Current Topics in Medicinal Chemistry - Online First

Synthetic drugs are the drug of choice for topical treatment of psoriasis. However, these are associated with side effects; hence, there is a need to explore effective alternative treatments for psoriasis. Jasminum auriculatum has been used in Ayurvedic and traditional medicine as an ingredient for managing numerous skin ailments like eczema and ringworm.

This study aimed to evaluate the in vivo study of ointments prepared from chloroform and methanolic extracts of Jasminum auriculatum for the treatment of psoriasis.

Initially, pharmacogenetic and physicochemical characterization of Jasminum auriculatum was performed to check their presence. The ointments prepared from chloroform and methanolic extracts of Jasminum auriculatum were screened for acute toxicity studies and antipsoriatic activity by IMQ-induced psoriasis in the Swiss albino mice ear model. The parameters like ear thickness, ear weight, erythema, scales, and infiltration (Permeation into the skin) were evaluated. The histopathological studies were also conducted to support the findings.

The plant showed the presence of pharmacogenetic structures like Trichomes, Palisade cells, Xylem, Collenchyma Tous cells, Parenchymatous cells, Fibers, Pericyclic cells, Stomata, Phloem, and Sclerenchyma Tous cells responsible for the presence of phytoconstituents having antipsoriatic activity. The signs and symptoms increased in imiquimod-induced animals, but ointment of chloroform and methanolic extract of Jasminum auriculatum reduced the skin thickness, redness, scaling, and erythema. The study reveals along with the progression of disease topical formulation of the extract showed the effect on animals in a dose-dependent manner. Histopathological examination also supported the earlier results.

The present study demonstrates that ointments of chloroform and methanolic extract of Jasminum auriculatum are safe and effective in the treatment of psoriasis, as revealed by the in vivo study. These preclinical results could further be explored for the development of other topical formulations used in humans.

Ultrasonic extraction is a crucial technique for isolating active compounds from phytomedicine. However, as a batch process characterized by non-linearity and small sample size, it poses substantial challenges for real-time and prediction of extraction rates during the extraction of phytomedicinal. This work proposes an adaptive soft sensor for ultrasonic phytomedicine extraction.

An adaptive soft sensor based on an attention mechanism was first proposed. The attention mechanism calculates correlations between samples and assigns weights based on their similarity to the current query. Support vector regression (SVR) is then used to construct the soft sensor for extraction rate measurement. To further enhance sample information analysis, multi-head attention is employed. This allows the model to calculate the similarity between current queries and historical data across different feature spaces, thus improving the modeling capabilities of the intrinsic data structure. Finally, a dual-frequency ultrasonic extraction experiment of puerarin is designed and conducted. The experimental data is collected and labeled from different batches under varying initial extraction temperatures. This data is used to establish the soft sensor model and compare its performance.

The experimental results indicate that the proposed MHA-SVR model improved the coefficient of determination (R²) by 5.12% compared to the mainstream model and reduced the online prediction time by 88% compared to the JITL-SVR model. This work performance well exceeds the others while maintaining good real-time capabilities for the dual-frequency ultrasonic extraction of puerarin.

The multi-head attention and SVR-integrated soft sensor method proposed in this study effectively addresses the soft measurement challenges in online monitoring of multi-batch ultrasonic extraction processes. This approach demonstrates significant enhancement in extraction yield detection accuracy across varying batches and diverse initial operating conditions, thereby providing a robust technical solution for real-time quantification of extraction efficiency in botanical material processing.

Exploring the correlation between ovarian cancer and aging has great significance for understanding the pathogenesis of ovarian cancer and formulating targeted therapeutic regimens.

This computational study aims to identify and validate key genes in monocyte subtypes related to ovarian cancer and aging, exploring potential causal relationships.

We collected single-cell RNA sequencing data (GSE157007, GSE184880), GWAS data (14,049 samples and 40,941 controls from a European population), and eQTL data of ovarian cancer and aging. Using R software packages like Seurat and singleR, we conducted data integration, quality control, cell classification, and differential gene expression analysis to identify intersecting monocyte subtype genes in ovarian cancer and aging. We employed summary data-based Mendelian randomization (SMR) analysis and Heterogeneity in Dependent Instruments (HEIDI) tests to pinpoint causal genes. Further single-cell functional analyses (gene switching, cell communication, metabolic pathway analysis), Bulk RNA sequencing validation, functional enrichment, and protein-protein interaction (PPI) analyses elucidated these genes' biological roles.

The dataset included 123,280 cells, revealing differential gene expression in classical monocytes (104 genes), intermediate monocytes (43 genes), and myeloid dendritic cells (39 genes). SMR and HEIDI identified causal relationships for 7 genes in classical monocytes, 3 in intermediate monocytes, and 3 in myeloid dendritic cells with ovarian cancer. Bulk RNA seq validation confirmed six monocyte genes as causal in ovarian cancer and aging. TREM1, SERPINB2, and CD44 were upregulated, while DST was downregulated; SLC11A1 and PNRC1 showed contradictory patterns. Interactions with NK and T cells involved LGALS9 - CD44/45 receptors. Riboflavin metabolism was a common enriched pathway.

This study identified six specific monocyte genes as potential therapeutic targets for ovarian cancer and aging.

Skin cancer is one of the most prevalent cancers globally and is considered a serious public health problem associated with high death rates. The current therapeutic regimes for skin cancer are limited by their low bioavailability, generation of resistance, or adverse side effects. Many fruit extract-based nutraceuticals hold potential as topical treatment methods. Pyrus communis (Pear) fruit extract is a rich source of cholinergic acid, presently used as therapy for various skin diseases. Thus, it qualifies as a promising candidate for skin cancer treatment.

The objective of the study is to evaluate the cytotoxicity of Pyrus communis extract entrapped in ethosomes.

In this study, Pyrus communis fruit extract was formulated in ethosomes using the hot method and optimized using central composite design. The optimized ethosomes were characterized in vitro for particle size distribution, zeta potential, entrapment efficiency, morphology, and particle stability.

Preliminary phytochemical screening results suggest that PCHE contains a significant amount of phenolic compounds compared to other extracts (PCEA and PCAE). The presence of these phenolic compounds contributes to the strong antioxidant and cytotoxic effects of PCHE, which are observed in a dose-dependent manner. Analysis through GC-MS has identified chlorogenic acid, arbutin, ursolic acid, quercetin, and epicatechin are present in PCHE. Based on the initial testing of the extracts, PCHE was chosen for the preparation of ethosomes. The optimized ethosomes were found to have a particle size of 699 nm and a zeta potential of -16.07. Transmission Electron Microscopy illustrated a closed, spherically symmetrical structure of the ethosomes. Additionally, the Franz diffusion cell analysis for percutaneous absorption using egg membrane indicated a steady-state flux of the drug from the ethosomes. The formulation's cytotoxicity potential was assessed using the epidermoid carcinoma cell line (A431) through the MTT assay. The results show that the ethosome formulations exhibit cytotoxic activity better than PCHE extract. 1

In sum, the result of this study clearly points out that Pyrus communis extract entrapped in ethosomes, prepared by hot method, displayed a cytotoxic potential against skin cancer cell lines. This ethosomal formulation can be harnessed for skin cancer therapy through further mechanistic analysis and animal studies.

Cellular aging is a complicated event known for gradually reducing homeostasis, leading to a higher susceptibility to diseases and mortality. Since the behavior of Hematopoietic Stem Cells (HSCs) is potentially affected by plasma-derived exosomes, this study aimed to investigate whether the plasma-derived exosome of young and elderly human donors can deliver “youth” or “aging” signals into human umbilical cord blood-derived HSCs in vitro.

Exosomes were isolated from four young (Y-exo) and four old (O-exo) donors. Umbilical cord blood-derived HSCs were exposed to two concentrations of exosomes (5 and 10 μg/mL). Then, lineage differentiation (CD41 and CD38), the mRNA and protein expression of IL-1β and IL-6, and NFκB activity were evaluated using flow cytometry, qRT-PCR Enzyme-Linked Immunosorbent Assay (ELISA) methods, and western blot techniques, respectively.

The lineage-specific markers CD41 and CD38 expression were increased after exposure to O-exo compared to Y-exo at the concentration of 10 μg/mL (P<0.001). The HSCs treated with 10 μg/mL O-exo increased protein and mRNA expression of IL-1β and IL-6 compared to Y-exo at 10 μg/mL concentration (P<0.01). Furthermore, a significant difference was seen in p-NF-κB levels between O-exo and Y-exo at the concentration of 10 μg/mL (P=0.0014).

Our findings advocated the concept that circulating exosomes of old and young individuals may differently affect the pathways involved in the aging process in HSCs.Therefore, exosomes may be applied as therapeutic agents for regenerative medicine.

1,4-Dihydropyridines (1,4-DHPs) serve as versatile scaffolds in medicinal chemistry, exhibiting multitarget potential with anticancer, cardiovascular, antioxidant, anti-inflammatory, antimicrobial, and analgesic effects. Structural modifications enhance their binding affinity, bioavailability, and selectivity.

This review aims to explore the broad therapeutic potential of 1,4-DHPs by analyzing their biological activities and structure-activity relationships (SAR). Additionally, it seeks to provide medicinal chemists with insights into key structural modifications that can optimize their pharmacological efficacy.

A comprehensive literature search was conducted in PubMed, ScienceDirect, Elsevier, and Google Scholar, prioritizing peer-reviewed studies from the last decade. Inclusion criteria focused on pharmacological properties, SAR, and therapeutic potential of 1,4-DHPs, while non-peer-reviewed or irrelevant studies were excluded. Data extraction analyzed SAR trends, emphasizing the impact of structural modifications on binding affinity, bioavailability, and biological activity.

The review highlights that specific modifications in aromatic substituents, ester groups, and heterocyclic rings play a crucial role in enhancing the biological activity and selectivity of 1,4-DHPs. Their ability to modulate key enzymes and receptors contributes to their effectiveness as multitarget agents. Comparative SAR analysis provides evidence of the potential of 1,4-DHPs as next-generation therapeutics.

1,4-DHPs offer a promising framework for drug development, with the potential to address complex, multifactorial diseases. By understanding and optimizing SAR, medicinal chemists can design more selective and potent 1,4-DHP-based drugs. Future research should focus on refining these structural modifications to unlock their full therapeutic potential.

Neisseria gonorrhoeae is a notorious superbug responsible for causing ‘Gonorrhoea’ in humans. Recently, it has been classified as a high-priority pathogen by the World Health Organization due to its increasing resistance to available antibiotics. A multi-prolonged approach is needed to combat the growing problem of drug resistance caused by N. gonorrhoeae. This study evaluates Glutamate Racemase (GR), a moonlight protein of N. gonorrhoeae (Ng-GR), as a novel therapeutic target with potential for both inhibitor design and peptide vaccine development. Ng-GR plays a crucial role in the peptidoglycan biosynthetic pathway and is highly conserved across bacterial species. Additionally, this protein moonlights to perform a secondary function by binding to DNA gyrase in various organisms.

Homology modeling, molecular docking, and molecular dynamics simulations were used to design inhibitors targeting the moonlight function of Ng-GR. The immunogenicity of this protein was assessed using ABCPred-2.0, BepiPred-2.0, and ProPred softwares.

Bisleucocurine A was found to bind at the ectopic site of Ng-GR, disrupting its crucial moonlight function and interfering its interaction with N. gonorroheae DNA Gyrase (Ng-gyrase). Interestingly, residues important for its moonlight function were also identified as key immunogenic sites using ABCPred-2.0, BepiPred-2.0, and ProPred softwares, enhancing the potential of this protein as a vaccine candidate.

The GR enzyme’s moonlight function is highlighted as a promising novel target for therapeutic intervention and vaccine development in N. gonorrohoeae.

Alzheimer's disease (AD) is a prominent neurodegenerative ailment characterized by the constraints of conventional therapies stemming from insufficient medication transport to the brain. This review examines the function of polymeric nanocarriers (PNCs) in improving therapeutic efficacy for Alzheimer's disease treatment.

We analyze the principal obstacles to Alzheimer's disease drug delivery: the blood-brain barrier, the blood-cerebrospinal fluid barrier, and multidrug resistance proteins. The review examines three categories of PNCs: polymeric nanoparticles, polymeric micelles, and dendrimers, and their capacity to surmount these obstacles. Literature investigations used search engines like PubMed, Google Scholar, and ScienceDirect.

PNCs exhibit superior drug delivery via better biocompatibility, regulated release, and targeted delivery mechanisms. Recent studies demonstrate the effective delivery of several pharmaceuticals, including rivastigmine and galantamine, resulting in enhanced cognitive outcomes in Alzheimer's disease models. Patent research indicates an increase in innovation for PNC-based Alzheimer's disease treatments.

Despite ongoing hurdles in biocompatibility and scalability, PNCs exhibit significant potential to transform Alzheimer's disease treatment by improving medication delivery across biological barriers. Current investigations in nanotechnology and combinatorial medicines indicate a favorable outlook for PNC-based medicinal strategies.

Colorectal cancer (CRC), the world's third leading cause of death, can be caused by a variety of reasons, one of which is a valine-to-glutamate mutation at position 600 in the BRAF gene. Nonetheless, the prognosis of patients with BRAF mutations remains poor, necessitating additional research in this field.

This work aims to recognize and validate innovative and effective BRAF inhibitor.

A merged-featured ligand-based pharmacophore model was validated and screened against various external databases. The pharmacokinetic and toxicological characteristics of the 102 hits were analyzed, and the appropriate ligands were docked against BRAF protein. The top four protein-ligand complexes with the lowest binding energies were chosen, and their Molecular Dynamic (MD) simulation studies were accomplished.

The finest complex selected has a Root Mean Square Deviation (RMSD) value of 2.229A⁰ and a Radius of Gyration (RoG) value of 25.770A⁰. The LC50 of the best ligand was experimentally calculated to be 102.83 µg/ml. The ligand was found to destroy CRC cells, but it did not affect normal non-cancerous cells much.

This work thus proposes 3-(6,7-dimethoxy-3,4-dihydroisoquinoline-2-carbonyl)-N-(2-methoxyphenyl)benzenesulphonamide as a potential BRAF V600E inhibitor for the CRC treatment.

In this study, we report on the synthesis and characterization of new silicon (IV) phthalocyanine compounds (SiPcs) axially substituted with coumarin-linked derivatives, designed for potential application in photodynamic therapy (PDT) due to their photophysical properties.

Characterization was carried out using FT-IR, UV-Vis, MALDI-TOF-MS, and ¹H NMR spectroscopy. In dimethyl sulfoxide (DMSO), the SiPcs produced singlet oxygen with quantum yields of 0.17 to 0.19, assessed by the DPBF quenching method. DNA binding studies via UV-Vis spectroscopy and molecular docking suggested high binding affinities (ΔG⁰ values between -9.90 to -10.4 kcal/mol) and stable interactions with calf thymus DNA (ct-DNA).

The compounds showed promising inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with IC50 values indicating higher potency and selectivity compared to galantamine, a known cholinesterase inhibitor.

The combined singlet oxygen generation, DNA binding, and enzyme inhibition data underscore the potential of these SiPc-coumarin derivatives as multifunctional agents for PDT and neuroprotective applications such as Alzheimer's disease (AD).

This study systematically reviews the clinical applications, toxicological profile, and quality markers of Guchang Zhixie Pill, offering a reference for its rational clinical use, as well as its quality and safety assessment.

Relevant literature on the historical development, clinical applications, toxicology, and molecular characteristics of Guchang Zhixie Pill was retrieved from CNKI (https://www.cnki.net/), VIP (https://www.cqvip.com/), Sci-Hub (https://sci-hub.hkvisa.net/), TCMSP (https://old.tcmsp-e.com/tcmsp.php), Google Scholar (https://scholar.google.cz/schhp?hl=zh-CN), and PubMed (https://pubmed.ncbi.nlm.nih.gov/). Quality markers were predicted and analyzed based on established criteria to provide a scientific basis for ensuring clinical safety and efficacy.

Formulated based on Wumei Pill, Guchang Zhixie Pill is widely used in the treatment of ulcerative colitis and irritable bowel syndrome. Quality marker prediction and analysis, conducted in accordance with the “five principles” of quality marker identification, indicated that ursolic acid, oleanolic acid, chlorogenic acid, neochlorogenic acid, citric acid, 5-hydroxymethylfurfural, coptisine, berberine hydrochloride, (+)-magnoflorine, 6-shogaol, 10-gingerol, dehydrocostus lactone, papaverine, noscapine, palmatine, and corydaline serve as potential Q-markers for this formulation.

As a classical prescription for intestinal astringency and antidiarrheal therapy, ensuring its rational clinical application is essential. The identification of 16 quality markers provides a scientific reference for quality control in future research.

To investigate the antimicrobial potential of methanol fruit extract of Solanum xanthocarpum against Methicillin-Resistant Staphylococcus aureus (MRSA) and elucidate its mode of action.

The rise of antimicrobial resistance (AMR) demands the exploration of alternative therapeutic strategies to combat resistant pathogens.

To evaluate the efficacy of Solanum xanthocarpum methanol extract against MRSA, and identify its active constituents and mechanism of action.

The fruits of Solanum xanthocarpum were extracted using various solvents, with hexane and methanol yielding the highest results. Microbroth dilution assays assessed antimicrobial activity, while in vitro assays such as Alamar blue, Scanning Electron Microscopy (SEM), protein, and nucleic acid leakage examined metabolic disruption and cell membrane integrity. Gas Chromatography-Mass Spectrometry (GC-MS) was used to identify active compounds, and molecular docking studies assessed interactions with key MRSA proteins.

The methanol extract demonstrated significant antimicrobial activity against MRSA, causing metabolic disruption and leakage of cellular contents as evidenced by various in vitro assays including alarm blue, SEM, and protein and nucleic acid leakage assay. GC-MS analysis identified alpha-linoleic acid and palmitic acid as key active components. Molecular docking studies confirmed their inhibition of beta-lactamase activity, cell wall biosynthesis, efflux pumps, and virulence factors.

The findings suggest that Solanum xanthocarpum methanol fruit extract has promising potential as a natural remedy against AMR associated with MRSA.

This review is delving into determining the content and significance of hypericin, a pharmacologically important constituent commonly known as St. John's Wort (SJW). The paper explores the rich history of Hypericin's traditional use in alternative medicine and the recent surge in scientific interest surrounding its bioactive properties.

This review aims to provide a comprehensive analysis the therapeutic potentials of hypericin, focusing on its chemistry, extraction, sources, stability, pharmacokinetics, safety profile, and multifunctional applications in drug and medicinal fields as well as advancements in Bioengineering Approaches for Enhanced Hypericin Delivery.

We performed a non-systematic search of journals. Literature using computerized methods was conducted, utilizing databases such as Medline (PubMed), ChemSciFinder, China National Knowledge Infrastructure (CNKI) and Scirus Library. To effectively identify the most important and relevant research articles, scientific studies, clinical studies and review articles on hypericin were searched using different keywords: “Hypericum”, “traditional use”, “phytochemistry”, “pharmacology”, “drug delivery” and “bioactivity”. Thus, articles available from 1984 to 2024 were analyzed and collected. The selection process for the review primarily considered the originality of the paper and its clinical applications.

Although hypericin is not a novel compound within the research community, it is gaining renewed recognition and showing great effectiveness as a promising agent in the field of medical diagnostics and has promising applications as a therapeutic.

Here, our current comprehensive review of hypericin, its potential and its activities is intended to contribute to this ongoing process actively. Overall, this review provided theoretical direction for future hypericin research. Future studies should, therefore, focus further on the pharmacological processes, pharmacokinetics, and chemistry of hypericin and hypericin-based drug delivery systems. This comprehensive review of hypericin aims to actively contribute to ongoing research and provide a theoretical direction for future studies.

CCN6/WISP3 is a member of the CCN adipokines family that can exert multiple effects on metabolic pathways. So far, the function of CCN6 in the pathogenesis of NAFLD has not been known well. Hence, we aimed to examine CCN6 serum levels in patients with NAFLD compared to healthy individuals and its association with some risk factors for the first time.

This case-control study measured serum levels of CCN6, TNF-α, IL-6, adiponectin, and fasting insulin using ELISA kits in 88 NAFLD patients and 88 controls. In addition, other biochemical variables, including AST, ALT, lipid profiles, and FBG, were determined using an Auto analyzer instrument.

A remarkable decrease in CCN6 levels was found in the NAFLD patients (1501.9543 ± 483.414 pg/ml) compared to the healthy group (1899.4856 ± 559.704 pg/ml, P < 0.001). In NAFLD patients, a negatively notable correlation was observed between CCN6 and the levels of insulin (r = -0.278, P = 0.011), HOMA-IR (r = -0.268, P = 0.014), as well as TNF-α (r = -0.343, P = 0.001). A remarkable association was found between CCN6 and the risk factor of NAFLD in the adjusted model for gender, age, and BMI with OR = 0.867 (95% CI, [0.806-0.931], P < 0.001).

Our findings showed a significant reduction in CCN6 levels in the NAFLD patients compared to the healthy group, as well as the developing risk of NAFLD enhanced with the decrease of CCN6 levels.

6-hydroxybenzothiazole-2-carboxamide is a novel, potent, and specific monoamine oxidase B inhibitor that can be used to study the structure of molecules and come up with new ways to protect neurons.

The objective of this work was to create an effective model using derivatives of 6-hydroxybenzothiazole-2-carboxamide and establish a dependable predictive foundation for the development of neuroprotective monoamine oxidase B inhibitors for the treatment of neurodegenerative diseases.

The construction and optimization of all compounds were carried out sequentially using ChemDraw software and Sybyl-X software. The optimized compounds were further analyzed using the COMSIA approach and the Sybyl-X software tool for QSAR modeling. A set of novel compounds of 6-hydroxybenzothiazole-2-carboxamide were created and their IC50 values were forecasted using QSAR modeling. Ultimately, the recently developed compounds underwent a screening process using their IC50 values, and molecular docking tests were conducted on the ten most promising compounds with the highest IC50 values.

The 3D-QSAR model exhibited favorable outcomes. The value of q² in the COMSIA model was 0.569. The model demonstrated a superior r² value of 0.915, a lower SEE of 0.109, and a higher F-value of 52.714. The statistical findings and validation of the model were deemed adequate. Furthermore, analyzing the contour plots might assist in identifying the necessary structural specifications.

This work has the potential to provide an insight into the development of active medicines that protect the nervous system against neurodegenerative disorders.