used as primary disinfectants – there is an urgent need for structurally distinct alternatives to effectively combat infectious threats. Quaternary phosphonium compounds (QPCs) have recently emerged as a promising alternative class, demonstrating strong activity even against highly drug-resistant strains. Herein, we present a novel series of 16 all-alkyl biscationic QPCs, designed to expand the scope of atom-economical cationic biocides and evaluate their potential as next-generation disinfectants. Strong and broad bioactivity against a panel of eight bacterial pathogens was observed, with six analogs achieving single-digit micromolar activity across all strains tested. Structure–activity analysis revealed that optimal bioactivity correlates with 10–12 carbon alkyl side chains and longer charge-separating linkers (m = 8–10), which render the structures bolaamphiphilic. Comparisons between bisQAC and bisQPC analogs suggest that substituting the ammonium center with phosphonium had minimal impact on antimicrobial potency, but synthetic versatility allowed access to novel and potent QPC structures. This work underscores the potential of bisQPCs in the development novel and potent disinfectants.

A fundamental biological mechanism, programmed cell death (PCD), is essential for tissue homeostasis, immunological control, and development. Its dysregulation is a characteristic of many diseases in multicellular organisms, including cancer, where unchecked proliferation is made possible by evading cell death. Therefore, one of the main tenets of contemporary anticancer therapies is the restoration or induction of PCD in cancer cells. One potential, least invasive method among these is photodynamic treatment (PDT). PDT uses light-activatable photosensitisers, which cause cancer cells to explode with reactive oxygen species (ROS) when exposed to light. These ROS harm important biomolecules, throw off the cellular redox equilibrium, and cause cells to die. PDT-induced cell death was previously believed to be mostly caused by autophagy, necrosis, or apoptosis. Recent research, however, has shown that it can trigger a wider range of unconventional cell death pathways. ROS can cause ferroptosis by oxidising membrane lipids, fragmenting DNA, and lowering intracellular glutathione (GSH) levels. Similarly, necroptosis or pyroptosis can result from severe oxidative stress activating death receptor signalling. Sometimes, in response, cells use survival strategies like autophagy, which can also lead to cell death. This review explores these new, unconventional methods of cell death and how PDT can be used to take advantage of them. Next-generation photosensitisers based on iridium (Ir), ruthenium (Ru), and rhenium (Re) complexes are given special attention because they provide deep tissue penetration, improved photostability, and adjustable ROS production. Their incorporation into PDT has revolutionary potential for improving cancer treatment precision and conquering therapeutic resistance.