Current Topics in Medicinal Chemistry - Online First

The goal of this study is to provide a comprehensive review of physicochemical and pharmacological properties, including pharmacokinetics and pharmacodynamics parameters, with an overview of preclinical and clinical trial data, chemistry, and multiple routes of synthesis, bioanalytical methods, and patents of the API: Vadadustat

A review was conducted by compiling data from Science Direct, PubMed, Drug Bank, WIPO patent, Clinicaltrialgov, Wolters Kluwer, and many others to enhance understanding of the topic

The FDA approved Vadadustat on March 27, 2024, for treating anemia in adults with CKD on dialysis. Vadadustat effectively increased hemoglobin levels in both non-dialysis and dialysis-dependent CKD patients. It showed comparable efficacy to traditional erythropoiesis-stimulating agents (ESAs) like darbepoetin alfa. Multiple clinical trials, including Phase 2 and Phase 3 studies, demonstrated Vadadustat’s potential as an effective treatment for anemia in CKD patients.

Vadadustat, as an oral HIF-PH inhibitor, offers significant advantages in the treatment of anemia in CKD. Its oral route of administration improves patient compliance, and its efficacy is comparable to ESAs. Clinical and preclinical data support its safety and therapeutic potential, although long-term cardiovascular effects remain under observation.

This review examines therapeutic, pharmacological, analytical, and regulatory aspects related to Vadadustat.

The limitations of conventional drug delivery methods, such as systemic side effects and poor absorption, highlight the need for safer and more effective alternatives. Polysaccharides, due to their biocompatible, biodegradable, and mucoadhesive properties, have shown promise in formulations for the oral cavity, particularly in localized delivery systems and tissue regeneration. This study aims to conduct a bibliometric analysis to characterize the scientific output on the use of polysaccharides in the oral cavity, identifying trends, international collaborations, and research gaps.

A Web of Science search was conducted in January 2025 using keywords related to polysaccharides and mucosal adhesion. The analysis included original articles published in English between 2015 and 2024. Bibliometric data and study characteristics were extracted and analyzed, focusing on study types, formulation types, and international collaborations.

The analysis included 66 articles with 1144 citations. In vitro studies were predominant, while clinical trials were lacking. Chitosan and alginate emerged as the most commonly used polysaccharides, with gels and hydrogels being the most prevalent formulations. International collaborations involved 28 countries, with China, Brazil, and Italy standing out in terms of scientific production.

The results highlight important advancements in the use of polysaccharides for oral cavity formulations, particularly in gels and hydrogels. However, the predominance of in vitro studies and the lack of clinical trials suggest limitations for translating these findings into clinical practice. The strong performance of countries such as China, Brazil, Italy, Spain, and Norway underscores the relevance of international collaborations and the global potential of this topic.

The increasing scientific output reflects the growing interest in the use of polysaccharides for oral health applications. Despite these advancements, critical gaps remain, such as the lack of clinical studies. Future research should prioritize translational studies, personalized therapies, and the sustainable development of biomaterials.

Cancer remains a devastating global health burden. Despite the identification of numerous biological targets, effective therapeutic agents remain limited. As a highly promising novel target, the role of Discoid Domain Receptors (DDRs) in pan-cancer biology is still poorly characterized. Thus, this study aims to elucidate the regulatory mechanisms and diagnostic potential of DDR1 across different cancer types.

Herein, we used UCSC, SangerBox, GEPIA, GSCA, and GeneMANIA online databases to analyze the expression and role of DDR1 in pan-cancer.

The expression levels of DDR1 showed significant differences in some tumour T, N, and M stages. Importantly, DDR1 expression was associated with clinical prognosis in five cancers. In addition, DDR1 was inversely correlated with most immune checkpoint pathways, immunomodulatory genes, and immune cell infiltration in a few cancers. Furthermore, in most cancers, DDR1 promotes cancer progression by promoting apoptosis, inhibiting cell cycle and EMT, activating hormone AR activity, activating PI3K/AKT pathway, RASMAPK pathway, and RTK pathway. Finally, we also found that the DDR1 gene was positively associated with stemness scores in most tumors.

Our findings demonstrate that DDR1 exhibits diagnostic utility and holds promising translational potential as a therapeutic target across multiple cancer types.

Many metabolic diseases, such as Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), are largely caused by obesity, a complicated ailment characterized by excessive fat buildup. By 2030, obesity is expected to have increased in prevalence, affecting over 1 billion people worldwide. MASLD, formerly known as NAFLD, is a broad category of liver illnesses caused by metabolic dysfunction and frequently linked to obesity. Drugs are available for obesity, but long-term use causes serious adverse effects, as reported. Currently, there are no FDA-approved therapies for MASLD. Interest in marine animals and their metabolites for their potential as therapeutics is growing, given the shortcomings of traditional medicines. This review emphasizes different marine species and metabolites, and macromolecules and tabulates all the pre-clinical studies targeting obesity and MASLD.

For this review, the authors have gone through a vast number of article sources from different scientific databases like PubMed, Google Scholar and ScienceDirect.

Algae, fungi, and bacteria found in the ocean are abundant in bioactive chemicals that have anti-obesity and anti-MASLD properties. A variety of studies have reported the anti-obesity and anti-MASLD effects of marine species such as Spirulina platensis, Chlorella vulgaris, Caulerpa okamurae, and bioactive macromolecules like dieckol, fucosterol, fucoxanthin, sodium alginate and paramylon.

These marine-derived substances have a variety of pharmacological characteristics, including lipid-modulating, anti-adipogenic, antioxidant, and anti-inflammatory activities. These qualities are crucial for treating the underlying mechanisms that underlie obesity and MASLD. These marine species may be useful as natural supplements or therapeutic agents in the management and treatment of metabolic diseases associated with obesity. Some of these bioactive phytoconstituents have been identified for their potential against obesity and MASLD; however, more investigation is necessary to identify the precise bioactive substances causing these advantageous effects and assess their safety and effectiveness in clinical trials.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. M1 macrophages exhibit dual roles in the tumor microenvironment (TME), but the specific mechanisms underlying their involvement in HCC remain unclear.

M1-polarized macrophages were differentiated from THP-1 monocytes employing Phorbol 12-Myristate 13-Acetate (PMA) and lipopolysaccharide (LPS). Then, macrophage activity was determined based on Mean Fluorescence Intensity (MFI), and their metabolic capacity was assessed according to extracellular acidification rate (ECAR) and Oxygen Consumption Rate (OCR). Quantitative Real-Time PCR (qRT-PCR) was performed to assess the expression of polarization-related genes.

The results showed that LPS at a concentration higher than 10 ng/mL significantly affected the viability of macrophages differentiated from THP-1 monocytes but promoted the MFI of CD86. At the same time, LPS treatment notably enhanced the M1 polarization of macrophages, as evidenced by the upregulated expression of markers related to the M1 phenotype. Moreover, the mitochondrial oxidative metabolism of M1 macrophages shifted toward aerobic glycolysis under LPS treatment. When T-cells and HCC cells were co-cultured with M1 macrophages, the reactivity of T cells was enhanced, and the level of Bax (an apoptosis-enhancer) was increased. At the same time, the expression of Bcl-2 (an apoptosis-suppressor) was suppressed.

LPS-induced M1 macrophages exert antitumor effects through metabolic reprogramming and immune modulation, though further mechanistic studies are needed.

M1 macrophages inhibit HCC progression by activating T cells and inducing tumor cell apoptosis, offering novel insights for HCC immunotherapy.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are one of the most widely prescribed medications in the world, yet their applications as anti-inflammatory, analgesic, and anti-pyretic drugs remain principally restricted by their detrimental effects on the gastrointestinal tract (GIT) systems. The prodrug approaches have substantially combated the drawbacks of currently available marketed NSAIDs and also showed increased activity.

In the present study, an extensive literature review on mutual prodrugs of NSAIDs with natural antioxidants has been presented.

Different databases like ScienceDirect, Elsevier, PubMed, Google Scholar, etc. were used for an extensive search of articles related to NSAIDs, prodrug concepts, as well as research based on all of the NSAIDs-prodrug molecules prepared to date.

Recent developments in prodrug design have been explored that utilize naturally occurring antioxidants, including Thymol, Guaiacol, Menthol, Eugenol, Sesamol, Vanillin, and Umbelliferon, for the synthesis of mutual prodrugs by esterification methods. Many studies have shown that these prodrugs have significant stability in acidic pH while hydrolyzing in neutral and alkaline pH environments. This indicates their potential as advantageous therapeutic agents with enhanced safety profiles.

The mutual prodrug strategy offers a chance in medicinal chemistry to enhance the therapeutic and clinical efficiency of a drug that has certain unfavorable qualities that limit its clinical utility. This review enlightens mutual prodrugs of NSAIDs and antioxidants that are less harmful and beneficial to mankind, respectively.

Myocyte enhancer factor 2C (MEF2C) is a pivotal transcription factor that is responsible for maintaining myocyte differentiation. MEF2C is multifunctional, participating in diverse biological processes, including cardiac morphogenesis, angiogenesis, neurogenesis, and cortical development. Emerging evidence has identified MEF2C as a novel oncogene with dual regulatory functions in tumorigenesis. However, the mechanisms by which MEF2C regulates the progression of various malignant tumors are unknown. Therefore, it is crucial to further investigate the multiple signaling pathways under different expression levels of MEF2C. In this review, the expression level of MEF2C in various malignant tumors and its specific pathways are described.

This review systematically summarizes and critically analyzes the current studies on MEF2C’s biological function in malignant tumors by comprehensively searching them in PubMed databases.

MEF2C demonstrates aberrant expression patterns across multiple tumor types, spanning both solid tumors (e.g., glioma, breast cancer, hepatocellular carcinoma) and hematological malignancies (e.g., leukemia). MEF2C orchestrates multiple oncogenic processes, including tumor cell proliferation, migration, and invasion, while also modulating cancer drug resistance and systemic manifestations, like cachexia and apoptosis resistance.

Given its multifaceted roles in tumor initiation, progression, and clinical aspects, MEF2C has the potential to serve as both a diagnostic biomarker and a therapeutic target for various malignancies.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent of renal cancers, with a 5-year survival rate of less than 10% for metastatic cases. The most efficient current strategies to treat ccRCC in advanced settings slightly increase progression-free survival. Chimeric antigen receptor T cells (CAR T cells) targeting carbonic anhydrase IX (CAIX) have reemerged as a promising alternative to ccRCC treatment based on recent preclinical data. CAIX and cyclooxygenase-2 (COX-2) are key players in tumor progression across various malignancies, overexpressed in 95% and 50% of ccRCC cases, respectively.

This study employed in silico analysis to examine the expression of CAIX and COX-2 in ccRCC cell lines. The effects of celecoxib, anti-CAIX monoclonal antibodies, and anti-CAIX CAR T cells were evaluated using immunofluorescence microscopy and flow cytometry techniques.

Herein, we show a positive correlation between CAIX and COX-2 expression in ccRCC cell lines in vitro and in silico. Notably, COX-2 blockade with celecoxib led to a significant downregulation of CAIX expression in ccRCC cell lines. This effect is retroactive since treatment of these ccRCC cells with two different anti-CAIX monoclonal antibodies (mAbs) resulted in the downregulation of COX-2 expression. The association of celecoxib with anti-CAIX CAR T cell therapy impaired their cytotoxic potential over ccRCC in vitro, depending on CAIX cellular density.

These findings suggest a regulatory interaction between CAIX and COX-2 levels, indicating that COX-2 inhibitors may diminish the efficacy of CAIX-targeted therapies and should be avoided in combination treatments.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by the impaired utilization of glucose, insulin resistance, or reduced insulin production. Although conventional pharmacologic agents like metformin, sulfonylureas, and thiazolidinediones are effective in regulating elevated blood glucose levels, they are often associated with some adverse effects, such as weight gain and liver problems.

The present review summarizes the possibility of using phytochemicals as safer alternatives for the management of DM by modulation of molecular receptors.

Several studies have reported that certain antioxidant phytochemicals exhibit inhibitory effects on key signaling pathways involved in glucose metabolism and insulin sensitivity under in vitro conditions. Therefore, this review will focus on the therapeutic potential of phytochemicals in modulating molecular targets, such as PPARs, GPR119, free fatty acid (FFA) receptors, glucocorticoid receptors, and others. For this purpose, a systematic and extensive literature search was carried out to obtain relevant data, focusing on the prospect of phytochemicals in modulating molecular receptors for diabetes mellitus (DM) management. Electronic databases, including PubMed, Scopus, ScienceDirect, and Google Scholar, were accessed for articles up to March 2025.

Curcumin, resveratrol, and quercetin are bioactive molecules that increase the sensitivity of the body to insulin and protect the pancreatic β-cells from oxidative stress. Natural agents, such as garlic, green tea, and blackcurrants, possess an antidiabetic action by inhibiting enzymes, such as α-glucosidase, and increasing the uptake of glucose. The co-administration of synthetic drugs along with natural agents has a synergistic effect in improving glycemic control with fewer side effects. Examples include resveratrol with metformin or curcumin with thiazolidinediones.

The findings of this review should be validated at the clinical level in future research studies, including toxicity profiling and formulation optimization, to maximize the therapeutic potential of phytochemicals in the management of DM.

Cancer continues to be a significant public health issue and one of the leading causes of death globally. In this context, developing new, potent, and more specific treatments against this disease is urgent.

A total of 15 benzoxathiolone-thiazolidinones hybrids were synthesized in a 5-step route and tested for their cytotoxicity against five human cancer cell lines: AGP-01 (gastric), SKMEL-103 (melanoma), HCT-116 (colon), CAL27 (tongue), and K562 (leukemia), as well as a non-tumoral cell line MRC-5.

Compounds 3-(6-hydroxy-2-oxobenzo[d][1,3]oxathiol-5-yl)-2-(4-nitrophenyl)thiazolidin-4-one and 2-(2,4-dichlorophenyl)-3-(6-hydroxy-2-oxobenzo[d][1,3]oxathiol-5-yl)thiazolidin-4-one exhibited good activity against the K562 leukemia cell line, with IC50 values of 4.0 μM and 5.3 μM, respectively. Docking studies demonstrated that these compounds likely bind to the BCR-ABL1 kinase, a key protein in the pathogenesis of chronic myeloid leukemia (CML).

The study suggests these benzoxathiolone-thiazolidinone hybrids could be promising lead compounds for developing new anticancer agents targeting leukemia.

Although E. coli is considered a normal human microbiota, it may cause life-threatening infections such as septicemia, urinary tract infections, and enteric infections. Moreover, multidrug-resistant strains are a serious challenge in the clinic due to high mortality rates and the limited number of therapeutic options. Hence, the current study aimed to benefit from pink rose petals as a source of green synthesis of copper nanoparticles (Cu-NPs), to investigate the antibacterial features against multidrug-resistant E. coli, and to measure the cytotoxicity of Cu-NPs.

Pink rose petals were used as a reducing agent for Cu-NP synthesis, and then XRD, zeta potential, UV-Vis, FTIR, SEM, and DLS analyses were performed to characterize the synthesized NPs. Moreover, the MIC and zone of inhibition values of Cu-NPs were measured and compared to common antibiotics. Additionally, the MTT assay was performed to assess the cytotoxicity.

The green synthesized Cu-NPs were spherical and uniform with a size of ~200 nm. The MIC of Cu-NPs was 1024 μg/ml on the MDR strain of E. coli, representing the antibacterial activity comparable to levofloxacin (p-value>0.05) but less than imipenem and trimethoprim (p-value<0.001). Moreover, the CC50 of synthesized Cu-NPs was 731.2 μg/ml and significantly lower than the studied antibiotics (p-value<0.001).

The findings may suggest Cu-NPs as a promising antibacterial strategy against MDR strains of E. coli, however, further studies are encouraged to clarify the safety of optimized doses.

Genistein, a natural isoflavonoid found predominantly in legumes and soy-based foods, has garnered significant attention due to its multifaceted mechanisms and potential therapeutic applications. Chemically, genistein is a 4',5,7-Trihydroxyisoflavone having a molecular formula of C15H10O5, which enables its interactions with diverse biological targets.

The main objective of this review is to summarize the pharmacological effects of genistein, elucidating its potential mechanisms of action. Furthermore, the review emphasizes genistein's impact on human health when used as a dietary supplement.

The authors have gone through a vast number of article sources from various scientific databases like Google Scholar, PubMed and Web of Science.

Genistein exhibits antioxidant properties by countering free radicals and reducing lipid peroxidation. Genistein's anti-inflammatory effects involve inhibiting proinflammatory pathways and cytokine production. Notably, it shows anticancer potential against various malignancies by promoting apoptosis, inhibiting angiogenesis, and hindering metastasis. Moreover, genistein has antidiabetic properties, enhancing insulin secretion, protecting β-cells, and improving glucose tolerance. Its antiviral and antibacterial actions contribute to inhibiting pathogen growth and viral replication. Genistein accelerates wound healing by minimizing oxidative stress, facilitating re-epithelialization, and suppressing inflammation. Its potential in peptic ulcer treatment is supported by anti-inflammatory and antioxidant effects. Hepatoprotective activities include inhibiting lipid peroxidation, bolstering antioxidant defences, and modulating metabolic enzymes. Furthermore, genistein positively impacts the immune response, influencing cytokine levels, lymphocyte proliferation, and interferon production.

Genistein's multifaceted pharmacological activities render it a promising dietary supplement with implications for diverse health conditions, warranting further comprehensive research to optimize its clinical utility.

The dihydroorotate dehydrogenase (DHODH) enzyme plays a crucial role in the de novo pyrimidine biosynthesis pathway, catalysing the conversion of dihydroorotate to orotate in the cells. This pathway is important for the synthesis of nucleic acids and vital molecules essential for homeostasis, cellular functioning, and survival. So, targeting this enzyme can be an effective approach for the treatment of cancer, arthritis, malaria, viral or microbial infections, and other autoimmune diseases.

In this review, we have highlighted the therapeutic implications of DHODH inhibition in cancer, rheumatoid arthritis and multiple sclerosis through an extensive literature survey from various scientific databases like PubMed, Google Scholar, Science Direct, Embase, clinical trials.gov.in, Google Patents, etc.

We have tried to identify the pharmacophores from synthetic, phytochemical, and microbial origins, effective as DHODH inhibitors. The effect of structural changes on activity has been summarised, providing insights into the efficacy and mechanisms of these inhibitors at the molecular level. Furthermore, this review also presents a comprehensive analysis of clinical trials and patents related to DHODH inhibition to extract the valuable information to be used for clinical drug development in cancer, rheumatoid arthritis, and multiple sclerosis.

By integrating data from synthetic, plant, and microbial sources, along with clinical trial and patent outcomes, this review highlights the diverse role of DHODH. Its inhibition offers a more targeted approach to reduce the proliferation of rapidly dividing cells while sparing normal cells, modulating specific immune responses. But, limiting understanding of resistance mechanisms and potential for toxicity are the current challenges. It offers a roadmap for future research and drug discovery endeavours focused on harnessing the beneficial potential of DHODH inhibition, including the development of novel inhibitors with improved selectivity and pharmacokinetics across a wide array of pathological conditions.

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.

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).