Search Results (489)

This study integrated non-targeted metabolomics and transcriptomics to investigate dynamic changes in Antheraea pernyi pupae across five developmental stages. Metabolomic analysis identified 1246 metabolites, primarily organic acids, lipids, heterocyclic compounds, and oxygen-containing organics. Principal component analysis revealed stage-specific metabolic profiles: amino acid derivatives (pyruvate, proline, lysine) declined, while pyrimidines (cytidine, uridine, β-alanine) and monosaccharides (glucose, mannose) increased. 18β-glycyrrhetinic and ursolic acids accumulated significantly in the middle and late stages. Transcriptomic analysis identified 7230 differentially expressed genes (DEGs), with 366, 1705, and 5159 significantly differentially expressed genes in the T1, T3, and T5 comparison groups, respectively. KEGG enrichment highlighted ABC transporters, amino acid/pyrimidine metabolism, and tyrosine pathways as developmentally critical, with aminoacyl-tRNA biosynthesis upregulated in later phases. Integrated multi-omics analysis revealed coordinated shifts in metabolites and genes across developmental phases, reflecting dynamic nutrient remodeling during pupal maturation. This study systematically delineates the molecular transitions driving pupal development in Antheraea pernyi pupae, uncovering conserved pathway interactions and mechanistic insights into nutrient metabolism. These findings provide a scientific foundation for leveraging pupal resources in functional food innovation and bioactive compound discovery for pharmaceutical applications. Full article

This study reports an improved diastereoselective synthesis of substituted spiro[chromane-2,4′-pyrimidin]-2′(3′H)-ones via the acid-catalyzed condensation of 6-styryl-4-aryldihydropyrimidin-2-ones with resorcinol, 2-methylresorcinol, and pyrogallol. The optimized method allows for the isolation of diastereomerically pure products, with stereoselectivity controlled by varying acid catalysts (e.g., methanesulfonic acid vs. toluenesulfonic acid) and solvent conditions. The synthesized compounds were evaluated for antimicrobial and antioxidant activities. Notably, the (2S*,4R*,6′R*)-diastereomers exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains with minimal inhibition concentration down to 2 µg/mL, while derivatives containing vicinal bisphenol moieties demonstrated potent antioxidant activity, with IC₅₀ values (12.5 µg/mL) comparable to ascorbic acid. Pharmacokinetic analysis of selected hit compounds revealed favorable drug-like properties, including high gastrointestinal absorption and blood-brain barrier permeability. These findings highlight the potential of spirochromane-pyrimidine hybrids as promising candidates for further development in the treatment of infectious diseases and oxidative stress-related pathologies. Full article

The pyrrolo[2,3-d]pyrimidine (7-deazapurine) scaffold is a unique heterocyclic system included in the composition of most nucleotides. In this study, series of the pyrrolo[2,3-d]pyrimidine-imines and 3-halo-substituted pyrrolo[2,3-d]pyrimidines were designed and prepared in high yields. Condensed pyrimidines are obtained via carbonyl-amine condensation and carbon-halogen bond formation. Pyrrolo[2,3-d]pyrimidine-imines containing a bromine substituent at position C-4 of the phenyl ring and azepine side-ring exhibited superior antitumor activity on the colon cancer HT-29 cell line; IC₅₀ values were 4.55 and 4.01 µM, respectively. These results revealed an interesting pattern, where condensed pyrimidinones containing an azepine ring demonstrated selective antitumor activity on the colon cancer cell line HT-29. In addition, the molecular docking results suggest that compound 8g provided a thorough understanding of its interactions with the DDR2 active site. This could pave the way for further development and optimization of DDR-targeting drugs, contributing to advancements in cancer therapeutics. This lead compound may serve as design templates for further studies. Full article

This study describes the synthesis of heterocyclic derivatives containing multiple nitrogen atoms serving as important moieties for developing novel antidiabetics through a simple synthetic pathway. We herein describe the synthesis and characterization of novel pyrimidine derivatives using one-pot reactions in a catalyst-free and efficient manner through a two-stage process involving the synthesis of 2-amino-4-hydrazinyl-6-methoxy pyrimidine, followed by a reaction with phenyl isothiocyanate derivatives. The structures of all the new compounds were confirmed via physical and spectral analysis. Furthermore, we evaluated the synthesized pyrimidine derivatives’ biological activities in relation to their potential roles as novel anti-diabetic agents by testing their activity profiles against the enzymes α-glucosidase and α-amylase. Compound 4 expressed the highest level of activity against α-glucosidase and α-amylase, with a greater inhibitory concentration (IC₅₀ of 12.16 ± 0.12 µM and IC₅₀ 11.13 ± 0.12 µM) compared to that of acarbose (IC₅₀ = 10.60 ± 0.17 µM and IC₅₀ = 11.30 ± 0.12 µM), which is widely used as a standard antidiabetic drug. The primary structure activity relationship analysis identified the impact of an electron- withdrawing group, especially with respect to fluorine on inhibitory activity. This was further confirmed in molecular docking studies, which demonstrated that both compounds exhibited similar inhibition patterns and emphasized the significance of incorporating a lipophilic electron-withdrawing substituent on the phenyl ring, along with the 2,4-diaminopyrimidine scaffold. Full article

Pyrazolopyridines and pyrazolopyrimidines are 5:6 aza-fused N-heteroaromatic compounds (NHACs) comprising a pyrazole ring fused to a pyridine or pyrimidine ring. They exhibit dipolar behavior due to their π-excessive and π-deficient characteristics conferred by their five- and six-membered rings. These features favor their stability, reactivity, and structural diversity, offering numerous modular and functional derivatives (e.g., pyrazolo[1,2-a]pyridines, pyrazolo[1,5-a]pyrimidines, etc.). They have been utilized to obtain relevant chemicals in pharmaceuticals, photophysics, industry, and materials science; thus, their synthesis is highly desirable for discovering novel or improved applications. Therefore, this review focuses on recent advances in the synthesis and applications of these compounds, considering reports from the last decade (2015–2024), with particular emphasis on photophysics, as they contain dipolar 5:6 aza-fused rings as essential scaffolds for this purpose. Full article

Cancer is a leading cause of death globally, claiming millions of lives each year. Despite the availability of numerous anticancer drugs, the need for new treatment options remains essential. Many current therapies come with significant toxicity, lead to various side effects, or do not consistently deliver the expected therapeutic results. Purines and pyrimidines are fundamental building blocks of nucleic acids and play crucial roles in cellular metabolism and signaling. Recent advances in medicinal chemistry have led to the development and synthesis of various derivatives that exhibit selective cytotoxic effects against cancer cells while minimizing toxicity to healthy tissues. Purine and pyrimidine scaffolds, due to their well-established biological roles and structural versatility, have emerged as key pharmacophoric fragments in anticancer drug discovery. In recent years, the rational design of hybrid molecules incorporating these heterocycles has shown promise in overcoming drug resistance, improving target selectivity, and enhancing pharmacological profiles. Purine and pyrimidines scaffolds hold significant potential as foundations for novel antitumor drugs, with established representatives in cancer treatment, including 5-fluorouracil, cladribine, capecitabine, and several others. In addition, the article discusses the challenges and future developments of purine and pyrimidine derivatives and hybrid molecules as antitumor drugs and emphasizes the need for continued research to optimize their effectiveness and reduce side effects. Overall, the innovative use of these compounds represents a major advance in targeted cancer therapy and holds promise for improving the therapeutic efficacy of malignant diseases. Full article

6-Aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC₅₀ profiling showed that 27 of the 28 derivatives had lower IC₅₀ than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC₅₀ well below 1 µM. Profiling of the most promising triazole analogue (compound 27a) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but 27a also inhibits ABL, SRC, and YES kinases. Molecular docking of 27a toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations. Full article

Background/Objectives: Colony stimulating factor 1 receptor kinase (CSF1R) is a well-validated molecular target in drug discovery for various reasons. Based on the structure of an early lead molecule identified in our lab and the marketed drug Pexidartinib (PLX3397), we merged fragments of Pexidartinib with our pyrrolo[2,3-d]pyrimidine nucleus, and the idea was supported by initial molecular docking studies. Thus, several new compounds were synthesized with Pexidartinib fragments on C4, C5, and C6 on the pyrrolopyrimidine scaffold using molecular hybridization. Methods: Nine final products were synthesized using a combination of Buchwald-Hartwig and Suzuki-Miyaura cross-coupling reactions in three to four steps and in good yields. The analogues were subsequently profiled as CSF1R inhibitors in enzymatic and cellular assays, and ADME properties were evaluated for some derivatives. Results: N-Methyl-N-(3-methylbenzyl)-6-(6-((pyridin-3-ylmethyl)amino)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12b) emerged as the most potent CSF1R inhibitor, showing low-nanomolar enzymatic activity, cellular efficacy, and favorable ADME properties, highlighting its promise as a lead compound for further development. Conclusions: These findings suggest that combining structural elements from previously reported CSF1R inhibitors such as Pexidartinib could guide the development of improved drug candidates targeting this kinase. Full article

This study demonstrates that Bacillus subtilis GDAAS-A32-derived postbiotics (BSP) enhance yogurt production by optimizing lactic acid bacteria (LAB) viability and functionality. BSP enhanced the growth kinetics and biomass accumulation of Streptococcus thermophilus and Lactobacillus bulgaricus in both an anaerobic and aerobic pure system. The addition of BSP significantly increased the viable cell counts of S. thermophilus and L. bulgaricus, milk-clotting activity, sensory properties, and extracellular polysaccharide content and improved the rheological properties. Moreover, BSP elevated viable counts of S. thermophilus and L. bulgaricus to 6.18 × 10⁸ CFU/g and 1.03 × 10⁸ CFU/g, respectively, by day 7—representing 11.3-fold and 9.3-fold increases versus controls at 20% supplementation. Metabolomic signatures confirmed peptidoglycan reinforcement and flavor enhancement. Mechanistically, BSP supplementation might reduce urate and H₂O₂ toxicity through NH₃-mediated proton neutralization and oxygen scavenging, while establishing a pyrimidine salvage network and redirecting one-carbon metabolism, resulting in enhanced stress tolerance and significant improvements in bacterial viability. Full article

Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure–activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC₅₀ = 1.40 μM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC₅₀ > 10 μM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC₅₀ = 0.009 μM) through homopiperazine-mediated interactions with Glu92/His95. Derived PROTACs 26a/b exhibited reduced potency (IC₅₀ = 3–5 μM vs. parental 10k: 2.22 μM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development. Full article

In this study, we synthesized a novel trimethoprim derivative, 4-(((2-amino-5-(3,4,5-trimethoxybenzyl) pyrimidine-4-yl)imino)methyl)benzene-1,3-diol (HD), by the reaction of trimethoprim with 2,4-dihydroxybenzaldehyde. We then prepared metal complexes of this derivative with Cu(II), Co(II), Ni(II), Ag(I), and Zn(II) and functionalized them with ZnO and Au nanoparticles. Their structures were confirmed through ¹H NMR, mass spectrometry, FTIR, conductivity, thermal analysis, magnetic susceptibility, X-ray diffraction, UV-Vis spectroscopy, and TEM, revealing octahedral geometries for all complexes. Surface features were investigated using density functional theory (DFT) analysis. Pharmacokinetic parameters and target enzymes for HD and its complexes were computed using the SwissADME web tool, with the BOILED-Egg model indicating that HD and its Cu complex should be passively permeable via the blood-brain barrier and highly absorbed by the gastrointestinal tract (GIT), unlike the Ni, Co, Ag, and Zn complexes, which are predicted to show low GIT absorption. Molecular docking studies with the Caspase-3 enzyme (PDB code: 3GJQ) using the AutoDock 4.2 software demonstrated binding energies of −7.66, −8.36, −9.05, −8.62, −6.90, and −7.81 kcal/mol for HD and the Cu, Co, Ni, Ag, and Zn complexes, respectively, compared to −6.54 and −4.63 kcal/mol for TMP and 5-FU (5-fluorouracil), indicating a potential superior anticancer potential of the novel compounds. The anticancer activities of these complexes were evaluated using the MTT assay. The IC₅₀ values for 5-FU, TMP, HD, Cu-HD, HD@ZnONPs, Cu-HD@ZnONPs, HD@AuNPs, and Cu-HD@AuNPs were found to be 32.53, 80.76, 114.7, 61.66, 77, 53.13, 55.06, and 50.81 µg/mL, respectively. Notably, all derivatives exhibited higher activity against the HepG-2 cancer cell line than TMP, except for HD, which showed similar effectiveness to TMP. Real-time PCR analysis revealed that the Au-HD@AuNPs and Cu-HD@AuNPs significantly increased caspase-3 inhibition by 4.35- and 4.5-fold and P53 expression by 3.05- and 3.41-fold, respectively, indicating enhanced pro-apoptotic gene expression and apoptosis induction in HepG2 cells. Our findings demonstrate that these novel derivatives possess significant anticancer properties, with some complexes showing superior activity compared to standard drugs such as 5-Fluorouracil (5-FU) and Trimethoprim (TMP). This study highlights the potential of these nanocomposites as promising candidates for cancer therapy. Full article

Background/Objectives: The thiazolo [5,4-d]pyrimidine scaffold is a class of drugs known for its anticancer, antitumor, anti-inflammatory, and antimicrobial properties. In this study, the electrochemical properties of novel thiazolo [5,4-d]pyrimidine derivatives and their interactions with DNA were characterized for the first time using voltammetric methods. Determining the interactions of new drug candidate molecules with DNA is crucial for drug development studies and is the main objective of this research. Methods: Both molecules were immobilized on the surface of the electrodes by passive adsorption, and their electrochemical properties were determined by voltammetric methods through reduction currents. Their interactions with DNA were carried out in the solution phase and examined by the changes in the oxidation peak potential and current of the guanine base. Results: For both molecules, it was determined that the electrochemical reduction processes are diffusion-controlled and irreversible, with an equal number of protons and electrons being transferred during this process. The detection limits for TP-NB (4-chloro-N-(5-chlorothiazolo [5,4-d]pyrimidin-2-yl)-3-nitrobenzamide) and TP-PC (1-(2-(4-(4-carbamoylpiperidin-1-yl)-3-nitrobenzamido)thiazolo [5,4-d]pyrimidin-5-yl)piperidine-4-carboxamide) were determined to be 12 µg/mL and 16 µg/mL, respectively. As a result of the interaction between both molecules with DNA, the guanine oxidation current decreased. It was found that TP-NB could act as an intercalator, while TP-PC could affect DNA electrostatically, both showing toxic effects on DNA. Conclusions: An electrochemical method was developed for the rapid, cost-effective, and sensitive detection of both molecules and their DNA interactions. Both compounds exhibited notable affinity towards DNA, as evidenced by significant changes in oxidation peak currents, shifts in peak potentials, and calculated toxicity values. These findings suggest their potential use as DNA-interacting drugs, such as anticancer and antimicrobial agents. Our study offers a quick, cost-effective, and reliable electrochemical approach for the evaluation of drug–DNA interactions. Full article

Xanthomonas oryzae pv. oryzae (Xoo) is a biotrophic bacterial pathogen, which causes devastating bacterial blight disease worldwide. In this study, we thoroughly investigated the antimicrobial effect of the plant-derived extract chelerythrine against Xanthomonas oryzae pv. oryzae (Xoo) and elucidated its mechanism. Chelerythrine is a quaternary ammonium alkaloid with a 2,3,7,8-tetrasubstituted phenanthridine structure, extracted from plants, such as the whole plant of Chelidonium majus, and the roots, stems, and leaves of Macleaya cordata. We found that chelerythrine significantly inhibited the growth of Xoo at a concentration of 1.25 μg/mL. Further experiments revealed that chelerythrine interfered with the division and reproduction of the bacterium, leading to its filamentous growth. Additionally, it increased the permeability of Xoo cell membranes and effectively decreased the pathogenicity of Xoo, including the inhibition of extracellular polysaccharide production, cellulase secretion, and biofilm formation. Chelerythrine induced the accumulation of reactive oxygen species in the bacterium, triggering oxidative stress. The result showed that chelerythrine inhibited the formation of the Z-ring of Xoo, interfered with the synthesis of pyrimidine and purine nucleotides, inhibited DNA damage repair, and inhibited the formation of peptidoglycan and lipid-like A, thus interfering with cell membrane permeability, inhibiting carbohydrate metabolism and phosphorylation of sugars, reducing pathogenicity, and ultimately inhibiting bacterial growth and leading to the destruction or lysis of bacterial cells. Altogether, our results suggest that the antimicrobial effect of chelerythrine on Xoo exhibits multi-target properties. Additionally, its effective inhibitory concentration is low. These findings provide a crucial theoretical basis and guidance for the development of novel and efficient plant-derived antimicrobial compounds. Full article

The World Health Organization has recently underlined the increasing global burden of cancer, with a particularly alarming impact on underserved populations. In recent years, 1,3,4-thiadiazole has emerged as a versatile pharmacophore to obtain bioactive compounds. The pharmacological properties of this ring are primarily attributed to its role as a bioisostere of pyrimidine, the core structure of three nucleic bases. This structural feature endows 1,3,4-thiadiazole derivatives with the ability to interfere with DNA replication processes. Additionally, the mesoionic behavior of this heterocycle gives it important properties, such as the ability to cross biological membranes and interact with target proteins. Noteworthy, in analogy to the other sulfur heterocycles, the presence of C-S σ* orbitals, conferring small regions of low electron density on the sulfur atom, makes interaction with the target easier. This review focuses on the most promising anticancer agents with 1,3,4-thiadiazole structure reported in the past five years, providing information that may be useful to medicinal chemists who intend to develop new anticancer derivatives. Full article

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability. Full article