Current topics in medicinal chemistry最新文献

1,3,4-Thiadiazole is a multiform heterocyclic compound whose expansion in the field of medicinal chemistry is due to its unique structure and a variety of biological activities. The fivemembered ring system which contains sulfur and nitrogen atoms and is a hallmark scaffold for the manufacture of pioneering therapeutic agents, is the basic element of this compound. The 1,3,4- thiadiazole group exhibits a wide range of pharmacological activities, including antimicrobials, anti-inflammatories, anticonvulsants, antivirals, and antioxidants. This compound is a great candidate for drug discovery as it is a simple molecule subject to synthesis and interact with many different targets found in organisms. This paper aims to review recent research findings on this nucleus, highlighting the structural modifications of various thiadiazole derivatives for diverse pharmacological activities. Furthermore, this review also examines patents from 2019 to 2024 on thiadiazole derivatives for their applications in various diseases. Through the explication of the latest advancements and the comment on new trends, this study spotlights the capability of 1,3,4- thiadiazole as a core ring for the advancement of next-generation drugs.

Oxidative stress plays a critical role in many diseases, making it essential to study its impact on disease progression. However, clinical trials have many limitations and, in some cases, may not be possible at all. In this case, the development of in vivo models is highly anticipated. This is especially relevant for neurodegenerative diseases. Drosophila melanogaster models have a number of advantages over many other animal models, including the availability and costeffectiveness of breeding, the accumulated knowledge of the Drosophila genome, and the ability to manipulate a large number of individuals. The latter allows for rapid screening and in-depth studies of potential therapeutic agents, including natural compounds with antioxidant activity. This review describes genetic models of such pathologies as Parkinson's disease, Huntington's disease, Alzheimer's disease and hereditary spastic paraplegia created on Drosophila melanogaster. Studies conducted on such models are presented with an emphasis on the role of oxidative stress analysis. Oxidative stress is proven to be a link between neurodegenerative and metabolic diseases. In addition, studies on Drosophila melanogaster have been analyzed, in which the prospects of natural compounds as therapeutic agents for neurodegenerative and metabolic diseases have been demonstrated.

Introduction: Schizophrenia is a heterogeneous chronic brain disorder driven by multiple pathophysiological processes. While dopaminergic theories dominate current therapies, emerging evidence highlights glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDAR) hypofunction, as a key mechanism alongside dopaminergic, serotonergic, and neurodevelopmental pathways. This article synthesizes mechanistic insights, focusing on neurotransmitter disruptions, oxidative stress, neuroinflammation, and Wnt signaling, to elucidate the clinical diversity of schizophrenia and identify biomarkers for precise diagnostics and therapeutics.

Methods: A comprehensive literature search was conducted using Web of Science, Scopus, Google Scholar, and PubMed, with keywords including "schizophrenia," "psychosis," "pathophysiology," "mechanism," and "biomarker." Studies were selected to explore NMDAR hypofunction, glutamatergic dysregulation, and associated signaling pathways, integrating preclinical and human data to map circuit-based interactions and biomarker profiles.

Results: We present a novel circuit-based model of schizophrenia pathophysiology, centered on NMDAR hypofunction and glutamatergic dysregulation, integrating dopaminergic, GABAergic, and inflammatory pathways. Key biomarkers, including inflammatory (e.g., high-sensitivity Creactive protein [hs-CRP], interleukin-6 [IL-6]), neurochemical (e.g., brain-derived neurotrophic factor [BDNF]), and functional (e.g., mismatch negativity [MMN]), are categorized by symptomatic domains and clinical stages, providing diagnostic and prognostic insights.

Discussions: The findings underscore NMDAR hypofunction's role in driving schizophrenia's symptomatic spectrum, though its interplay with other pathways highlights the disorder's complexity. Neuronal loss, although not universal, is context-specific (e.g., hippocampal interneurons), complementing functional biomarkers such as MMN. Limitations include the need for robust human validation of biomarkers and broader exploration of non-glutamatergic mechanisms.

Conclusion: Considering the multifaceted nature of the disorder, our emphasis on the NMDAR hypofunction model can help explain many of the synergies involved among the seemingly independent dysregulated events.

Introduction/objective: African swine fever virus poses a persistent threat to the global pork industry owing to its severe impact on animal welfare, the economy, and food security. Currently, no antiviral medicines are available, and biosecurity measures, such as quarantine and culling, have proven insufficient, often resulting in further economic losses. Given the widespread impact of ASFV, there is an urgent need to explore and develop new treatment strategies to mitigate its spread.

Methods: 1,212 secondary metabolites from brown algae were screened using ADMET profiling. Compounds with favorable properties were selected for molecular docking against A179L, an antiapoptotic protein of ASFV. The top-scoring metabolites were further analyzed through molecular dynamics simulations, principal component analysis (PCA), and binding energy calculations.

Results: ADMET profiling identified compounds with drug-like pharmacokinetic properties. Consensus molecular docking using two docking programs predicted the binding poses of the metabolites, and the top ten candidate ligands with the strongest docking scores were selected. We then performed 300 ns molecular dynamics simulations to assess the stability of the protein-ligand complexes, which were further validated through Principal Component Analysis (PCA). Finally, binding energies were estimated using both MMPBSA and MMGBSA approaches, and the key residues involved during binding were identified. All ten final candidate ligands demonstrated stability and favorable binding affinity (-27.78 kcal/mol to -38.58 kcal/mol).

Conclusion: Five compounds (CID: 24796376, sargachromanol G, strictaepoxide, CID: 163107957, and saringosterone) with the strongest binding energies are recommended for in vitro and in vivo testing to validate their potential as therapeutic agents against ASFV.

Introduction: Glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) are distributed in the brain, and they are particularly dense in the hippocampus. The two receptors are implicated in stress-related psychiatric diseases, such as anxiety, autism spectrum disorders (ASD) and depression. This study aims to investigate the alterations in neurological behaviour and the expression of GRs and MRs in male offspring from prenatal stress-exposed dams that were subjected to chronic stress.

Methods: In our study, we conducted the elevated plus maze (EPM) test on adult offspring of pregnant mice exposed to chronic stress, as well as on mice in the control group, to examine their neurological behaviors. Expression levels of GRs, MRs, and interleukin 6 (IL-6) were detected by Real- Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT PCR). After euthanizing the adult mice from both groups, we dissected their cortex and hippocampus for immunofluorescence staining.

Results: We observed an increase in the IL-6 mRNA content in the cerebral cortex of male offspring from the stress group, which was accompanied by the activation of microglial cells. Additionally, the relative mRNA expression levels of GRs and MRs in the hippocampus of male offspring from the stress group were found to be decreased. As a result, adult offspring from the stress group exhibited anxiety-like behavior.

Discussion: The observed reduction in hippocampal GR and MR expression, alongside increased cortical IL-6 and anxiety-like behavior in male offspring, suggests that prenatal stress disrupts neuroendocrine and inflammatory pathways, supporting previous findings on stress-induced neurodevelopmental vulnerability, although further studies are needed to address sex differences, long-term behavioral outcomes, and causal mechanisms.

Conclusion: Our study indicates that chronic prenatal stress induces anxiety like behaviour in offspring and decreases the expression levels of GRs and MRs.

Lung cancer continues to be a leading cause of cancer-related mortality worldwide, underscoring the urgency for innovative and targeted drug discovery strategies. This review critically explores the role of Quantitative Structure-Activity Relationship (QSAR) modelling, particularly its integration with artificial intelligence (AI), in accelerating the identification and optimization of lung cancer therapeutics. Recent progress in multi-target approaches, machine learning (ML) algorithms with mathematical representations, and molecular descriptor engineering has been analyzed, with a special focus on clinical translations. Rather than offering a generic overview, we evaluate how AI-powered QSAR addresses key bottlenecks in drug development, such as data imbalance, model interpretability, and ADMET prediction failures. Notable case studies are examined to highlight translational success stories in lung cancer-specific pathways. This review offers a cohesive synthesis of current advancements, identifies critical gaps and limitations, and proposes future directions for enhancing the real-world applications of QSAR methodologies in oncological drug discovery.

A novel class of nanomaterials known as silver nanoparticles (AgNPs) changes the potential in modern medicine. AgNPs are rapidly gaining significance in therapeutic applications ranging from tissue engineering to drug delivery systems due to their strong antibacterial, anticancer, anti-inflammatory, and wound-healing properties. This review presents a comprehensive analysis of the biomedical potential of AgNPs, physical, chemical and biological features that allow for regulated release mechanisms, improved bioavailability, and selective cellular targeting. Considering their obvious promise, there are significant challenges due to concerns about longterm exposure, toxicity, and regulatory uncertainty. We cover new developments, clinical studies, and safety evaluations, providing a balanced perspective of the advantages and disadvantages of AgNP or drug-based therapies. This review proposes a framework for scientists, physicians, and legislators to harness the full therapeutic power of silver nanoparticles while directing associated risks.

Introduction: Skin wounds represent a worldwide problem. Biopolymers have been attracting interest in healthcare products for wound dressing. Among these, bacterial nanocellulose membranes (BNC) are attractive for their unique structure, but they lack antimicrobial activity. Thus, the incorporation of the monoterpenes Carvacrol (Car) and Thymol (Thy) - which present antimicrobial and healing properties - toward the improvement of skin wound healing, consists of an appealing approach. This research aimed to produce and characterize nanocellulose membranes containing carvacrol and/or thymol, and investigate their release behavior, cytotoxicity, and antimicrobial properties.

Method: BNC/Car, BNC/Thy, and BNC/Car-Thy membranes were produced at doses of 0.1 and 1.0 mg/cm2.

Results: The natural components incorporation into the nanocellulose did not interfere with the ultra-structure or its physical characteristics. Pilot studies showed that membranes with 1.0 mg/cm² of monoterpenes were toxic to fibroblasts. Therefore, all further studies used the lower dose of 0.1 mg/cm². Release experiments showed a burst release between 2-4 h with sustained release till 24 h, reaching around 80% of the initial amount of the incorporated monoterpenes. Studies with fibroblast and keratinocytes indicated no cytotoxicity and that cells could proliferate over the BNC/Car- Thy membranes. Microbiological studies suggested some antimicrobial potential of the BNC doped with Car and Thy.

Discussion: BNC membranes incorporated with Car and Thy were successfully produced and the monoterpenes incorporation into the BNC did not interfere with either ultra-structure or with its physico- chemical characteristics. Natural products incorporation induced cell proliferation and presented antimicrobial properties, besides increasing the solubility and stability of these natural compounds.

Conclusion: This innovative biomaterial has the potential for healthcare products.

Introduction: Prostate cancer is among the most prominent malignant tumors in the male population, characterized by growing morbidity, a high fatality rate, and currently limited therapeutic options, necessitating the urgent development of novel clinical medications. The objective of the current study was to examine the therapeutic potential of zingerone in prostate cancer cells.

Methods: In this study, we investigated the underlying mechanism by which zingerone exerts its anticancer effects in prostate cancer cells. We conducted various in vitro and in silico experiments to determine the therapeutic efficacy and mechanism of action of zingerone.

Results: Cytotoxicity analysis of zingerone revealed its substantial cytotoxic impact and ability to elevate lactose dehydrogenase levels in DU145 cells. Using the MTT assay, we determined that a concentration of 24.84 μM zingerone in DU145 cells grown for 24 h resulted in an IC50 value. Zingerone effectively induced apoptosis by increasing the levels of cytochrome c and caspase in DU145 cells. Regarding the identification of signs of ferroptosis, evidence has been shown for the presence of heightened mitochondrial ROS, disrupted mitochondrial membrane potential, increased levels of glutathione (GSH) and malondialdehyde (MDA), and reduced expression of SCL7A11 and GPX4.

Discussion: Importantly, our study confirms that zingerone triggered both apoptosis and ferroptosis in DU145 cells by downregulating SLC7A11 and GPX4 expression.

Conclusion: This study provides evidence that makes zingerone a potent therapeutic agent for prostate cancer.