Current Topics in Medicinal Chemistry - Online First

Skin cutaneous melanoma (SKCM) is a life-threatening malignancy, and pyroptosis-mediated inflammatory response is associated with SKCM progression. We aimed to uncover the underlying pathogenesis of SKCM based on pyroptosis features.

The single-cell and bulk RNA-seq data and clinical information of SKCM patients were downloaded from the TCGA and GEO databases, and the REACTOME_PYROPTOSIS.v2024.1.Hs.gmt from the MSigDB database was used for Gene Set Enrichment Analysis (GSEA). Differentially expressed gene (DEG) analysis was performed utilizing the “limma” R package, and the “GSVA” R package was used for the analysis of pyroptosis pathway activation. In addition, scRNA-seq analysis and cell communication analysis were carried out by employing the “Seurat” R package and “CellChat” R package, respectively. Gene expression was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR), while cell counting kit-8 (CCK-8), wound healing, and Transwell assays were carried out to assess cell proliferation, migration, and invasion, respectively.

DEGs analysis detected no significant pyroptosis-related DEGs. Analysis of the expression of two representative pyroptosis genes (GZMA and GSDMB) revealed that GZMA was significantly upregulated in the SKCM tissues, but the expression of GSDMB was downregulated. The pyroptosis pathway was not activated in the tumor group. In addition, we observed that high expression of GZMA and GSDMB was closely associated with a favorable outcome in SKCM. The two genes were downregulated in SKCM cells, while the overexpression of GZMA significantly impaired the proliferation, migration, and invasion ability of SKCM cells. Nine main cell subpopulations were identified, and GZMA was specifically overexpressed in CD8+ T cells. Gene function analysis revealed that specific genes of CD8+ T cells were enriched in cell death-related and inflammation activation pathways. Cell communication demonstrated that CD8+ T cells interacted with melanocytes through the CD99-CD99 and HLA-C-KIR2DL3 ligand-receptor pairs.

Based on the pyroptosis features in SKCM, this study found that blocking GZMA protein in CD8+ T cells within melanocytes may be the potential underlying pathogenesis for tumor immune escape in cancer.

CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms.

A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4-arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity.

The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy.

Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders.

The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.

During cerebral ischemia, brain tissue is damaged in two successive stages: ischemia and reperfusion (I/R). In the ischemic phase, brain tissue undergoes energy failure due to an impaired circulatory system (cerebrovascular), resulting in oxygen and glucose deprivation and consequent brain damage.

The study aimed to determine the effect of a two-week administration of naringin on caspase-3, IL-17, and NF-κB levels in cerebellar tissue in experimental focal brain ischemia-reperfusion in rats.

The research was conducted on 10- to 12-week-old Wistar-type rats obtained from the Selcuk University Experimental Animals Research and Application Center. Experimental brain ischemia-reperfusion in rats was performed under general anesthesia (carotid arteries were exposed to ischemia for 30 minutes). Experimental groups were formed as follows. 1) Control group, 2) Sham, 3) Sham + vehicle, 4) Ischemia-reperfusion, 5) Ischemia-reperfusion + Naringin supplemented group for two weeks (100mg/kg). At the end of the experiments, the levels of IL-17, caspase-3, and NF-κB were determined in the cerebellum tissue of the animals under general anesthesia. First of all, blood was drawn from the heart, and the animals were killed by cervical dislocation.

Experimental brain ischemia-reperfusion significantly increased caspase-3, IL-17, and NF-κB levels in the brain tissue of rats. In contrast, naringin supplementation for 2 weeks significantly suppressed the ischemia-reperfusion-induced inflammatory process.

The findings obtained from our research generally showed that, as a result of focal brain ischemia-reperfusion in rats, the levels of NF-κB, a key molecule involved in inflammatory pathways, as well as the pro-inflammatory cytokine IL-17 and caspase-3, an indicator of apoptosis, increased significantly in cerebellar tissue. However, intragastric naringin supplementation for two weeks following ischemia-reperfusion led to significant improvements in the adverse effects caused by the ischemic injury.

The study's results demonstrate that naringin treatment effectively mitigates inflammatory activation in the cerebellum following brain ischemia-reperfusion in rats.

This study explores the unbinding dynamics of alpha-ketoglutarate (AKG) from wild-type and mutant IDH1/IDH2 enzymes through steered molecular dynamics (SMD) simulations, examining how mutations influence binding, stability and enzymatic behaviour.

Isocitrate dehydrogenase (IDH) enzymes are essential for cellular metabolism, catalyzing the conversion of isocitrate to AKG in the tricarboxylic acid cycle. Mutations in IDH1 and IDH2 lead to the aberrant accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), disrupting normal metabolic processes and contributing to tumorigenesis.

SMD simulations were employed to investigate AKG unbinding from both wild-type and mutant IDH1/IDH2. External forces were applied to quantify rupture forces and assess differences in stability among enzyme variants.

Wild-type IDH1 exhibited strong and stable AKG interactions, reflected by higher rupture forces and a greater number of hydrogen bonds, consistent with its normal catalytic function. In contrast, the R132H mutation in IDH1 weakened AKG binding, facilitating dissociation and potentially promoting 2-HG formation. Among IDH2 variants, the R140Q mutant demonstrated lower binding stability compared to R172K, while the wild-type enzyme maintained stronger interactions.

Mutations in IDH1 and IDH2 disrupt AKG binding and alter the stability, which may contribute to the pathological accumulation of 2-HG. These findings provide molecular insights into the oncogenic effects of IDH mutations and may aid in the development of targeted therapeutic strategies to inhibit mutant enzyme activity in cancer.

Diabetic nephropathy is a common microvascular complication that affects 20-40% of individuals with diabetes worldwide. This study aimed to evaluate the therapeutic potential of amla fruit against streptozotocin-induced diabetic nephropathy using animal models.

The male Wistar rats procured for the study were divided into four groups randomly, G1 (negative control group), G2 (positive control group), G3 (rats receiving amla powder at 5% of their diet), and G4 (rats receiving amla powder at 7% of their diet). Diabetic nephropathy (DN) was induced using streptozotocin at a dose of 65 mg/kg. High-performance liquid chromatography (HPLC) was used to quantify the bioactive constituents of amla. Physical, glycemic, oxidative, inflammatory, and renal biomarkers were assessed periodically.

HPLC analysis confirmed the presence of high levels of vitamin C, gallic acid, and quercetin in amla. Amla supplementation significantly improved body weight, controlled kidney hypertrophy, reduced blood glucose levels, enhanced antioxidant enzyme activity such as superoxide dismutase (SOD) and catalase (CAT), and suppressed inflammatory cytokines. Renal function markers, including serum creatinine, blood urea nitrogen (BUN), and urine albumin, were significantly improved in the amla-treated groups. The 5% amla diet showed slightly superior effects compared to the 7% amla diet, although the differences were not statistically significant.

The findings suggested that amla mitigates DN progression by targeting key pathological pathways, particularly oxidative stress and inflammation. Its bioactive compounds appear to modulate glucose homeostasis, restore antioxidant defence, and reduce inflammatory responses. The findings also suggested a potential non-linear dose-response relationship, indicating 5% as a more effective dietary inclusion.

Conclusively, amla fruit effectively alleviated streptozotocin-induced diabetic nephropathy in rats by controlling oxidative stress, inflammation, and hyperglycemia.

Diabetes affects over 537 million people, with 20% developing chronic wounds. These wounds are made worse by inflammation, stress, immune problems, and poor blood vessel growth. Plants like Aloe barbadensis, Nigella sativa, and Moringa oleifera contain compounds that help heal wounds by reducing inflammation, stress, and boosting tissue growth.

This review explains why diabetic wounds heal slowly, focusing on factors like ROS, NO, and immune problems. It also looks at natural compounds that help healing and how traditional medicines can work with modern treatments for better wound care.

A systematic literature review was conducted using Scopus, Elsevier, PubMed, ScienceDirect, and Web of Science for studies published between 2000 and 2024. Inclusion criteria comprised clinical trials, preclinical studies, and ethnopharmacological research related to diabetic wound healing, pathophysiology, herbal medicine, active constituents, and mechanisms of action. Studies lacking diabetic wound specificity or methodological clarity were excluded. PRISMA guidelines were followed for study selection and synthesis.

Numerous studies demonstrated that traditional medicines enhance diabetic wound healing by regulating cytokine levels, promoting macrophage polarization, reducing oxidative damage, and remodelling the extracellular matrix. Flavonoids and polyphenols notably improved angiogenesis and tissue repair, while alkaloids and saponins exhibited antimicrobial and anti-inflammatory effects.

Traditional medicinal plants, through their diverse bioactive constituents, offer significant therapeutic potential for diabetic wound care. By targeting key molecular pathways involved in immune regulation and tissue repair, they present a viable adjunct to conventional therapies, potentially improving clinical outcomes in diabetic wound management.

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.

This study aims to discover and design β-5 tubulin-specific covalent inhibitors for non-small cell lung cancer (NSCLC) that can minimize hematotoxicity, a major side effect of current microtubule-targeting agents (MTAs).

Current microtubule-targeting drugs cause toxicities such as hematotoxicity and multidrug resistance (MDR). The colchicine binding site in β-5 has Cys-239, whereas β-1 has Ser-239, allowing selective inhibition based on the reactivity differences for covalent reactions.

β-5 and β-1 tubulin models were developed, and covalent docking and virtual screening were conducted to identify selective inhibitors targeting the β-5 tubulin colchicine binding site. Twenty hits were selected, and a comparative study was carried out between β-5 and β-1 to evaluate the selectivity and binding potential of the inhibitors.

Among the 20 identified hits, four compounds demonstrated selective inhibition of β-5 tubulin, exhibiting stronger binding affinity for β-5 over β-1 tubulin. Molecular dynamics studies further confirmed their stability and enhanced binding, highlighting their potential as promising candidates for further drug development.

The study identified four novel β-5 tubulin-specific covalent inhibitors that may act as potential therapeutic agents for NSCLC, with the possibility of reduced hematotoxicity. These findings suggest that selective inhibition could help minimize side effects, addressing a critical need in cancer treatment.

Nanomedicine is a rapidly growing field in pharmaceutical science, driven by the enhanced quality of nano-formulations that improve the treatment of various diseases. Nano-sized novel drug delivery techniques for herbal pharmaceuticals have the potential to enhance activity and address concerns related to medicinal plants in the future. Natural chemicals show promise in various neurodegenerative diseases, but their permeability across the blood-brain barrier prevents them from reaching the nervous system. By improving molecular monitoring, synthesis, and diagnostics, pharmaceutical nanotechnology provides improved controlled drug delivery for the treatment of neurodegeneration.

The evaluated and investigated data from recent studies were gathered using Google Scholar as a search engine. We reviewed and analysed research publications from databases like Bentham Science, Elsevier, PubMed, and ScienceDirect, among others, to summarize the findings.

Curcumin, Centella asiatica, thymoquinone, Hypericum perforatum, Panax ginseng, quercetin, piperine, and a variety of other herbs and herbal medicines have all been examined for their potential to aid in the treatment of brain disorders like Alzheimer's disease. To enhance drug bioavailability in the brain, nanoformulations, including phytosomes, transferosomes, ethosomes, and niosomes, have been utilized as pharmaceuticals.

Herbs and herbal medicines have been synthesized into nanoparticle form to enhance tissue distribution, achieve sustained delivery, and protect against physicochemical degradation while also increasing the solubility and bioavailability of poorly soluble herbal products. To overcome physiological complications, researchers must develop lab-scale approaches, characterization methodologies, and targeting tactics for nanoformulations with high translational potential early in product development.

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.

Breast cancer has become the most commonly diagnosed cancer worldwide and represents a major burden to public health. Advances in understanding ferroptosis pathways and identifying new therapeutic targets raise hope for using ferroptosis modulators to treat untreatable diseases.

In this study, BALB/c mice were divided into several groups: model, Doxorubicin-treated, FINO2-treated, Pirfenidone-treated, and a combined Pirfenidone + FINO2 group. After treatment, we assessed iron content in cancer cells, fibrosis area, CD34 expression, and mRNA levels of solute carrier family 7 member 11(SLC7A11) and heme oxygenase 1 (HMOX1).

Results showed that the average tumor size in the Pirfenidone + FINO2 group was significantly smaller than in the doxorubicin group. Treatments with FINO2, Pirfenidone, or their combination significantly increased iron content in cancer cells and reduced the fibrosis area. Co-treatment with FINO2 and Pirfenidone also led to notable decreases in CD34 expression and mRNA levels of SLC7A11 and HMOX1.

These findings suggest that FINO2 ferroptosis agonists, when combined with other anticancer agents like Pirfenidone, can enhance ferroptosis and reduce tumor fibrosis. Additionally, the overexpression of SLC7A11 and HMOX1 in breast cancer model mice is associated with increased tumor growth and reduced metastasis, indicating that targeting these proteins with specific inhibitors may be a promising strategy for breast cancer treatment.

Existing research has suggested that the JNK/AP-1/NF-κB/Caspase-1 pathway may account for the activation of HMC-1 mast cells under inflammatory circumstances, and our current study aims to validate whether Tomatidine could act as the candidate to modulate this pathway in Allergic Rhinitis (AR).

This study aimed to characterize the effect of Tomatidine on inflammation in C48/80-activated HMC-1 cells in vitro and to explore the underlying mechanisms involved.

The inflammation in HMC-1 cells was triggered via C48/80 induction to mimic the AR, and the effects of Tomatidine on the viability of HMC-1 cells were tested using the Cell Counting Kit-8 assay. Thereafter, the concentrations of inflammation-related cytokines, Interleukin-1β, tumor necrosis factor-α, as well as the histamine and β-hexosaminidase, were quantified by enzyme-linked immunosorbent assay. The activation status of the JNK/AP-1/NF-κB/Caspase-1 pathway in HMC-1 cells following C48/80 and/or Tomatidine intervention was determined based on immunoblotting assay.

The viability was elevated in HMC-1 cells following C48/80-induced activation, and the concentration of inflammation-related cytokines and mediators was increased as well. Meanwhile, the protein levels of active Caspase-1 and the phosphorylation of JNK/AP-1/NF-κB/Caspase-1 pathway-related proteins were also observed in HMC-1 cells after the treatment of C48/80. On the contrary, Tomatidine intervention suppressed the viability and the concentration of inflammation-related cytokines and mediators of modeled HMC-1 cells and led to the inactivation of the JNK/AP-1/NF-κB/Caspase-1 pathway in modeled HMC-1 cells.

Our study demonstrates that Tomatidine can attenuate C48/80-induced inflammatory responses in HMC-1 cells in vitro, potentially through modulation of the JNK/AP-1/NF-κB/Caspase-1 signaling pathway. These findings provide preliminary evidence supporting Tomatidine as a candidate for further investigation in allergic inflammation.

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.