Current Topics in Medicinal Chemistry - Online First

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.

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.

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 C-reactive 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.

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.

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.

The present study is based on the most recent and extensive research on the Thiazolidine structure in the fields of organic synthesis and biological activities from 2015 to 2024, as well as the most widely used methodologies in recent years.

The three methods described in this review for the synthesis of thioazolidine derivatives are the most commonly used in recent decades and have given rise to interesting biological activities and the promotion of compounds with chemical and biological significance.

The synthesis of compounds with a thiazolidine skeleton plays a vital and interesting role in organic chemistry, with methods that are becoming increasingly sophisticated and easy to use, making it possible to obtain derivatives of biological and pharmacological importance, and a basis for future research.

The thiazolidine scaffold provides an efficient synthetic route for constructing complex molecular structures with significant biological activities. Their versatile reactivity makes them particularly interesting in organic chemistry, as well as biochemistry and pharmacology.

Oroidins are marine-derived alkaloids known for their structural complexity and a broad range of pharmacological activities. This review aims to explore their emerging role as promising scaffolds in medicinal chemistry, particularly focusing on their unique chemical structure, diverse biological effects, and recent synthetic advancements.

An extensive literature review was conducted to analyze peer-reviewed articles on the isolation, synthesis, structural characterization, and pharmacological evaluation of oroidins and their derivatives. The review highlights significant developments in synthetic strategies, including the incorporation of pyrrole carboxamide units, isotopic labeling approaches, and palladium-catalyzed reactions.

Oroidins exhibit a wide spectrum of biological activities, including antibacterial, antiviral, antimalarial, antiprotozoal, anticancer, anti-inflammatory, neurotropic, and antimuscarinic properties. Their characteristic pyrrole-imidazole core, containing a glycocyamidine moiety and azepinone ring, has been instrumental in targeting key biological pathways such as kinases, NF-κB, and the Raf/MEK-1/MAPK cascade. Structural modifications have led to enhanced potency and specificity of oroidin-based compounds.

The findings emphasize the potential of oroidins as lead compounds in drug development. Their structural diversity, bioactivity profile, and ability to inhibit critical cellular targets position them as attractive templates for therapeutic design. However, further research is needed to optimize their pharmacokinetic properties and evaluate their clinical relevance.

Oroidins represent a valuable class of marine alkaloids with significant therapeutic promise. Advances in synthetic methodologies have expanded their applicability in drug discovery, supporting continued exploration of these compounds for the development of novel therapeutic agents.

This study aims to establish a novel, straightforward, and reliable UPLC-MS method for determining the stability and impurity profile of Nirogacestat under various stress conditions, in accordance with ICH guidelines. The stability of Nirogacestat was investigated under various stress conditions, including acid/base hydrolysis, oxidation (H2O2​), photolysis, reduction, and thermal degradation. This research addresses the need for a validated, stability-indicating method that performs reliably across key analytical parameters, thereby contributing to pharmaceutical quality assurance.

Stress testing was performed by exposing Nirogacestat to various degradation conditions, including acid (0.1 and 1N HCl), base (NaOH), oxidative (30% H2O2), thermal (105°C), photolytic, and reductive environments. The mobile phase consisted of acetonitrile and 0.1% triethylamine/formic acid, adjusted to pH 2.5 in a 30:70 (v/v) ratio. Chromatographic separation was achieved using an Acquity UPLC BEH Shield RP-18 column (50 × 1.0 mm, 1.7 µm), with a flow rate of 0.5 mL/min and detection at 251 nm. Linearity was evaluated over a concentration range of 0.25 to 1.5 µg/mL. Validation studies assessed parameters such as selectivity, linearity, accuracy, precision, robustness, and solution stability.

The method demonstrated excellent linearity (r² = 0.999), with peak area directly proportional to concentration within the studied range. All validation parameters were within acceptable limits. Forced degradation studies revealed distinct degradation products under each stress condition. Notably, alkaline degradation resulted in the least degradation, while acid, peroxide, photolytic, thermal, and reductive conditions produced a variety of degradation products. These were effectively separated from Nirogacestat using the developed method. The relative retention times for Nirogacestat and its impurities remained consistent, and mass spectrometry confirmed the identities of the degradation products.

The validated UPLC-MS method exhibited high sensitivity, selectivity, and robustness in detecting Nirogacestat and its impurities. It effectively distinguishes degradation products even within complex matrices and fully complies with ICH guidelines for analytical method validation. The degradation profile of Nirogacestat under various stress conditions provides critical insights into its stability behavior, which is essential for formulation development and regulatory compliance. The successful separation and identification of degradation products further underscore the method’s applicability as a stability-indicating assay.

The developed UPLC-MS method is the first validated stability-indicating technique for Nirogacestat, offering comprehensive impurity profiling. It is precise, accurate, linear, and robust, making it highly suitable for routine quality control and regulatory submission. This method enables the reliable detection of degradation products, thereby enhancing the safety and efficacy profile of Nirogacestat in pharmaceutical preparations.

To explore the molecular mechanism of α7 nicotinic acetylcholine receptor (α7nAChR) mediated by Formononetin (FMN) in inhibiting macrophage inflammatory polarization and stabilizing atherosclerotic plaque.

SiRNA α7nAChR was transfected into THP-1-induced M0 cells and treated with FMN. Oil Red O staining was used to evaluate macrophage lipid deposition. RT-qPCR was used to detect α7nAChR, COX-2, IL-1β, IL-6, HO-1, and SHIP1 expression in M1 and M2 macrophages. Western blot was used to detect α7nAChR, iNOS, CD206, CD68, p-JAK2, and p-STAT3 protein expression in M1 and M2 macrophages.

Compared with the control group, FMN-mediated α7nAChR reduced lipid deposition in M1 and M2 macrophages. RT-qPCR results showed that FMN intervention significantly downregulated COX-2 and IL-1β expression in M1 (P < 0.05). α7nAChR expression significantly reduced COX-2, IL-6, and IL-1β expression in M2 (P < 0.05) and significantly increased HO-1 and SHIP1 expression (P < 0.05). FMN-mediated α7nAChR significantly decreased the expression of iNOS, CD68, p-JAK2, and p-STAT3 in M1 and M2 macrophages and significantly increased the expression of CD206 protein by Western blot (P < 0.05).

This study, for the first time, elucidated the mechanism of FMN regulating macrophage polarization through the α7nAChR/JAK2/STAT3 axis, providing new experimental evidence for the role of the cholinergic anti-inflammatory pathway in cardiovascular diseases. However, there are some limitations, such as the limited applicability of the THP-1 cell line, the need to strengthen the dose correlation study, the bioavailability and solubility limiting clinical translation, and the lack of human toxicological data.

FMN effectively modulates macrophage polarization through inhibition of the JAK/STAT signaling pathway while promoting α7nAChR expression.

Crohn's disease (CD) is a complex inflammatory bowel disorder with incompletely understood mechanisms. This study aimed to identify novel biomarkers and elucidate macrophage-related pathogenesis in CD.

Using gene expression data (GSE17928522) from the Gene Expression Omnibus (GEO) database, we compared 1135 CD patients with 180 healthy controls to identify altered gene expression profiles. Immune infiltration analysis was conducted to evaluate changes in immune cell subpopulations. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to construct gene co-expression networks and identify macrophage-associated modules. Mendelian randomization was used to validate the causal role of macrophages. For ex vivo validation, immunohistochemical staining of GBP4 protein expression was performed in colonic tissue samples from 6 CD patients (with ileal or colonic lesions). Non-lesional tissues from the same patients served as intra-individual controls to minimize inter-patient variability.

Our analysis revealed significant changes in immune cell subpopulations, particularly macrophages, within the CD microenvironment. A macrophage-associated module was identified, with GBP4 emerging as a critical gene. Immunohistochemical staining confirmed differential expression of GBP4 in CD tissue samples compared to controls.

This multi-modal study establishes GBP4 as a novel macrophage-associated biomarker for CD, supported by causal Mendelian randomization and immunohistochemical validation. The integration of WGCNA and genetic evidence strengthens the role of macrophage dysregulation in CD pathogenesis. Limitations include population bias in genomic data and small validation cohorts, but the consistency across methodologies underscores GBP4's potential as a therapeutic target.

Our findings highlight GBP4 as a novel potential biomarker and therapeutic target in CD, providing insights into the immune-mediated mechanisms underlying the disease. These results contribute to a better understanding of CD pathogenesis and may lead to new therapeutic strategies.