Search Results (529)

The present study aimed to design, synthesize, and evaluate a new series of thieno[3,2-d]pyrimidin-4(3H)-one-based Schiff bases as potential antileishmanial agents against Leishmania major (L. major). A series of twenty thieno[3,2-d]pyrimidine Schiff base derivatives were synthesized and characterized using FTIR, NMR, and HRMS techniques. Their antipromastigote activities were evaluated in vitro against L. major, while cytotoxic effects were assessed on HUVECs to determine selectivity indices. The most active compound was further investigated using molecular docking against several L. major proteins. Among the tested compounds, compound 12, bearing a 2-hydroxy-5-bromophenyl moiety, exhibited the most potent activity against L. major promastigotes with an IC₅₀ value of 13.7 µM, along with a favorable selectivity index (SI = 17.5), outperforming the reference drug miltefosine (IC₅₀ = 31 µM and SI = 0.2). Docking studies demonstrated that compound 12 showed the strongest binding affinity toward phosphodiesterase B1, supported by a docking score of −9.042 kcal/mol and an MM-GBSA value of −67.21 kcal/mol. This study highlights thieno[3,2-d]pyrimidin-4(3H)-one as a promising scaffold in the context of in vitro antileishmanial screening and suggests the role of ortho-phenolic substitution in enhancing activity and selectivity. Compound 12 emerges as a promising lead, warranting further optimization and biological evaluation in future studies. Full article

Background/Objectives: Diabetes mellitus (DM) is a critical metabolic condition with escalated blood glucose levels caused by insulin resistance, restricted insulin production, and the activity of alpha-amylase and alpha-glucosidase enzymes. Methods: This current work focuses on the synthesis and evaluation of novel Pyrimidine-derived pyrazole-based thiadiazole derivatives to target DM by inhibiting α-amylase and α-glucosidase. Results: The findings exhibited that, except for three compounds, all other synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC₅₀ values ranging from 5.17 μM to 29.84 μM on α-amylase and 7.60 μM to 31.62 μM on α-glucosidase, in comparison to the standard drug Acarbose (α-amylase IC₅₀ = 8.25 ± 0.80 μM; α-glucosidase IC₅₀ = 10.75 ± 1.10 μM). Analogs 8g, 8k, and 8b displayed superior or comparable inhibitory activity compared to the reference drug Acarbose. The inhibition potential of the derivatives can be attributed to their stable contacts with crucial amino acid residues of targeted enzymes, as shown through molecular docking analysis. Moreover, DFT-calculated HOMO–LUMO parameters and electrostatic potential (ESP) maps were used to gain complementary insight into the electronic characteristics, charge distribution, and potential interaction behavior of the synthesized derivatives, which supported the molecular docking observations. Conclusions: Experimental outcomes and in silico support display that these derivatives serve as potential leads for anti-diabetic drug development. These potent pyrimidine-derived pyrazole-based thiadiazole derivatives were comparable to an existing diabetic mellitus inhibitor, specifying potential for further therapeutic development and optimization against diabetic mellitus. Full article

A series of substituted pyrrolo[2,3-d]pyrimidines was designed, synthesized, and evaluated in vitro against two protozoan parasites: Plasmodium falciparum and Trypanosoma brucei brucei. Pharmacological studies revealed antiprotozoal activity with IC₅₀ values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new compounds was assessed using human HepG2 cells. Among them, the pyrrolopyrimidine derivative 1d emerged as the most potent antimalarial compound, exhibiting a selectivity index (SI) of 600.81 against the P. falciparum chloroquine-resistant W2 strain. For the chloroquine-sensitive 3D7 strain, the most notable selectivity index (SI) was observed for pyrrolo[2,3-d]pyrimidine 1c, with a value of approximately 123. Furthermore, compound 1b demonstrated the most interesting activity against Trypanosoma brucei brucei, with an SI of 39.52, marking it as a promising trypanocidal agent. FRET melting assays confirmed that these nitrogen-containing heterocyclic compounds bind to telomeric G-quadruplexes in P. falciparum and Trypanosoma. However, no clear correlation was found between G-quadruplex binding and antiparasitic activity or selectivity, suggesting that G-quadruplex targeting is unlikely to be the main mechanism underlying cytotoxicity. Full article

Severe cutaneous adverse reactions (SCARs) are rare, life-threatening drug hypersensitivity syndromes. Although pharmacovigilance can identify drugs disproportionately reported with SCARs, it does not reveal which local chemistries recur among them. To address this, we assessed whether drugs with FAERS-derived SCAR disproportionality signals share interpretable chemical motifs. We screened FAERS data from 2004Q1 to 2024Q3, identified 5523 drugs with available Simplified Molecular-Input Line-Entry System (SMILES) representations, and constructed a signal-enriched dataset of 1676 compounds with nominally significant broad-SCAR associations after excluding predefined therapeutic/supportive confounders. Compounds were assigned to positive-signal [natural logarithm of reporting odds ratio (lnROR) > 0, n = 1219] or non-positive-signal (lnROR ≤ 0, n = 457) classes and encoded with 9753 explicitly mappable atom-centered local substructure descriptors. A LightGBM signal-classification model evaluated using random repeated nested cross-validation (six-fold outer × 50 repeats) achieved moderate internal discrimination (mean area under the receiver operating characteristic curve = 0.7041 ± 0.0337). Descriptor-space cluster-based repeated nested cross-validation, designed to reduce train–test structural leakage, yielded lower but still above-chance performance (mean ROC AUC = 0.6409; permutation p = 0.001), indicating that random-split estimates should be interpreted as optimistic for structurally novel compounds. Sensitivity analyses using minimum SCAR case-count thresholds and retention of predefined therapeutic/supportive drugs showed broadly similar performance and motif rankings. SHapley Additive exPlanations (SHAP) analysis revealed a fragment-level contrast: allylamine-like, ethanolamine-related, and diaminopropane-related motifs were associated with higher positive-signal class probability, whereas phenol and pyrimidine motifs were associated with lower positive-signal class probability. These findings suggest that FAERS-derived broad-SCAR signal direction is not chemically random within the selected dataset. Overall, the proposed framework should be viewed not as a direct predictor of absolute clinical SCAR risk but as an exploratory, pharmacovigilance-driven cheminformatics approach for prioritizing compounds and motif families for further SCAR-focused evaluation. Full article

The gut microbiota plays a crucial role in regulating fish growth. In this study, we performed 16S rRNA sequencing and metabolomics to compare the gut microbiota and metabolic profiles of fast-growing (FG) and slow-growing (SG) brass gudgeon (Coreius heterodon) from the same family, reared under identical conditions for 12 months. Our results revealed that there was no significant difference in the overall gut microbiota structure between FG and SG groups, but significant differences were observed at specific phylum and genus levels. The FG group harbored a greater abundance of potential probiotics (e.g., Prevotella, Lactobacillus, and Lachnospiraceae NK4A136_group), while opportunistic pathogens such as Klebsiella and Pseudomonas were less abundant. Metabolomics analysis identified 136 differential metabolites, among them, 61 were upregulated and 75 were downregulated in the FG group, with higher levels of phosphatidylcholine, acylcarnitine, and amino acid derivatives in the FG group. KEGG pathway analysis showed enrichment of butanoate metabolism, tryptophan metabolism, and pyrimidine metabolism in the FG group. Spearman correlation analysis indicated that specific gut microbiota was significantly correlated with metabolites involved in energy metabolism, gut homeostasis, and oxidative balance. These findings revealed associations between specific gut microbiota, gut metabolites, and growth performance in brass gudgeon. Although overall community structure did not differ significantly between groups, the compositional and metabolic shifts observed suggest that the gut microbiota–metabolite association might be linked to growth variation. This study provided new insights into the microbiota–metabolite–growth axis of brass gudgeon and offers valuable reference information for the development of specialized probiotic feeds for this species. Full article

Background: Cancer is a leading cause of mortality worldwide. Discovery of small molecules as anticancer agents is an active area of research, as these molecules possess the remarkable ability to interact with specific targets within cancer cells. Objectives: In vitro anticancer activity of six hit derivatives from a series of 2-phenyl-substituted 4-amino–6, 7-dihydro-5H-cyclopenta[d]pyrimidines was tested against human cancer cell lines, viz., A549 (human lung cancer) and A431 (human skin cancer). Methods: Cytotoxicity was evaluated for six hits by the standard MTT assay. Further, their effect on clonogenic potential and cell cycle was tested using colony forming assay and flow cytometric analysis, respectively. Apoptosis-inducing potential was confirmed using Caspase-3/7 Glo assay and detection of cleaved caspase-3 by immunofluorescence. The effect on cell migration was tested using a wound healing assay. Target analysis, Molecular docking and ADMET simulations were performed to identify molecular targets, interactions and assess pharmacokinetic profiles. Results: Specific derivatives showed good to moderate cytotoxicity against A549 and A431 (with average IC50 in the range of ~30 µM), and these hits led to apoptosis and G1 arrest in these cell lines, respectively. Furthermore, identified hits inhibited cell migration in A549 cells. Computational consensus target analysis identified EGFR and CDK2 as high-confidence targets. Docking studies indicated favorable interactions and stability, whereas the ADMET analysis confirmed the drug-likeness and optimal pharmacokinetic and safety profiles of the small molecules. Conclusions: Our current study demonstrates the anticancer potential of novel pyrimidine derivatives. We envisage the use of these small molecules as promising anticancer agents, particularly in skin and non-small cell lung cancer. Full article

Porcine epidemic diarrhea virus (PEDV) is the pathogen responsible for porcine epidemic diarrhea, causing significant economic losses to the swine industry. During the replication of PEDV, the genome mutates rapidly, making the effectiveness of commercial vaccines uncertain when facing newly emerging prevalent variants. More importantly, there are currently no safe and effective specific antiviral drugs available. YT1418, a pyrido[1,2-c]pyrimidin-1-one (PPO) compound, exhibited anti-PEDV activity in a previous study. To expand the chemical space of the PPO scaffold and clarify the influence of substituents at different positions on the antiviral activity of the compounds, 36 new compounds were designed and synthesized, and then their abilities to inhibit viral replication in a PEDV-infected cell model were evaluated. Furthermore, the hepatic microsomal metabolic stabilities of compounds with potent antiviral activity were assessed. The results showed that compounds N1 and N2 exhibited antiviral activity (EC₅₀ = 0.32, 0.37 μM, respectively) superior to that of YT1418, with selective index values of 43.78 and 42.89, respectively. Meanwhile, compound J4 demonstrated good hepatic microsomal stability and low cytotoxicity, which requires further investigation. This study identified lead compounds featuring a novel PPO core and established their structure–activity relationships, providing important insights for the development of anti-PEDV drugs. Full article

Pyrrolo[2,3-d]pyrimidine is a privileged fused heterocyclic scaffold that has attracted considerable attention in medicinal chemistry due to its diverse biological activities. Herein, we report an efficient synthesis strategy for the preparation of the pyrrolo[2,3-d]pyrimidine-based natural toyocamycin aglycone and pyrrolo[2,3-d]pyrimidine derivatives. The synthesis of toyocamycin aglycone features a key benzylamine nucleophilic substitution followed by a palladium-catalyzed cyanation reaction. From a key intermediate derived from this route, nineteen new pyrrolo[2,3-d]pyrimidine derivatives were rapidly synthesized via key Suzuki–Miyaura coupling and amine nucleophilic substitution reactions. Their cytotoxic activities were evaluated against Huh-7 and HepG liver cancer cell lines. Most derivatives were inactive after 24 h. However, 28a–28c, 28e and 28f exhibited moderate cytotoxicity with IC₅₀ values ranging from 5.7 to 62.6 μM. Among them, compound 28e displayed the highest potency against HepG cells, with IC₅₀ values of 5.7 μM. Compared with normal HEK293 cells, it showed a selectivity index (SI) of 3.60 against HepG cells. Preliminary structure-activity relationship analysis suggested that incorporation of a cyclopropyl group further improves antitumor activity. Full article

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson’s disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14–C15, and C17 positions. Systematic structure–activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC₅₀ = 4.18 μM), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP⁺-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD. Full article

Castanopsis hystrix (C. hystrix) is one of the most dominant and ecologically important species in subtropical evergreen broad-leaved forests of China. Interactions between its root and rhizosphere microorganisms play a pivotal role in nutrient acquisition and in mediating plant response s to environmental stresses. In this study, high-throughput 16S ribosomal RNA (16S rRNA) sequencing combined with untargeted metabolomics was employed to systematically characterize the rhizosphere microbial community and root exudates in C. hystrix. The results showed that, compared with non-rhizosphere soil, bacterial diversity in the rhizosphere of C. hystrix was significantly reduced, while several specialized and potentially efficient taxa were selectively enriched, particularly Candidatus_Solibacter, Candidatus_Xiphinematobacter, and Candidatus_Koribacter, thereby reshaping a distinct rhizosphere-specific community structure. Metabolomic analyses further revealed that 129 metabolites were significantly enriched in the rhizosphere, including four major classes of compounds associated with plant stress resistance: lipids and lipid-like molecules, organoheterocyclic compounds, organic acids and derivatives, and phenylpropanoids and polyketides. The enrichment of these metabolites likely contributes substantially to stress tolerance in C. hystrix. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified six defense-related metabolic pathways, including pyrimidine metabolism, steroid biosynthesis, nucleotide metabolism, plant hormone signal transduction, ATP-binding cassette transporter (ABC transporters), and the biosynthesis of various plant secondary metabolites. Further correlation analysis and co-occurrence network analysis suggested that C. hystrix may potentially influence the enrichment of beneficial microorganisms through rhizosphere metabolites selectively, which could reduce the reliance on external nutrient acquisition and enhance the stress resilience of C. hystrix. Our study provides a comprehensive perspective for elucidating rhizosphere interaction networks and their ecological functions in C. hystrix, thereby enhancing our understanding of the environmental adaptability of dominant tree species in subtropical forests. Full article

Immunosuppression is associated with impaired immune responses and increased susceptibility to disease, highlighting the need for safe and effective immunomodulatory strategies. Oligosaccharides derived from natural sources have attracted growing interest due to their bioactivity and regulatory effects on host immunity. The present study was designed to evaluate the immune-enhancing potential of Periplaneta americana oligosaccharides (PAOSs) and to explore their association with SCFA-producing gut microbiota and metabolic regulation in an immunosuppressed mouse model. PAOS administration significantly increased serum immunoglobulin levels (IgG and IgM), promoted the secretion of immunoregulatory cytokines (IFN-γ, IL-2, TNF-α, IL-10, and IL-4), and elevated the proportion of CD4⁺ T cells in the spleen. In addition, PAOSs alleviated oxidative stress by reducing malondialdehyde accumulation while promoting the activity of key antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase. Metabolomic analysis revealed that PAOSs altered host metabolic profiles, particularly enhancing pyrimidine metabolism. Furthermore, PAOSs markedly enriched short-chain fatty acid (SCFA)-producing bacteria, and elevated colonic short-chain fatty acid levels. These changes were closely associated with the observed improvement in immune function. Collectively, this study demonstrated that PAOSs exerted immunomodulatory effects through coordinated regulation of SCFA-producing gut microbiota and host metabolism, elucidating the mechanisms underlying the bioactivity of insect-derived oligosaccharides. Full article

Background: Glutaric aciduria type-1 (GA-1) is a genetic disorder caused by glutaryl-coenzyme A dehydrogenase deficiency, leading to the accumulation of glutaryl-CoA and its derivatives. Clinical manifestations include neurological abnormalities; however, the underlying pathological mechanisms remain unclear. Early diagnosis and intervention are crucial for minimizing adverse outcomes. To date, diagnostic methods have certain limitations, and there is a critical need for a sensitive biomarker for diagnosis. We aimed to characterize metabolic dysregulation and identify candidate biomarkers associated with GA-1 in biochemically confirmed patients compared to age- and sex-matched control subjects. Methodology: Untargeted metabolomics profiling of GA-1 patients (n = 29) was compared to matched control subjects by age and sex. Multivariate and univariate statistical analyses were performed to identify dysregulated metabolites. Results: Our findings revealed 220 endogenous human metabolites. Notably, there was a strong enrichment in carboxylic acids and derivatives, including amino acids and derivatives, hydroxy and keto acids, fatty acyls, sphingolipids, phosphatidylcholines, and nucleotides and nucleosides. Pathway analysis indicates alterations in the biosynthesis of cardiolipin and phosphatidylcholine, as well as in pyrimidine metabolism, the urea cycle, and amino sugar metabolism. We demonstrated a robust performance model for 6-Methylnonanoyl-CoA, displaying strong discriminative power. Conclusions: We identified broad dysregulation across various biochemical classes, reflecting an imbalance in energy metabolism that involves carbohydrate and lipid pathways. The results also highlight dysregulation in sphingolipids, phospholipids, and nucleotide metabolism. These findings are preliminary and the clinical relevance of these findings in patients with GA-1 requires further investigation. We identified candidate biomarkers capable of distinguishing GA-1 patients from controls; however, these findings require validation in independent cohorts. Full article

The N-ferrocenoylation of uracil was studied to evaluate regioselectivity and optimise preparation protocols. Regioselectivity was monitored under various reaction conditions, with particular attention paid to the effects of the solvent and the base. Reactions in DMF were regiospecific, yielding only the N1 product, while reactions in CH₃CN produced both N1 and N1/N3 products, with ratios depending on the reaction conditions. The highest yield of N1/N3-diferrocenoyl uracil was achieved with an extended reaction time of 90 min using uracil and triethylamine. Optimised conditions were applied to C5-uracil derivatives, producing N1 and N1/N3 products. Regioselectivity and N-substitution were confirmed by NMR, and solvent effects were supported by quantum chemical calculations. The resulting ferrocene–pyrimidine conjugates exhibited oxidative and immunomodulatory activity, highlighting their biological potential. Full article

Nanoparticle-catalysed microwave-aided multicomponent reactions (MCRs) have been demonstrated to be competent and environmentally benign tools for the quick synthesis of a wide spectrum of fused heterocyclic systems. The distinctive physicochemical properties of nanoparticles, including a substantial surface area, readily modifiable surface functionality, and heightened catalytic activities, when coupled with microwave irradiation, have enabled a marked improvement in reaction rates, product yields, and selectivity compared to conventional heating methods. This review highlights recent advancements in microwave-assisted MCRs facilitated by diverse nanomaterials, such as magnetic nanocatalysts, metal and metal oxide nanoparticles, mesoporous silica systems, and nanohybrids. It emphasises catalyst design, catalytic efficacy, scope, recyclability, and alignment with green chemistry principles in both solvent-free and aqueous environments, as well as the utilisation of recyclable catalysts. In summary, microwave-assisted multi-component reactions catalysed by nanoparticles are ecofriendly and versatile methods for the sustainable synthesis of such fused heterocycles containing bioactive pyridine, pyrazole, phenazine, pyrimidine, pyran, imidazole, and relevant pyridine derivatives, possessing potential in medicinal and material chemistry. Full article

The essential reaction of CO₂ hydration, fundamental to all living organisms, is facilitated by the enzyme carbonic anhydrase (CA, EC 4.2.1.1). This enzyme plays a crucial role in regulating various physiological and pathological processes. A series of heterocyclic benzenesulfonamide derivatives (19 compounds) were evaluated as possible inhibitors of human CAs. Their inhibitory properties were tested against several isoforms such as the cytosolic hCA I and hCA II, as well as the transmembrane isoforms hCA IV, hCA IX and hCA XII. The tested molecules demonstrated notable inhibitory potential, particularly toward hCA II and hCA IV, where five and four compounds, respectively, exhibited greater potency than the reference inhibitor, acetazolamide. Molecular docking simulations were further performed to elucidate the binding interactions of the most active compounds with the human CA II, IV IX and XII isoforms Full article