Current Medicinal Chemistry - Online First

The disability and mortality related to Parkinson's disease (PD), a neurodegenerative disease, are increasing globally at a faster rate than other neurological disorders. With no permanent cure for PD, there is an urgent need to develop novel and effective anti-PD drugs.

Targeting monoamine oxidases (MAO), which catalyze the breakdown of neurotransmitters, is one way to treat neurodegenerative diseases. In this context, an initial molecular docking of twenty designed sulfonyl derivatives of benzimidazole against monoamine oxidase B (MAO-B) associated with PD was conducted using AutoDock Vina.

The results were compared with those of the conventional inhibitors, selegiline and rasagiline. Based on the docking score, the in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of the newly synthesized molecules were examined using SwissADME, PreADMET, ProTox-3.0, vNN, and ADMETlab web tools. Then, twelve potential derivatives were synthesized and characterized by IR, ¹H-NMR, ¹³C-NMR, ¹⁹F-NMR (for some compounds), and mass spectrometry. Derivatives 2cj and 1bj were the two molecules having the best binding affinity of -11.9 and -11.8 kcal/mol, respectively, against MAO-B, exhibiting a higher binding affinity compared to that of some commercially available drugs. A 50 ns MD simulation run was performed to observe the stability of the top two docked complexes, MAO-B-2cj and MAO-B-1bj, in order to further validate the efficacy of those two substances. Moreover, the MM-PBSA method was used to calculate the final, binding free energy of the simulated (MAO-B-2cj) complex.

This study indicates that the binding affinity of most of the hits was superior to that of known MAO inhibitors; therefore, these newly synthesized benzimidazole derivatives may be developed into essential drug candidates for the treatment of PD.

We aimed to develop a macrophage signature for predicting clinical outcomes and immunotherapy benefits in cholangiocarcinoma.

Macrophages are potent immune effector cells that can change phenotype in different environments to exert anti-tumor and anti-tumor functions. The role of macrophages in the prognosis and therapy benefits of cholangiocarcinoma was not fully clarified.

The objective of this study is to develop a prognostic model for cholangiocarcinoma.

The macrophage-related signature (MRS) was developed using 10 machine learning methods with TCGA, GSE89748 and GSE107943 datasets. Several indicators (TIDE score, TMB score and MATH score) and two immunotherapy datasets (IMvigor210 and GSE91061) were used to investigate the performance of MRS in predicting the benefits of immunotherapy.

The Lasso + CoxBoost method's MRS was considered a robust and stable model that demonstrated good accuracy in predicting the clinical outcome of patients with cholangiocarcinoma; the AUC of the 2-, 3-, and 4-year ROC curves in the TCGA dataset were 0.965, 0.957, and 1.000. Moreover, MRS acted as an independent risk factor for the clinical outcome of cholangiocarcinoma cases. Cholangiocarcinoma cases with higher MRS scores are correlated with a higher TIDE score, higher tumor escape score, higher MATH score, and lower TMB score. Further analysis suggested high MRS score indicated a higher gene set score correlated with cancer-related hallmarks.

With regard to cholangiocarcinoma, the current study created a machine learning-based MRS that served as an indication for forecasting the prognosis and therapeutic advantages of individual cases.

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic cells and as of now, there is no established definitive treatment available for this condition.

In this study, the focus was on investigating the impact of SVAK-12, a small molecule that can cross the blood-brain barrier and remain stable without structural changes. The effect of SVAK-12 was investigated in vitro on neurotoxicity, in vivo model of Parkinson's Diseases and in silico.

Through in vitro and in vivo experiments, as well as molecular docking simulations, it was found that SVAK-12 (375 ng.ml) led to increased cell viability, reduced cellular damage, and decreased production of NO and ROS. Additionally, it boosted levels of important neurotrophic factors like BDNF (130.49%) and GDNF (116.38%), potentially aiding in alleviating motor disability and depression. The study also highlighted SVAK-12's potential as a therapeutic candidate for neurological disorders due to its ability to increase tyrosine hydroxylase expression and dopamine levels (4.84 times). While it did not significantly improve motor symptoms in vivo, it did enhance motor asymmetry in the forelimbs and gene expression related to brain regions. Besides, it induced significant BMP-2 gene expression in substantial nigra regions without significant changes in GDNF and Nurr1 gene expression in the striatum expression. The docking of SVAK-12, Levodopa, Amantadine, Biperiden, Selegiline, and Rasagiline to the binding site of GFRα1, sortilin, and TrkB showed that SVAK-12 had greater MolDock score than Selegiline and Amantadine for GFRα1 and greater than amantadine for Sortilin and TrKB.

Overall, the study suggests that SVAK-12's neuro-biocompatibility, ability to reduce free radicals, and enhanced neurotrophic factors make it a promising candidate as a neuroprotective drug.

Alzheimer's disease (AD) is the most common neurodegenerative disease in older people, characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of aggregated of hyperphosphorylated tau protein, which normally helps stabilize microtubules in neurons.

Nowadays, artemisinin (ART) as well as its semisynthetic derivatives (ARTs) are seen as potential neuroprotectors. The goal of the present study is the assessment of neuroprotective, antibacterial activity of ART, as well as in silico studies of ART affinity to Aβ-peptides and the search of potential targets for ART. The study is referring to explores the impact of ART on an animal model of AD that is induced by the aggregated amyloidogenic peptide Aβ1-42 by electrophysiology and morphology analysis. Specifically, the focus is on the activation of the entorhinal cortex (ENT) as synaptic potentiation.

Electrophysiological and histochemical have demonstrated that therapeutic injection of ART or its derivatives acts as a neuroprotective This treatment appears to prevent or slow down damage to brain tissue, and it promotes the restoration of neurons and their surrounding environment. The protective effects of ART may involve various mechanisms, including antioxidant activity, anti-inflammatory effects, and the inhibition of apoptosis.

in silico studies revealed a direct, strong interaction of ART with the amyloidogenic peptides 5Aβ17-42, 12Aβ9-40, and 18Aβ9-40. in silico screening revealed several protein targets for ART, including cytochrome P-450 2B6 (CYP2B6). The highest binding affinity was found on the active site of CYP2B6. ART has great potential for discovering new drugs using combined therapies.

Tyrosine kinase inhibitors (TKIs) target certain cell signalling pathways, and have become a promising class of medications for the treatment of cancer in recent years. Because of their distinct structure and adaptable chemistry, pyrazolines have drawn a lot of interest from organic and medicinal chemists. Their exceptional TKI activity has prompted them to investigate chemotherapy for cancer.

We aim to develop agents that inhibit tyrosine kinases highly effective with the least amount of harm possible, perhaps improving the course of cancer treatment.

This review compiled current information from recent literature sources, including in vitro, in vivo, approved medications, active clinical trials, and the structure-activity relationships (SAR) linked to various pyrazoline analogues used as small-molecule Tyrosine Kinase Inhibitors in cancer treatment.

This study focuses on SAR inside the pyrazoline ring and its derivatives as TKIs, and it emphasizes current developments, including patents, authorized medications, and compounds in clinical trials.

By enhancing our understanding of these compounds, our goal is to aid in making the roles of pharmacologists, scientists, and researchers who are designing and developing next-generation anticancer drugs with pyrazoline scaffolds easier. The future holds immense potential for the continued evolution of pyrazoline-based therapies, offering renewed hope in the ongoing battle against cancer.

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder that negatively affects female reproductive capacity. Although the association between autophagy and PCOS is known, there are few detailed studies on the association between autophagy-related genes and PCOS.

Publicly available gene expression datasets (GSE102293, GSE138518, GSE34526, GSE114419, GSE137684, GSE155489) were used in a comprehensive analysis to identify a role for autophagy in PCOS. Batch effects were mitigated using the sva package, followed by WGCNA (weighted gene correlation network analysis) and ssGSEA (single sample gene set enrichment analysis) to identify autophagy-related genes. Recursive feature elimination (RFE) and LASSO COX methods were used to identify important hub genes, and their correlation with immune cell activity was assessed using ssGSEA and Pearson correlation analysis.

High autophagy scores were observed in PCOS samples, and the dark green gene module with the highest autophagy correlation was identified. The differential analysis identified a total of 169 up-regulated genes versus 2 down-regulated genes in the PCOS samples, which were intersected by taking the intersection with the deep green module genes and resulted in 121 key genes. Subsequently, 6 hub genes (MMP25, CSF3R, SLPI, MMP9, CLEC4E, and SIGLEC10) were further identified based on RFE and LASSO algorithms. Diagnostic efficacy based on ROC curves showed six autophagy-associated hub genes with AUC values as high as 0.959 and 0.896 in the training and validation sets, respectively. Finally, we observed that these hub genes are strongly associated with immune function, especially chronic inflammation and aberrant immune activation pathways.

In this study, we identified autophagy genes closely related to PCOS and constructed a gene model with high diagnostic accuracy. These findings not only provided potential new biomarkers for the diagnosis of PCOS but also revealed the key role of autophagy in the pathogenesis of PCOS.

This study seeks to develop a prognostic risk signature for head and neck squamous cell carcinoma (HNSCC) based on cholesterol-related genes (CholRG), aiming to enhance prognostic accuracy in clinical practice.

HNSCC poses significant challenges due to its aggressive behavior and limited response to standard treatments, resulting in elevated morbidity and mortality rates.In order to improve prognostic prediction in HNSCC, our study is inspired by the realization that cholesterol metabolism plays a critical role in accelerating the progression of cancer. To this end, we are developing a unique risk signature using CholRG.

The aim of this study was to create a CholRG-based risk signature to predict HNSCC prognosis, aiding in clinical decision-making accurately.

The TCGA HNSCC dataset, along with GSE41613 and GSE65858, was obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. A CholRG-based risk signature was then developed and validated across various independent HNSCC cohorts. Moreover, a nomogram model incorporating CholRG-based risk signature was established. Additionally, functional enrichment analysis was conducted, and the immune landscapes of the high- and low-risk groups were compared. Finally, in vitro experiments were performed using lipid-based transfection to deliver siRNAs targeting ACAT1 to SCC1 and SCC23 cell lines, further examining the effects of ACAT1 knockdown on these cells.

Utilizing RNA-seq, microarray, and clinical data from public databases, we constructed and validated a CholRG-based risk signature that includes key genes such as ACAT1, CYP19A1, CYP27A1, FAXDC2, INSIG2, PRKAA2, and SEC14L2, which can effectively predict the clinical outcome of HNSCC. Additionally, our findings were reinforced by a nomogram model that integrates the risk score with clinical variables for more clinically practical prognostic assessment. In addition, patients at high risk show hypoxia and increased oncogenic pathways such as mTORC1 signaling, as well as a suppressed immune microenvironment marked by a reduction in the infiltration of important immune cells. Notably, in vitro experiments showed that ACAT1 depletion significantly suppressed the proliferation, colony formation, and invasion capabilities of HNSCC cells, confirming ACAT1's role in promoting malignancy.

Collectively, our study not only underscores the importance of cholesterol metabolism in HNSCC pathogenesis but also highlights the CholRG-based risk signature as a promising tool for enhancing prognostic accuracy and personalizing therapeutic strategies.

Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia.

The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde-based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in-vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 µM).

Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 µM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 µM) indicated competitive inhibition of the aforementioned enzyme.

Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health.

This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-like cells.

Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry.

The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing.

The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

Mitochondrial fission and fusion play important roles in tumorigenesis, progression and therapy. Dysregulation of these processes may lead to tumor progression, and regulation of these processes may provide novel strategies for cancer therapy. The involvement of genes related to mitochondrial fission and fusion (MD) in gastric cancer (GC) remains poorly understood.

The aim of this study was to establish an MD gene signature for GC patients and to investigate its association with prognosis, tumor microenvironment and treatment response in GC.

We use the TCGA-GC database as the cohort, focusing specifically on genes associated with MD. We conducted identification and consistency clustering analysis of differentially expressed genes in MD, conducted MD gene mutation and copy number variation analysis, as well as correlation and functional enrichment analysis between MD gene cluster classification and immune infiltration. TCGA-GC and GSE15459 were used to construct training and validation cohorts for the model. We used various statistical methods, including Cox and Lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE13861, GSE26901, GSE66229, and GSE13450). We used GSEA enrichment, CIBERSORT algorithm, ESTIMATE, and TIDE to gain insight into the annotation of MD signature and the characterization of the tumor microenvironment. OncoPredict was used to analyze the relationship between the PRG signature and the drug sensitivity. We validated the expression of several key genes in MD signature on GC cell lines using quantitative real-time PCR (qRT-PCR).

These MDs-related subtypes exhibited different prognosis and immune filtration patterns. A five-gene signature, comprising AGT, HCFC1, KIFC3, NOX4, and RIN1, was developed. There was a clear distinction in overall survival between low- and high-risk patients. The analyses showed further confirmation of the independent prognostic value of the gene signature. There was a notable correlation between the MD signature, immune infiltration and drug susceptibility. The expression levels of AGT, HCFC1, KIFC3, NOX4 and RIN1 mRNA were all increased in these GC cells.

The MD signature has the capacity to significantly contribute to the prediction of personalized outcomes and the advancement of novel therapeutic strategies tailored for GC patients.

Tobacco smoke is an important inducer of airway epithelial cell aging. Punicalagin(PCG) is a natural anti-aging compound. The effect of PCG on tobacco smoke-induced airway epithelial cell senescence is unknown.

Our study investigated whether PCG can treat the human bronchial epithelial cell line (BEAS-2B) aging by inhibiting the protease-activated receptor 2 (PAR2)/mTOR pathway.

Bioinformatics techniques were used to analyze the potential biological functions of PAR2. Molecular dynamics evaluated the binding ability of PCG and PAR2. The CCK8 assay was used to detect the cytotoxicity of CSE and PCG. The activity of the PAR2/mTOR pathway and the expression of the characteristic aging markers p16, p21, and SIRT1 are detected by qRT-PCR and Western blotting. Cell senescence was observed by Senescence-associated β-galactosidase (SA-β-gal) staining. The senescence-associated secretory phenotype (SASP): concentrations of interleukin IL-6, IL-8, and TNF-α were detected by ELISA.

The GSE57148 bioinformatics analysis dataset showed that PAR2 regulates lung senescence through the mTOR signaling pathway. Molecular dynamics results found that PCG and PAR2 had a strong and stable binding force. CSE induces BEAS-2B cell senescence and activates the PAR2/mTOR pathway. Inhibition of PAR2 mitigated the senescence changes. In addition, PCG's pretreatment can significantly alleviate CSE-induced BEAS-2B cell senescence while inhibiting the PAR2/mTOR pathway.

PCG has a therapeutic effect on the senescence of airway epithelial cells.