Future medicinal chemistry最新文献

Autophagy-mediated targeted protein degradation, exemplified by technologies such as autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting chimeras (AUTOTACs), and autophagy-targeting chimeras (AUTACs), leverages the autophagy-lysosome pathway for the clearance of challenging substrates that often exceed proteasomal capacity. These substrates include large protein aggregates, multi-protein complexes, and even entire organelles. This review synthesizes key advances in the development of autophagy-based degraders since 2022, highlighting their therapeutic potential through exemplar applications. We discuss their utility in oncology, neurodegenerative disorders, and inflammatory/cardiometabolic diseases. These novel modalities have demonstrated potent, selective, and durable substrate elimination in vivo, successfully overcoming resistance mechanisms associated with traditional occupancy-driven inhibition. Finally, we summarize the general workflow for developing autophagy-based degraders, outline the current challenges and future directions in this field, and aim to promote fundamental mechanistic studies and innovative medicinal chemistry research, thereby accelerating the clinical translation of autophagy-targeting degraders for the treatment of various human diseases.

Cancer therapy is still hampered by key challenges, including drug resistance, poor target selectivity, and narrow therapeutic spectra, driving the pursuit of novel anticancer agents with enhanced efficacy and safety. Indole-triazole/pyrazole hybrids, formed by fusing indole scaffolds with triazole/pyrazole, confer inherent structural diversity and high modifiability. Structurally, rational modification of indole/triazole/pyrazole moieties allows optimization of pharmacokinetic properties and improves cancer cell selectivity, minimizing toxicity to normal cells. Functionally, indole-triazole/pyrazole hybrids exhibit multitargeted activity to simultaneously inhibit key oncogenic pathways, addressing the heterogeneity of cancer pathogenesis, while their hybrid structure enhances anticancer potency. This multitargeted mode also aids in overcoming drug resistance, a major bottleneck in clinical therapy. Accordingly, indole-triazole/pyrazole hybrids have emerged as a promising class of anticancer candidates. This review summarizes recent advances in indole-triazole/pyrazole hybrids with anticancer potential, covering articles published from 2021 to the present. To delineate the key molecular features governing anticancer potency, this review further presents a detailed analysis of structure-activity relationships (SARs) and conducts an in-depth exploration of the underlying mechanisms of action.

Liver cancer, which originates from hepatocytes, ranks among the most commonly diagnosed cancers and stands as a leading cause of cancer-related deaths, primarily due to late diagnosis and its rapid progression. Liver cancer, especially metastatic liver tumors, often relies on chemotherapy. Still, drug resistance driven by the overexpression of efflux pumps, reduced systemic drug exposure due to hepatic metabolism, low efficacy, and high toxicity creates an urgent need to explore novel chemotherapeutic agents. Hydroxamic acid serves as the zinc-binding group (ZBG) in most histone deacetylase (HDAC) inhibitors and is an important anti-liver cancer pharmacophore. Hydroxamic acid hybrids harness the epigenetic potency of hydroxamic acid through modular pharmacophore integration, providing multitarget efficacy, resistance overcoming, and therapeutic versatility, and thus represent promising candidates for next-generation liver cancer therapies.

Autophagy is an evolutionarily conserved process in eukaryotic cells that degrades and recycles intracellular macromolecules and damaged organelles. It is closely related to a variety of physiological and pathological processes. Research on autophagy has become a current hotspot, with protein kinases regarded as crucial components that play essential roles throughout this process. During autophagy, diverse autophagy-related protein kinases continuously regulate different stages. Protein kinases are critical in signal transduction and the regulation of most cellular processes. Therefore, autophagy-associated protein kinases represent potential therapeutic targets for human diseases, and corresponding small-molecule compounds may provide promising therapeutic strategies. This review summarizes the current progress in autophagy research, with a focus on small-molecule drugs that influence autophagy-related kinases and their association with diseases.

Aims: To evaluate chromatographic lipophilicity of novel artesunate-pyrimidine hybrids and precursors using reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). The impact of measured and predicted lipophilicity on pharmacokinetic descriptors was evaluated. Principal component analysis (PCA) explored relationships among lipophilicity, PPB, and physicochemical descriptors. Quantitative structure-activity relationship (QSAR) and partial least squares (PLS) models linked molecular descriptors to cytotoxicity and resistance modulation in nonsmall cell lung cancer (NSCLC) cells.

Materials and methods: Lipophilicity was measured by RP-TLC. PPB was determined using human serum albumin (HSA)-modified high-performance liquid chromatography (HPLC). PCA characterized physicochemical-pharmacokinetic correlations. Cytotoxicity in sensitive NCI-H460 and multidrug-resistant (MDR) NCI-H460/R cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. QSAR and PLS models identified key descriptors.

Results: Lipophilicity strongly influenced adsorption, distribution, and protein binding. Highly lipophilic hybrids showed near-complete HSA binding. Compound 2k lost cytotoxicity in the presence of albumin, whereas 4k retained potency. Models indicated steric and electronic features, alongside lipophilicity, dictate efficacy and P-glycoprotein (P-gp) interactions, particularly in resistant cells.

Conclusions: Lipophilicity and steric/electronic descriptors govern distribution, protein binding, and anticancer activity. Integrating these features enables design of hybrids overcoming P-gp-mediated multidrug resistance, with hybrid 4k emerging as a promising candidate.

Aim: We aimed to design and synthesize novel pyrimidine-2-thione derivatives (1-13) as Topoisomerase I/II (Topo I/II) inhibitors with DNA intercalation potential for cancer treatment.

Materials & methods: Inhibitory concentration 50 (IC₅₀) against mammary gland breast cancer, hepatocellular carcinoma, and colorectal carcinoma was determined for all compounds. The frontier candidates (2, 6, 9, 10, and 11) were evaluated for their DNA-binding ability, Topo I, and Topo II inhibiting potential. Moreover, cell cycle and apoptosis analysis were carried out.

Results: Compound 2 displayed the best DNA-binding affinity with an IC₅₀ value of 37.24 µM in comparison to doxorubicin (Dox). Both compounds 2 and 9 showed superior nanomolar Topo I inhibitory potential, compared to Dox. Similarly, compounds 2 and 9 achieved better Topo II inhibition, exceeding that of Dox. It was revealed that compound 9 halted the cell cycle at both the P1 and G2 phases. In addition, compound 9 was able to boost the apoptosis at both the early and late apoptotic phases.

Conclusion: Consequently, the compounds afforded can be regarded as prominent lead anticancer compounds for further optimization and investigation.

Ferroptosis is a form of Regulated Cell Death (RCD) found in recent years. Its typical characteristics are the abnormal accumulation of intracellular iron ions and the accumulation of lipid peroxidation products. Since its first systematic elucidation in 2012, a large number of studies have shown that ferroptosis is involved in a variety of pathophysiological processes. It has been reported that the pathological process of diabetic cardiovascular diseases (DVD) is closely associated with the activation of ferroptosis. Due to the long-term hyperglycemic environment in diabetic patients, vascular endothelial cells (VECs) are susceptible to ferroptosis, ultimately contributing to vascular dysfunction. Therefore, the development of inhibitors targeting ferroptosis is of great significance for the prevention and treatment of diabetic vascular complications. This review systematically expounds the latest research progress of the molecular mechanism of ferroptosis, and discusses its role in DVD. In addition, this review also comprehensively summarizes the latest advances in the synthesis and application of drugs and specific inhibitors targeting the ferroptosis pathway for disease treatment, thereby providing new therapeutic strategies for DVD.

Cancer remains an incessantly rising cause of mortality worldwide, tempting millions of lives each year and posing a significant global health challenge. Available treatment modalities, including chemotherapy, have been associated with limited scope with severe side effects and complexities, underscoring the imperative need for more efficient and safe curative strategies. In this context, the rational design of multitargeted anticancer agents has gained momentum, aiming to enhance therapeutic outcomes while reducing systemic toxicity. The purine scaffold, a core structural motif found in essential biomolecules, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD), has emerged as a promising pharmacophore in anticancer drug discovery. Notably, several synthetic purine analogues have received clinical approval owing to their potent anticancer activity, particularly when integrated with diverse heterocyclic frameworks. This review comprehensively summarizes the advances made over the past decade in the development of purine-based hybrid molecules, highlighting their mechanistic roles in overcoming drug resistance and targeting multiple oncogenic pathways. The insights presented herein underscore the versatility and therapeutic relevance of purine-based scaffolds and aim to guide future efforts in the rational design and development of drug-resistant and safer anticancer agents.

Aims: This study aimed to evaluate the α-glucosidase inhibitory potential of newly synthesized aurone derivatives (1-14) using an integrated experimental and computational strategy, with emphasis on their antidiabetic potential.

Materials and methods: The compounds were evaluated through in vitro α-glucosidase inhibition and enzyme kinetic assays, along with in vivo studies to assess postprandial glucose control. Molecular docking, MM-GBSA calculations, and molecular dynamics (MD) simulations were performed to analyze interactions with diabetic targets (PDB IDs: 5NN4 and 6KK1). Furthermore, in silico ADME profiling and density functional theory (DFT) analyses were conducted to predict pharmacokinetic properties, drug-likeness, and electronic behavior.

Results: Several aurone derivatives exhibited strong α-glucosidase inhibition, surpassing standard drugs. Kinetic studies revealed a competitive inhibition mechanism, and in vivo evaluations confirmed their glucose-lowering effects - the first such report for aurones. Computational analyses indicated stable enzyme - ligand complexes with favorable binding affinities and ADME features. DFT results supported the observed structure - activity relationships and highlighted key electronic attributes influencing activity.

Conclusions: This comprehensive study identifies aurones as potent α-glucosidase inhibitors with significant therapeutic potential, providing a strong foundation for further development of aurone-based antidiabetic agents.

Diabetes mellitus develops because of the disturbance in carbohydrate metabolism. The therapeutic goal for antidiabetic medications is to manage blood glucose level and to prevent hyperglycemia-associated complications. α-Glucosidase inhibitors represent one of the widely used oral hypoglycemics. This review highlights the potential of 1,2,4-triazole-containing synthetic molecules as antidiabetic agents, particularly focusing on their α-glucosidase inhibitory activity. It argues the significance of targeting α-glucosidase in managing type 2 diabetes and presents recent synthetic approaches for synthesizing 1,2,4-triazole derivatives. The mechanisms of action, SAR analysis, and docking insights are summarized for various reported 1,2,4-triazoles between 2020 and 2025. A comparative analysis was conducted to identify the most effective methodology and the best starting material for the synthesis of this class. Relative potencies and drug likeness characteristics of the reviewed candidates were also evaluated to identify whether one deserves forwarding to pre-clinical and clinical assessments. Many of these derivatives exhibited potent α-glucosidase enzyme inhibition, often outperforming standard marketed drugs like Acarbose. The review paves the way for medicinal chemists to develop new 1,2,4-triazole-incorporating molecular entities to build safe and effective agents for diabetes treatment.