Current Medicinal Chemistry - Online First

More robust 4-substituted 7-chloroquinolines have been investigated for their diverse properties. However, there is still no systematic study that correlates the effects of the side chain at the 4-position of chloroquine and hydroxychloroquine derivatives with their lipophilicity, antimicrobial and toxicity properties.

To this end, a cleaner and facile approach was planned to obtain nineteen 4- substituted 7-chloroquinolines, whose influence of the substituent group and side chain extension at the 4-position on their properties was studied.

4-Alkoxy/amino-7-chloroquinolines were prepared by a nucleophilic aromatic substitution (SNAr) reaction between 4,7-dichloroquinoline and alcohols/amines, evaluated for their in silico ADMET test, in vitro antimicrobial activity against Gram-(+) and Gram-(−) bacteria, and Candida albicans fungus, and in vitro toxicity on Artemia salina larvae.

4-Alkoxy/amino-7-chloroquinolines were obtained in yields ranging from 81 to 100%. The best results showed antimicrobial activity against Pseudomonas aeruginosa for 4-amino-7-chloroquinolines 6-8, with halos greater than 20 mm, and against C. albicans for 4-amino-7-chloroquinolines 1-3, with halos close to 30 mm. A correspondence between Minnow toxicity prediction and in vitro toxicity on A. salina larvae was observed, where compounds 3 and 14, with R = Pent, were both predicted to have high acute toxicity (log LC50 < -0.3) and classified as highly toxic (LC50 < 100 µg mL^-1). It seems that increased lipophilicity in the side chain is harmful to A. salina larvae.

Considering the results for compounds 1-3 and 6-8 with greater activity against C. albicans and P. aeruginosa, respectively, especially for 4-amino-7-chloroquinolines 6 and 7, which are slightly toxic on A. salina larvae (LC50 500-1000 µg mL^-1), their antimicrobial studies deserve to be continued by the determination of Minimum Inhibitory Concentration (MIC) values.

The absence of physiologically relevant models for neuroinflammatory brain disorders, such as multiple sclerosis (MS), highlights the need for improved drug screening platforms. To bridge this gap, this study aimed to develop a human brain organoid (hBO) model incorporating essential neural cell types, including astrocytes, microglia, and oligodendrocytes.

hBOs were generated from H9 stem cells, and neuroinflammatory characteristics were elicited by lipopolysaccharide (LPS). The expression of specific neuronal and inflammatory markers was assessed through qRT-PCR, immunofluorescence staining (IFS), and ELISA.

IFS of mature hBOs with anti-SOX2, anti-SATB2, anti-MAPT, anti-GFAP, anti-MBP, and anti-IBA1 antibodies and images collected with the confocal microscope confirmed the differentiation of H9 cells into cortical neurons, astrocytes, microglia, and oligodendrocyte cell types. Elevated GFAP, IBA1, NF-κB, and IL-6 levels, along with reduced CNPase expression with LPS treatment, were considered reflective of MS-like pathology and were used to test fingolimod and its derivatives. Fingolimod and all its derivatives, specifically ST-1505, decreased MAPT (2.1-fold in ELISA, 1.7-fold in IFS), GFAP (1.8-fold in IFS), TNFα (5.4-fold in qRT-PCR), and FABP (1.5-fold in ELISA) levels, and increased IL-10 (11-fold in qRT-PCR) and MBP (2.9-fold in IFS) levels.

The present data collectively showed LPS to evoke neuroinflammation in the hBO model, while fingolimod and its derivatives, particularly ST-1505, exhibited significant anti-inflammatory and neuroprotective properties by counteracting these evoked changes in the hBO model.

The findings supported the applicability of brain organoids as a model system for drug screening studies for neuroinflammatory brain diseases.

Several pathological conditions, including glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas, are commonly associated with carbonic anhydrase type II (CA-II). Additionally, CA-II plays a critical role in regulating bicarbonate concentration in the eyes. The inhibition of CA-II reduces aqueous humor production and thus lowers intraocular pressure associated with glaucoma.

This study aimed to synthesize potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13).

In this study, a new series of potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13), were synthesized and characterized by IR, NMR, UV and mass spectroscopy and evaluated against bovine carbonic anhydrase-II (bCA-II).

Interestingly, most of the compounds showed better inhibition than the standard drug, acetazolamide (IC50: 18.2±0.51 µM), such as compounds 1 (IC50: 10.5±0.81 µM), 2 (IC50: 11.3±0.36 µM), 3 (IC50: 16.5±0.53 µM), 4 (IC50: 15.8±1.02 µM), 5 (IC50: 13.7±1.03 µM), and 9 (IC50: 12.2±1.03 µM). Among the synthesized compounds, compound 7 (IC50: 8.2±0.32 µM) exhibited the highest and compound 6 (IC50: 27.6±0.39 µM) showed the lowest inhibition. Structure-activity relationships suggest that the presence of nitro group on the phenyl ring contributed significantly to the overall inhibitory activity. Molecular docking of all the active compounds was performed to predict their binding behavior, which indicated good agreement between docking and experimental findings. Moreover, the MD simulation of compound 7 also showed excellent binding behavior and binding energy within the binding cavity of bCA-II.

These findings suggest that the synthesized 5NBIT and acylhydrazone derivatives exhibited potent CA-II inhibition, with several compounds outperforming the standard drug acetazolamide. These results provide valuable insights for the development of novel CA-II inhibitors with potential therapeutic applications in glaucoma and other related conditions.

“Penumbra freezing” aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers are crucial for identifying patients eligible for AIS treatment.

This study enrolled 141 AIS patients who exceeded the conventional treatment window. Using CT perfusion imaging, patients were categorized into “penumbra freezing” and “non-penumbra freezing” groups based on the EXTEND criteria. Multiple regression analysis assessed the association of nine baseline factors and five blood lipid indicators with “penumbra freezing.” Diagnostic accuracy was evaluated using ROC curves. Mendelian randomization (MR) analysis validated these findings using blood lipid indicators as exposures and penumbra biomarkers as outcomes.

Among AIS patients beyond the treatment window, males exhibited better penumbra preservation (OR=0.243, 95% CI=0.072-0.813, p=0.022), while those with hyperlipidemia showed poorer preservation (OR=2.429, 95% CI=1.027-7.747, p=0.043). In the “penumbra freezing” group, ApoA1 levels were significantly lower (1.29 ± 0.03 g/L) compared to the “non-penumbra freezing” group (1.42 ± 0.06 g/L, p=0.034). Conversely, Lp(a) levels were significantly higher in the “penumbra freezing” group (304.63 ± 52.44 mg/L) than in the “non-penumbra freezing” group (110.26 ± 40.71 mg/L, p=0.034). Higher ApoA1 levels increased the likelihood of “non-penumbra freezing” beyond the time window (OR=3.206, 95% CI=1.034-9.938, p=0.044), while elevated Lp(a) levels reduced this likelihood (OR=0.075, 95% CI=0.007-0.848, p=0.036). MR analysis confirmed genetic associations of ApoA1 and Lp(a) with penumbra biomarkers.

ApoA1 and Lp(a) may be linked to ischemic penumbra status, but further validation is needed due to limitations in sample size and study methodology.

ApoA1 and Lp(a) are promising biomarkers for identifying AIS patients eligible for “penumbra freezing,” suggesting the potential to extend the treatment window.

Coronary atherosclerotic disease (CAD), clinically manifesting as progressive coronary atherosclerosis (As), involves endothelial cell (EC) dysfunction. HYMAI may contribute to atherogenesis by acting on ECs, but its regulation of endothelial injury and role in As pathogenesis remain unclear.

HYMAI expression was assessed via PCR array in blood samples from healthy individuals, patients with premature coronary atherosclerotic disease (PCAD), and patients with mature coronary atherosclerotic disease (MCAD) (each group consisting of 4 males and 2 females). Using male ApoE^−/− and LDLR^−/− mice fed with a high-fat diet (HFD) to model As, we evaluated the effects of endothelial-specific HYMAI overexpression on aortic lesions. Autophagy and apoptosis were analyzed in ox-LDL-treated human coronary artery endothelial cells (HCAECs).

HYMAI levels increased sequentially in healthy individuals, PCAD, and MCAD patients. In HFD-fed ApoE^−/− and LDLR^−/− mice, aortic atherosclerosis progressed with age, while HYMAI expression in aortic tissue declined. HYMAI overexpression in ECs promoted autophagy and attenuated atherosclerosis. In vitro, ox-LDL suppressed HYMAI, triggering autophagic inhibition and apoptotic activation in HCAECs. HYMAI overexpression rescued ox-LDL-impaired autophagy and suppressed apoptosis through the miR-19a-3p/ATG14 pathway. MiR-19a-3p overexpression reversed autophagic rescue and promoted apoptosis by repressing ATG14.

HYMAI upregulation counteracts ox-LDL-treated endothelial autophagic inhibition via the miR-19a-3p/ATG14 pathway, rescuing apoptosis and attenuating As in both in vivo and in vitro settings.

Our results demonstrated that HYMAI attenuated As progression in As mice and ox-LDL-treated HCAECs by enhancing endothelial autophagy through the miR-19a-3p/ATG14 axis. These findings establish HYMAI as a novel regulatory mechanism and provide a potential druggable target for As and CAD.

Klotho is a multifunctional protein with anti-aging properties that plays a role in regulating vitamin D and phosphate metabolism. Sarcopenia is characterized by the loss of muscle mass and strength and is an important public health concern due to its negative effects on health. The aim of this study was to investigate the association between α-Klotho levels and the frequency of sarcopenia in a diverse population.

This study analyzed data from 1,250 participants in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. Participants were divided into four subgroups based on serum α-Klotho levels. Sarcopenia was assessed using skeletal muscle index and handgrip strength measurements. Multivariable logistic regression analysis was used to determine the association between serum α-Klotho levels and sarcopenia.

There was a significant difference in serum α-Klotho levels between patients with sarcopenia and patients without sarcopenia. In an unadjusted multivariable logistic regression model, higher α-Klotho serum levels were associated with a lower risk of sarcopenia (p < 0.05). This trend was maintained in the partially adjusted model, indicating that higher levels of α-Klotho were associated with a lower risk of sarcopenia. However, the fully adjusted model did not show significance.

Several factors significantly influence the relationship between serum α-Klotho levels and sarcopenia, including sex, ethnicity, alcohol consumption, body mass index (BMI), vitamin D levels, and disease status. Our findings indicate that the risk of sarcopenia is elevated in individuals within the lowest quartile of serum α-Klotho levels. Furthermore, a negative correlation exists between α-Klotho levels and grip strength, observed in both the overall sample and the aging-related subgroup. These results highlight the necessity for further investigation into the complex interplay between α-Klotho and grip strength, particularly in the context of sarcopenia associated with renal disease.

Serum α-Klotho levels in different populations are negatively correlated with the risk of sarcopenia, suggesting that α-Klotho may be involved in the occurrence and development of sarcopenia. Therefore, measuring α-Klotho levels in clinical practice may be a valuable diagnostic tool to identify individuals at high risk of developing sarcopenia.

Hepatocellular Carcinoma (HCC) exhibits high recurrence rates, particularly when accompanied by Microvascular Invasion (MVI). We identified MVI-related biomarkers and established a prognostic model for personalized HCC treatment.

Data were downloaded from The Cancer Genome Atlas (TCGA) and HCCDB databases. Key radiomics features were identified using the support vector machine-recursive feature elimination (SVM-RFE) algorithm, and differential expression analysis was performed with DESeq2. This was followed by functional enrichment analysis using the clusterProfiler package. Through univariate and Lasso regression analyses, we constructed a robust RiskScore model to effectively stratify HCC patients into distinct risk groups based on the median RiskScore value. The model prediction performance was evaluated using ROC curves and Kaplan-Meier (KM) analysis. We used the CIBERSORT algorithm to characterize immune cell infiltration patterns and conducted GSEA to identify differentially activated pathways between the risk groups.

Radiomic analysis revealed four significant features strongly associated with MVI, enabling the construction of a nomogram model with robust classification performance (AUC = 0.742). Subsequent analysis identified 241 overlapping MVI-related Differentially Expressed Genes (DEGs) enriched in critical tumor proliferation and invasion pathways. A 10-gene RiskScore model was developed, demonstrating excellent prognostic discrimination in training and validation cohorts. CIBERSORT analysis revealed significant correlations between specific immune cell infiltration and the 10 genes. GSEA analysis showed significant enrichment of cell cycle regulation pathways in the high-risk group, suggesting their important role in MVI.

The RiskScore was established using MVI-related features for prognosis assessment in HCC.

Our findings provided novel biomarkers and a theoretical basis for the early diagnosis and personalized treatment of HCC.

To identify the critical genes, biological mechanisms, and signaling pathways involved in the therapeutic effects of quercetin on diabetic foot ulcers using network pharmacology and molecular docking approaches.

We identified pathological targets of diabetic foot ulcers (DFU) from GeneCards, OMIM, and TTD, and pharmacological targets of quercetin from STP, TCMSP, and PharmMapper. Intersection analysis revealed potential therapeutic targets. Core targets were determined via GO/KEGG enrichment, PPI network construction, and Cytoscape screening algorithms (Degree, Closeness, Betweenness). Molecular docking and dynamics simulations assessed quercetin-core target interactions and binding affinity.

After screening and intersecting the targets of quercetin and diabetic foot ulcers, 236 genes related to quercetin's anti-diabetic foot ulcer effects were identified, with six key genes emerging as critical: SRC, TP53, MAPK1, JUN, HSP90AA1, and AKT1. Enrichment analysis suggested that quercetin may modulate inflammatory imbalance(HSP90AA1), immunosuppression(JUN), and oxidative stress(SRC, TP53, MAPK1, and AKT1) during diabetic foot ulcer progression.

The relationship between these core targets and biological pathways in diabetic foot ulcers requires further experimental validation. Notably, molecular docking and dynamics simulation results confirmed strong binding affinity between quercetin and the core targets, supporting their potential therapeutic relevance.

Quercetin exerts anti-diabetic foot ulcer effects by regulating SRC, TP53, MAPK1, JUN, HSP90AA1, and AKT1. These hub genes may serve as promising candidates for future therapeutic interventions in diabetic foot ulcers.

The receptor for pyroglutamylated RF amide peptide (QRFPR) is a G protein-coupled receptor that plays a role in various physiological and pathological processes. However, a gap remains in our understanding of QRFPR's pan-cancer properties.

This study performs an extensive pan-cancer analysis of QRFPR utilizing large-scale genomic datasets, including The Cancer Genome Atlas (TCGA). We evaluated QRFPR expression levels in multiple malignancies and examined their correlations with clinical outcomes. Additionally, we investigated associations between QRFPR expression and immune cell infiltration using bioinformatics tools.

Our results reveal significant alterations in QRFPR expression across several cancer types, particularly breast, colorectal, and prostate cancers. Elevated levels of QRFPR are linked to poor prognosis in certain malignancies, such as uterine corpus endometrial carcinoma (UCEC) and mesothelioma (MESO), and correlate with increased infiltration of immune cells, especially T cells and macrophages. Pathway enrichment analyses suggest that QRFPR may impact critical signaling pathways associated with cell growth, apoptosis, and immune regulation.

The observed variations in QRFPR expression across cancer types suggest its diverse roles in tumor biology. Its association with unfavorable clinical outcomes in specific cancers, as well as its link to immune cell infiltration, highlights its multifaceted impact on tumor progression and microenvironment modulation.

Our findings underscore the potential of QRFPR as a prognostic biomarker and therapeutic target in cancer biology. Further investigations into its functional mechanisms could pave the way for precision medicine approaches in oncology.