RSC medicinal chemistry最新文献

Histone deacetylase 8 (HDAC8) is a class I enzyme associated with various diseases, including cancer and neurological disorders. Although small-molecule HDAC inhibitors have been developed, their lack of selectivity often leads to off-target effects and toxicities. Alternatively, targeting specific HDAC isoforms for their degradation represents a more precise therapeutic strategy. This review focuses on the design and development of proteolysis-targeting chimeras (PROTACs) that selectively degrade HDAC8. We explore how existing selective HDAC8 inhibitors can be leveraged as warheads in PROTACs to effectively eliminate the enzyme. Recent studies have successfully designed HDAC8-selective PROTACs by linking HDAC8 inhibitors to E3 ubiquitin ligase recruiters such as VHL and CRBN. These PROTACs have demonstrated high potency in degrading HDAC8 in various cancer cell lines with single-digit nanomolar DC₅₀ values, showing superior anti-proliferative effects compared to their parent inhibitors. Therefore, apart from these handful of reports, more research related to HDAC8-PROTAC should provide a better therapeutic development technology for HDAC8-associated disorders while avoiding any therapy-related adversities and complications.

The identification of novel anti-tubercular agents capable of eliciting lethal responses against drug-resistant tuberculosis is critically needed to address the escalating mortality from tuberculosis. Mycobacterium tuberculosis, the etiological agent of this disease, employs a highly efficient energy-producing machinery, the oxidative phosphorylation pathway. Mycobacterium can withstand extreme environmental conditions due to the robust functionality of this multicomponent pathway, which satisfies its energy requirements, during both the persistent phase under stress and the active growth phase. Considering the significance of this biological pathway, in this review we described the dynamics of oxidative phosphorylation and the rationale for targeting its essential components. Furthermore, we provide a comprehensive overview of literature-reported inhibitors, targeting key elements of this pathway, namely, type II NADH dehydrogenase, cytochrome-bd oxidase, and ATP synthase.

Colorectal cancer (CRC) progression involves a coordinated interaction between COX-2-mediated inflammation and EGFR-driven proliferation. Current monotherapies often fail due to incomplete pathway suppression and resistance development, highlighting the need for multi-targeted strategies. This study aimed to design and synthesize novel pyrazole-ar-turmerone hybrids capable of simultaneously inhibiting COX-2 and EGFR, thereby achieving enhanced anti-proliferative efficacy in inflammation-associated colorectal cancer. Two hybrid molecules (compounds 1 and 2) were synthesized and characterized. Their dual-target potential was evaluated in silico using network pharmacology and molecular docking against COX-2 and EGFR crystal structures. In vitro assays in IL-1β-stimulated HT-29 colorectal cancer cells were used to assess anti-proliferative effects by MTT, clonogenic, and CFSE flow cytometry analyses. Mechanistic studies were performed through Western blotting and PGE₂ ELISA/rescue experiments to examine inhibition of COX-2 activity and EGFR-ERK1/2 signaling. Both compounds showed high COX-2 selectivity (SI = 14.38 and 23.57) and potent COX-2 inhibition (IC₅₀ = 0.63 and 1.04 μM), together with EGFR kinase inhibition (IC₅₀ = 37.56 and 57.56 μM). Both hybrids exhibited low cytotoxicity yet significantly suppressed IL-1β-induced HT-29 cell proliferation, with GI₅₀ values of 5.85 μM (compound 1) and 9.57 μM (compound 2). Mechanistic analysis confirmed reduced PGE₂ production, inhibition of EGFR-ERK1/2 activation, and downregulation of cyclin D1 and PCNA expression. The pyrazole-ar-turmerone hybrids function as potent dual COX-2/EGFR inhibitors exhibiting selective anti-proliferative activity in inflammation-driven CRC. These compounds represent promising leads for the development of next-generation dual-target therapeutics against colorectal cancer therapy.

Pharmaceuticals are increasingly detected in the environment, raising concerns about their ecological impact. Global monitoring efforts have revealed widespread contamination, with many sites exceeding safety thresholds for aquatic health. Traditional post-hoc monitoring approaches are reactive, identifying contamination only after environmental exposure has occurred. This highlights the need for predictive tools that assess environmental fate earlier in the drug development process. This review examines current and emerging strategies for early screening of pharmaceutical persistence, toxicity, and bioaccumulation, emphasising in silico approaches such as quantitative structure-activity relationship (QSAR) modelling, machine learning, and molecular docking, alongside complementary analytical techniques, including high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), liquid chromatography/gas chromatography-mass spectrometry (LC/GC-MS), and ion mobility spectrometry (IMS) for validating predictions and characterising complex environmental samples. Together, these tools offer a proactive framework for integrating environmental risk considerations into the pharmaceutical design and development pipeline.

The rapid spread of antibiotic resistance poses an escalating global health crisis. Polymyxin E, the antibiotic of last resort, is limited by dose-dependent toxicity. Antibiotic adjuvants offer a promising strategy to enhance efficacy while reducing dosages, potentially mitigating this critical issue. We conducted antibiotic potentiation assays on 1245 proprietary compounds, characterized using a hybrid PubChem-MACCS molecular fingerprint approach. Following evaluation of multiple machine learning models, we developed a stacking model, ADStack, combining random forest and extreme gradient boosting algorithms. Using 0.05 as the p-value cutoff, ADStack significantly outperformed the base-classifier RF in terms of AUC on the test set. While no significant difference was observed compared to ET, ADStack achieved a slightly higher average AUC (0.808 vs. 0.797) and a lower standard deviation (0.025 vs. 0.027), indicating improved stability. This model demonstrated superior performance in identifying active molecules. We applied ADStack to screen a drug repurposing library of 9938 compounds. The top 31 candidates were acquired and tested for potentiation activity, revealing six structurally diverse compounds that enhanced the activity of polymyxin E against Acinetobacter baumannii (A. baumannii). Based on these findings, we conducted an in-depth study of compound F26. Time-kill curves demonstrated that F26, in combination with polymyxin E, effectively inhibited bacterial growth. Moreover, F26 augmented polymyxin E's bactericidal activity against various carbapenem-resistant clinical strains of A. baumannii. In a mouse model of systemic infection, the combination of F26 and polymyxin E demonstrated significant therapeutic efficacy. In silico ADMET profile evaluation demonstrated that F26 possessed good pharmacokinetic profiles and drug-likeness properties. Shapley Additive exPlanations (SHAP) analysis elucidated the relationship between molecular substructures and potentiating activity. This study demonstrated the power of machine learning in identifying novel antibiotic adjuvants, offering an innovative approach to combat antibiotic resistance.

Acute myeloid leukaemia (AML) is a clonal proliferative malignant hematologic disease of hematopoietic stem cells, characterized by the accumulation of immature progenitor cells and the inhibition of hematopoietic function due to blocked differentiation, which is a genetically heterogeneous and dynamic disease and the most common type of leukemia in adults. Studies have shown that methyltransferase-like protein 3 (METTL3) is highly expressed in AML cells, regulating methylation modifications that drive the development of leukemia. This discovery has become a major breakthrough in the treatment of AML, as it is possible to address common issues in current chemotherapy, such as drug resistance, by developing METTL3 inhibitors. This review summarizes the strategies for discovering and optimizing the medicinal chemistry of METTL3 inhibitors, provides a reference for future drug development, and looks forward to the potential application prospects of METTL3 inhibitors in clinical practice.

Prodrug strategies are used to enhance the physicochemical and pharmaceutical properties of drug candidates that may not be suitable for specific delivery or are limited by formulation options. A prodrug derivative is converted into its active pharmaceutical ingredient (drug) through enzymatic or chemical reactions within the body. Antiviral nucleoside prodrugs have garnered considerable interest in drug discovery, leading to the approval of key drugs such as remdesivir (SARS-CoV-2), Sovaldi (hepatitis C virus, HCV), and tenofovir disoproxil fumarate [hepatitis B virus (HBV) and human immunodeficiency viruses (HIV)]. Their success lies in improving the oral bioavailability and delivering the parent drug to the targeted tissues. This review focuses on the prodrugs of antiviral nucleosides evaluated in humans (approved, in development or terminated), providing an overview of the different approaches utilized and discussing their in vitro and in vivo benefits.

Sustainability cannot be an afterthought; it must be embedded into every framework of medicinal chemistry. This opinion piece explores how integrating the dual pillars of Green Chemistry and One Health into drug design and development may drive innovation. Through case studies using renewable feedstocks, we highlight opportunities to create medicines that are effective, ethically sound, and environmentally responsible, for a more sustainable future.

Acetylcholinesterase (AChE) plays a pivotal role in Alzheimer's disease by accelerating acetylcholine breakdown, leading to cognitive decline. In this study, a series of novel isoxazolone derivatives were synthesized and structurally characterized using spectroscopic methods. The compounds were evaluated for their AChE inhibitory activity, where several candidates demonstrated stronger inhibition than the standard drug Donepezil. Molecular docking supported these findings, highlighting favorable interactions within the enzyme's active site. Selected compounds also exhibited promising antioxidant properties in the DPPH assay. A developed QSAR model provided insights into structural features contributing to bioactivity. In silico ADMET profiling indicated drug-like behavior, and molecular dynamics simulations confirmed the stability of the top ligand-enzyme complexes. Collectively, the results underscore the potential of isoxazolone-based scaffolds as multifunctional agents for managing Alzheimer's disease. Further biological evaluation is recommended to explore their therapeutic applicability.

Targeted protein degradation (TPD) has emerged as a powerful strategy for eliminating disease-causing proteins. The prolyl isomerase Pin1 is an attractive therapeutic target given its oncogenic function. Here, we develop PIPWF, a novel peptide degrader that induces Pin1 degradation through multivalent binding and conformational destabilization. Pin1 degradation attenuates cancer-associated fibroblast (CAF) activation to reshape the fibrotic tumor microenvironment and enhance chemosensitivity via ENT1-mediated gemcitabine uptake. In vivo results demonstrated that both PIPWF and its nanoformulation M-PIPWF synergized with gemcitabine to induce tumor regression and prolong survival, illustrating a novel peptide-based TPD strategy against Pin1-driven malignancies.