Current topics in medicinal chemistry最新文献

Introduction: DNA gyrase and topoisomerase IV (Topo IV) are essential bacterial enzymes absent in higher eukaryotes, making them attractive antibacterial drug targets. The rising prevalence of multidrug-resistant Streptococcus pneumoniae underscores the urgent need for novel therapeutic agents targeting these enzymes.

Methods: We designed fifteen novel 1-ethyl-3-(4-(hydrazinecarbonyl)-phenyl)urea derivatives using an in silico approach, followed by chemical synthesis and structural characterization (¹H NMR, ¹³C NMR, HRMS). The compounds were evaluated for inhibitory activity against S. pneumoniae DNA gyrase, Topo IV, and their ATPase domains, along with antibacterial activity (MIC assay) and cytotoxicity in HepG2 cells.

Results: All synthesized compounds inhibited the tested enzymes, with compounds 18GP06-15 and 18GP06-08 showing the most potent and balanced dual inhibition (IC₅₀ = 0.511 and 0.555 μM against DNA gyrase; IC₅₀ = 9.24 and 8.64 μM against Topo IV). These compounds also exhibited strong activity against Gyrase B ATPase (IC₅₀ = 0.49 and 0.51 μM) and moderate inhibition of Topo IV ATPase (IC₅₀ = 3.12 and 3.99 μM). Antibacterial assays revealed MIC values ranging from 1.1 to 7.8 μg/mL, with 18GP06-15 being the most potent (MIC = 1.1 μg/mL), comparable to doxycycline (MIC = 1 μg/mL). None of the compounds showed significant cytotoxicity against HepG2 cells (IC₅₀ = 63.11-67.83 μM) compared to cisplatin (IC₅₀ = 6.41 μM).

Discussion: The study demonstrated that ethylurea-hydrazine hybrids effectively inhibit both DNA gyrase and Topo IV, suggesting potential as dual-target antibacterial agents. Structure- activity relationship (SAR) analysis indicated that aliphatic linkers at the R position enhanced potency compared to aromatic substituents. Compounds 18GP06-15 and 18GP06-08 emerged as promising leads, showing strong enzyme inhibition, favorable antibacterial activity, and minimal cytotoxicity.

Conclusion: Compounds 18GP06-15 and 18GP06-08 exhibited potent dual inhibitory activity against S. pneumoniae DNA gyrase and Topo IV, with low cytotoxicity. These findings support their potential as lead candidates for further optimization in the development of novel antibacterial agents.

Heterocycles have attracted the attention of researchers for a long time due to their applications in various fields. S- and N-containing heterocyclic compounds have a significant impact in organic chemistry. They are important not only industrially and biologically but also in the development of human society. Thiazoles are essential components in medicinal chemistry as well as key structural elements in many naturally occurring substances. Because of their notable biological properties, thiazoles have been an interesting topic of research, and many drugs have been designed that possess the thiazole moiety. As a result, the development of innovative techniques for synthesizing these molecules remains highly interesting. Many methodologies have been developed for the preparation of thiazoles, and the emergence of novel, environmentally friendly synthetic approaches is highly desirable. The present review article provides an overview of the biological importance and synthetic methods for the formation of thiazoles, promoting further research on the development of thiazole-containing drugs. It encourages researchers to synthesize novel and potent thiazoles effective against mutant strains, and the development of synthetic protocols is a high priority in medicinal chemistry research. This review will help to advance the search for strategies for the synthesis of biologically active thiazoles.

Background: Novel potassium-competitive acid blockers (P-CABs) are recognized to have more potent acid-suppressive efficacy than proton pump inhibitors (PPIs). This study comprehensively summarizes the clinical evidence regarding P-CABs in patients with gastrooesophageal reflux disease (GERD), with a particular focus on erosive oesophagitis (EO).

Methods: A network meta-analysis was carried out by retrieving randomized controlled trials of P-CABs and PPIs for the management of EO patients from PubMed, Embase, and CENTRAL between January 1st, 1990, and November 19th, 2022. The selected participants received oral treatment with 20 mg keveprazan (KPZ), 10-40 mg vonoprazan (VPZ), or 30 mg lansoprazole (LPZ), once daily for 2-8 weeks. We compared the efficacy and safety of KPZ, VPZ, and LPZ at different doses and follow-up time points in EO patients.

Results and discussions: From 183 initially identified citations, six eligible studies were included, encompassing 2,864 participants. Robust evidence indicated that 20 mg VPZ was superior to 30 mg LPZ in achieving EO healing at the 2-week follow-up. Furthermore, 40 mg VPZ demonstrated greater efficacy than 5 mg VPZ. Both 20 mg VPZ and 30 mg LPZ were less effective in patients with severe reflux disease (LA classification C/D) than in those with mild disease (A/B). Additionally, 20 mg VPZ was more effective than 30 mg LPZ in reducing serum gastrin and pepsinogen I levels after 4 weeks of intervention. Notably, 20 mg KPZ was associated with a higher incidence of treatment-emergent adverse events (TEAEs) compared to 40 mg VPZ.

Conclusion: In patients with EO, both 20 mg VPZ and 30 mg LPZ demonstrated relatively lower efficacy in subtypes C/D compared to subtypes A/B. Furthermore, 8-week interventions with either 20 mg VPZ or 30 mg LPZ provided significantly greater clinical benefit compared to 2-week regimens. Notably, 40 mg VPZ was associated with the lowest incidence of TEAEs, as well as TEAEs occurring in at least 2% of patients (TEAEs ≥2%).

Introduction: Feline infectious peritonitis (FIP), a fatal disease caused by feline coronavirus (FCoV), poses a serious threat to feline health. Natural product-based virtual screening offers a promising avenue for identifying antiviral agents targeting FCoV. In this study, a structure-based computational approach was employed to discover potential inhibitors of the 3C-like protease (3CLpro) of FCoV.

Materials and methods: A library of 96,677 natural compounds from the ZINC database was screened using molecular docking to assess their binding affinities to the protease. The initial hits were refined by evaluating ADMET properties and visually inspecting the binding poses, yielding 68 candidate molecules. These were further assessed through 100-nanosecond molecular dynamics simulations and binding free energy calculations.

Results: Through computational filtering, 14 compounds were identified that exhibited strong interaction stability and minimal conformational fluctuation. An analysis of the binding modes revealed that key residues, such as His162, Glu165, and Cys144, formed crucial hydrogen bonds and hydrophobic contacts, contributing to the stability of the protein-ligand complexes.

Discussion: The identified interactions highlighted the importance of specific residues in stabilizing the protein-ligand complex. Among the 14 compounds, eight maintained stable binding profiles throughout extended 500-nanosecond molecular dynamics simulations and also exhibited elevated binding free energy values, suggesting a stronger potential for antiviral development.

Conclusion: The findings indicated the compounds' strong potential for further development as antiviral leads. The results also revealed several core molecular frameworks that may serve as an initial reference for designing FCoV 3CLpro inhibitors, laying the groundwork for structure-guided drug discovery efforts.

Introduction: To investigate the causal relationship between 1-palmitoyl-GPG (16:0) and serous ovarian cancer (SOC), and explore the underlying mechanisms.

Method: Two-sample Mendelian randomization (MR) and mediation effect analyses were employed to determine the causal effects of 1-palmitoyl-GPG (16:0) on serous ovarian cancer (SOC), focusing particularly on naive CD4+ T cell proportions as potential mediators. Single-cell RNA sequencing, immune infiltration analysis, and bulk machine learning algorithms were also integrated to examine the expression and impact of palmitoyl-CoA synthesis genes in CD4+ T cells. Lasso regression was utilized to refine the set of marker genes, and CatBoost machine learning algorithm was applied for predictive modeling. SHAP analysis was performed to interpret the model results.

Results: MR and mediation analyses indicated that 1-palmitoyl-GPG (16:0) has a causal effect on SOC, partly mediated by the proportion of naive CD4+ T cells, and partly through direct effects potentially involving metabolic gene expression (e.g., PIGB) in CD4+ T cells. Single-cell and immune infiltration analyses confirmed that key palmitoyl-CoA synthesis genes, including PIGB, were highly expressed in CD4+ T cells and may contribute to SOC both indirectly, by influencing naive CD4+ T cell proportions, and directly through metabolic modulation within CD4+ subsets. The bulk RNA-seq machine learning model showed good predictive performance on an independent validation dataset. SHAP analysis was used to interpret feature contributions, with PIGB having the greatest impact on model predictions. The immune-related genes, including upregulated PIGB, GZMA, PRF1, S100A4, and CCL5, while downregulated AHNAK and LGALS1 (except in fibroblasts). Furthermore, different patterns of gene expression were observed in different CD4+ T cell clusters, which corresponded to various developmental statuses and functional roles. We identified a causal relationship between 1-palmitoyl-GPG (16:0) and SOC, which is mediated by naive CD4+ T cells and key synthesis genes.

Conclusion and discussion: Our findings provide new insights into the metabolic and immunological mechanisms underlying SOC, and highlight potential targets for therapeutic interventions.

Introduction: This study aimed to investigate the effects of the extract and purified protein from the microalga Chlorella vulgaris against T. gondii in infected Vero cells.

Method: The extract was obtained through magnetic stirring with Tris-HCl buffer and evaluated for cytotoxicity and anti-Toxoplasma activity. The purified protein was isolated using Sephadex G- 75 chromatography and assessed in light microscopy assays.

Results: Results indicated that the CC50 of the C. vulgaris extract was > 2000 μg/mL. Both the extract and the purified protein effectively inhibited parasite multiplication, with IC50 values of 132.6 and 8.6 μg/mL, respectively, and selectivity indices of 11.5 and > 20, respectively.

Discussion: Microscopic analysis showed that the purified protein, even at higher concentrations, did not exhibit toxicity to the cells and reduced the number of intracellular tachyzoites.

Conclusion: These findings suggest that both the extract and purified protein of C. vulgaris possess the ability to inhibit T. gondii tachyzoites without causing toxicity to healthy cells, indicating their potential as bioactive compounds for pharmacological applications against toxoplasmosis.

Introduction: Considering the shared physiological mechanisms between type 2 diabetes (T2D) and colorectal cancer (CRC), it is plausible that certain compounds may exert therapeutic effects on both diseases. Opuntia ficus-indica (nopal) has been traditionally used to manage these conditions. This study aims to elucidate the molecular mechanisms through which nopal exerts its effects on T2D and CRC.

Methods: Bioactive compounds of nopal, their molecular targets, and genes associated with T2D and CRC were identified from public databases. Gene Ontology (GO) analysis, metabolic pathway analysis, protein-protein interaction (PPI) network construction, and molecular docking were conducted to investigate the shared molecular targets.

Results: Nopal contains bioactive compounds that interact with molecular targets common to both T2D and CRC. These shared targets are implicated in lipid metabolism, apoptosis, kinase activity, interleukin-related pathways (IL-2 and IL-3), inflammation, gastrin signaling, and other critical processes. Key molecular targets identified include HSP90AA1 and MAPK8, while the principal bioactive compounds of nopal are eriodictyol and aromadendrin.

Discussion: The identification of eriodictyol and aromadendrin as modulators of HSP90AA1 and MAPK8 elucidates a pleiotropic mechanism underlying the link between type 2 diabetes and colorectal cancer. By modulating apoptotic and inflammatory pathways, these bioactive compounds offer a promising foundation for developing dual-action therapies targeting both metabolic and oncogenic pathways in patients with comorbid conditions.

Conclusion: The bioactive compounds of nopal engage multiple biological pathways relevant to T2D and CRC, suggesting that this plant may serve as a promising pharmacological candidate for the management of these diseases.

Developing novel pharmacological compounds for disease treatment is an inherently time-consuming and costly process, yet research continues unabated. Leveraging existing data resources and identifying innovative therapeutic leads are critical steps in drug design. The integration of artificial intelligence (AI) and machine learning (ML) offers powerful tools for designing and developing translational nanomedicines. The biological activity of a nanomedicine is largely determined by its physicochemical properties, including size, shape, surface charge, and chemical composition. These properties can be systematically optimized using nanoinformatics approaches, such as quantitative structure-activity/property relationship (QSAR/QSPR) models, enabling enhanced functionality of engineered nanomedicines while minimizing potential health and environmental risks during development. Physiologically based pharmacokinetic (PBPK) models further complement these approaches by predicting drug and nanomedicine distribution in body fluids, extrapolating experimental data, and establishing correlations between physicochemical properties and biodistribution. Such models are particularly valuable for toxicity assessment. This review focuses on the implementation of nanoinformatics tools and AI to facilitate the translation of nanomedicines from bench to clinic. Computational strategies for designing nanodelivery systems are highlighted, including selecting suitable nanomaterials, assessing potential nanotoxicity, and developing simulation models for in vitro and in vivo analyses. Additionally, the review examines the contributions of AI and ML to the development of translational nanomedicines, as well as the associated challenges and future research directions. The compiled insights are highly relevant to research groups involved in drug discovery, nanotechnology, and the development of advanced drug delivery systems for biomedical applications. Importantly, the methodologies discussed have broad applicability across multiple scientific disciplines.

Introduction: The objective of this study was to synthesize and characterize the Formononetin- Celecoxib Conjugate, evaluate its efficacy both in vitro and in vivo, and ascertain its potential as a medicinal agent for osteoarthritis (OA).

Methods: Phytoconstituents from Glycine max and FDA-approved drugs were meticulously curated and subjected to computational analyses for target identification and molecular docking. The Formononetin-Celecoxib Conjugate was subsequently synthesized and characterized using spectroscopic techniques. In vitro assessments included MTT viability assays and ELISA analyses. In vivo efficacy was evaluated using an MIA-induced OA mouse model.

Results: Molecular Formononetin-Celecoxib Conjugate has high binding affinity towards MMP-9. In vitro, the conjugate was non-toxic and significantly reduced MMP-9 expression. In vivo, it attenuated paw volume (p < 0.05) and prevented body weight loss in OA-induced mice, especially at 200 mg/kg. Statistical analysis (Mean ± SD; two-way ANOVA with Tukey's test) confirmed significant therapeutic benefits.

Discussion: The study validates the conjugate's anti-inflammatory and disease-modifying potential through both computational and experimental approaches. Its effects on MMP-9 inhibition suggest translational relevance for human OA. However, small sample size and lack of blinding remain limitations requiring further investigation.

Conclusion: Our study demonstrates the promising potential of the Formononetin-Celecoxib Conjugate as a novel therapeutic intervention for OA. By integrating computational predictions with experimental validations, this approach represents a step toward precision medicine in managing OA.

Background: In recent years, oxazoles' usefulness as an intermediate in the synthesis of novel chemical entities has grown in medicinal chemistry. Oxazole is a significant heterocyclic nucleus with a diverse range of biological activities, attracting the interest of researchers worldwide to synthesize numerous oxazole derivatives because of their notable biological potential. Owing to their distinctive physicochemical characteristics, these nuclei frequently have enhanced pharmacokinetic profiles and therapeutic effects relative to those of analogous heterocycles.

Objective: This evaluation presents an overview of the advancement in biological activities of oxazole derivatives (2009-2025). The review elucidates the mechanisms of action of these chemicals across numerous disorders, identifies the most effective ones along with their associated IC50/MIC values, and examines the models employed for assessing their activity.

Discussion: According to the review, oxazole and its derivatives have powerful anti-inflammatory, anticancer, antibacterial, and antitubercular effects, and SAR evidence shows that substituting phenyl, methoxy, halogen, or electron-withdrawing increases effectiveness. The scaffold's adaptability and translational ability are demonstrated by its broad activity spectrum, which includes repression of COX/LOX and tubulin polymerisation blockage. As a whole, oxazoles are great leads for potential new drugs because of their structural adaptations at C-2, C-4, and C-5.

Conclusion: The literature analysis indicates that the anticancer and anti-inflammatory efficacy of oxazole derivatives is especially significant among their many actions. The inclusion of phenyl, methoxyphenyl, or halogen-substituted phenyl groups markedly improves therapeutic efficacy relative to reference medications. The substitution versatility at three positions of oxazole derivatives enhances their range of pharmacological actions.