Search Results (187)

Dorsomorphin, a pyrazolo[1,5-a]pyrimidine derivative, inhibits the bone morphogenetic protein (BMP) pathway by targeting the type I BMP receptors active in receptor-like kinases. However, the investigation of its—and its derivatives’—antiproliferative activity towards endothelial and cancer cell lines still requires reinforcement with additional studies. In the presented work, several dorsomorphin derivatives have been efficiently synthesized, based on a previously reported synthetic protocol with minor modifications. The endeavor was reinforced by a molecular docking study on the interactions of the designed derivatives with various protein targets, while the inhibitory effects of the synthesized novel molecules on the proliferation of murine leukemia cells (L1210), human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), and endothelial cells (human dermal microvascular, HMEC-1, and bovine aortic endothelial cells, BAECs) were investigated. Among the compounds tested, diphenol 22, emerged as the most promising bioactive lead since it demonstrated half-maximal inhibitory concentration (IC₅₀) values below 9 μM in all tested lines except HeLa cells. In the same context, the carbamate derivative 6 was determined as a potent inhibitor of endothelial cell proliferation in BAECs at a low micromolar range. In conclusion, the presented work not only reveals promising antiproliferative dorsomorphin derivatives but also sets the basis for further exploitation of dorsomorphin’s bioactive portfolio, based on bioactivity results and molecular modeling calculations. Full article

The introduction of cyano groups into aza-heterocyclic compounds plays a pivotal role in accessing diverse derivatives that are essential for the development of natural products, pharmaceuticals, and agrochemicals. Herein, we report a unified strategy for the direct ortho-C-H cyanation of a broad range of heterocyclic N-oxides, including pyridine, quinoline, isoquinoline, and pyrimidine derivatives. This transformation proceeds under mild conditions without the need for external activating agents or catalysts, and has been successfully applied to structurally complex, biologically relevant molecules. Compared to existing methodologies, our approach offers several distinct advantages: the use of non-prefunctionalized heteroarene substrates, environmentally benign reaction solvents, operational simplicity, broad substrate scope, and high efficiency in generating diverse ortho-cyanated heterocyclic compounds. Moreover, the method demonstrates considerable potential for scalable synthesis. Full article

Nile tilapia (Oreochromis niloticus) is a globally important aquaculture species. However, intensive farming conditions increase the risk of bacterial diseases. Despite the fact that a considerable number of transcriptomic studies have examined host responses to single bacterial infections, comparative analyses conducted within a unified experimental framework remain scarce, limiting the understanding of pathogen-specific defence mechanisms. In this study, tilapia were experimentally infected with Streptococcus agalactiae, Escherichia coli, or Vibrio harveyi via thoracic injection. Head kidney tissues were collected at 48 h post-infection for RNA sequencing. The identification of differentially expressed genes (DEGs) was conducted utilising the edgeR, and the assessment of functional enrichment was facilitated through the implementation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A comparative analysis was conducted between the bacterial infection groups and the control group. The results of this analysis revealed the identification of 2930, 3328, and 4850 DEGs were identified in the S. agalactiae, E. coli, and V. harveyi infection groups, respectively. Integrated transcriptomic analysis, combining KEGG enrichment and expression profiling of key genes, revealed distinct response patterns across pathogens. The S. agalactiae infection predominantly activated innate immune signaling pathways, including Toll-like receptor, NOD-like receptor, cytokine–cytokine receptor interaction, and NF-κB pathways. In contrast, E. coli infection induced extensive metabolic reprogramming, notably in purine and pyrimidine metabolism, carbon metabolism, and amino acid biosynthesis. Meanwhile, an infection caused by V. harveyi resulted in mucosal and lysosomal defence responses, as evidenced by an increase in lysosome, phagosome, extracellular matrix–receptor interaction, and cell adhesion molecule pathways. Collectively, this study suggests that the head kidney of Nile tilapia employs pathogen-specific defence strategies rather than a uniform antibacterial response, providing one of the first transcriptomic comparisons of distinct bacterial infections in this species. These findings provide fundamental data and theoretical insights for elucidating immune mechanisms in teleost fish and for developing targeted prevention and control strategies in aquaculture. Full article

Background: Glioblastoma (GBM) is an aggressive and treatment-resistant brain tumor with few effective therapies. Tubulin polymers are crucial for maintaining cell–cell signaling, cell proliferation, and cell division. Therefore, tubulin has been targeted by medicinal chemists to develop novel therapeutics to treat cancer. In this regard, we developed novel small-molecule tubulin inhibitors as potential therapeutics to treat GBM. Methods: We synthesized a focused library of pyrimidine-containing dihydroquinoxalinone-based analogs and tested nine compounds for cytotoxicity in GBM cell lines using the Sulforhodamine B (SRB) cell viability assay. We identified compound 8c as the most promising compound and evaluated the in vitro effects of 8c on GBM cell growth using live cell imaging and assessed apoptosis using a cell death ELISA. We then tested its anticancer activity in vivo on GBM xenografts grown in immunocompromised mice. Results: Several compounds demonstrated nanomolar IC₅₀ values in cell viability assays and outperformed temozolomide (TMZ), the current standard treatment for GBM patients. We identified compound 8c, which is a pyrimidine analog with a secondary amine, as the lead candidate for GBM studies in vitro and in vivo. Compound 8c reduced cell viability in a dose-dependent manner and induced complete growth arrest within 48 h at 3–10 nM concentrations in GBM cell lines. ELISA confirmed that compound 8c triggered dose-dependent apoptosis, whereas TMZ failed to induce apoptosis at nM concentrations. In vivo, compound 8c significantly inhibited GBM xenograft growth in immunocompromised mice by 66%. Conclusions: The potent tubulin inhibitor compound 8c has strong anti-GBM activity in vitro and in vivo and merits further preclinical development. Full article

A promising novel class of 2-(trihydroxyphenyl)thieno[2,3-d]pyrimidin-4(3H)-ones as HIV-1 integrase (IN) allosteric inhibitors is reported. All compounds were considerably more effective than the control compound LEDGIN-6, showing an inhibitory activity in the low micromolar range in both the HIV-1 integrase LEDGF/p75-dependent and independent activity assays. Selected compounds 6, 9, 10, and 12 were also able to affect the exchange of the HIV-1 IN-IN subunit and the interaction between IN and LEDGF/p75. Differently from LEDGINs, small-molecule inhibitors were able to interact with the IN binding domain (IBD) of Lens-Epithelium-derived Growth Factor/p75 (LEDGF/p75) and HIV-1 IN, and none of these compounds was able to induce multimerization, suggesting a different mechanism of action. In silico experiments carried out on compounds 6 and 10 suggest that a region adjacent to the sucrose binding site (SBS), together with a second nearby cavity, may represent relevant allosteric regions for their interaction with IN. In vitro experiments performed in the presence and absence of sucrose on selected IN mutants are qualitatively consistent with this model, although further structural and biophysical studies will be required to define the exact binding mode. Full article

Synthesis of 6-(5-mercapto-4R-4H-1,2,4-triazol-3-yl)pyrimidine-2,4(1H,3H)-dione derivatives offer a versatile platform for the development of new heterocyclic compounds. These molecules combine the biologically relevant 1,2,4-triazole ring, known for its antimicrobial and antioxidant properties, with a pyrimidine-2,4-dione core structurally related to vitamin B₁₃ (orotic acid), essential in nucleic acid metabolism. This dual structure opens a wide spectrum of synthetic possibilities, particularly in heterocyclization reactions. The synthesis usually begins with the formation of the triazole ring through cyclocondensation of thiosemicarbazides with appropriate carbonyl precursors, followed by functionalization of the thiol group via S-alkylation or S-arylation. Full article

Risdiplam is the first approved small-molecule therapy for spinal muscular atrophy (SMA), a severe, progressive neuromuscular disorder. In addition to its clinical significance, risdiplam is of a great interest for organic and medicinal chemistry due to its complex molecular architecture. Its structure incorporates three highly substituted heterocyclic fragments—imidazo[1,2-b]pyridazine, pyrido[1,2-a]pyrimidin-4-one, and 4,7-diazaspiro[2.5]octane—that serve as both versatile synthetic building blocks and critical pharmacophoric elements for drug design and discovery. The increasing scientific interest in risdiplam has led to numerous publications and patent applications that describe alternative synthetic methodologies. Recently, our group has also developed and introduced efficient, scalable manufacturing routes for the preparation of the target substance and the key intermediates of its synthesis. This mini-review systematically analyzes a plethora of risdiplam assembly strategies and synthetic approaches, covering developments from 2013 to the present. Full article

Nicotinamide N-methyltransferase (NNMT) enzyme catalyzes the N-methylation of nicotinamide and its overexpression has been reported in many neoplasms, favoring traits featuring an aggressive tumor cell phenotype. Our recent data demonstrated that NNMT upregulation in osteosarcoma (OS) and Merkel cell carcinoma (MCC) led to a significant increase in cell proliferation and migration ability, together with a reduction in sensitivity to chemotherapeutic treatment. Based on these findings, we investigated the impact of small molecule NNMT inhibitors 5-amino-1-methyl quinolinium (5-AMQ), 6-methoxynicotinamide (6MeONa) and Eli Lilly’s pyrimidine 5-carboxamide (EL-1) on U-2 OS and Saos-2 OS cell lines and MCC13 and MCC26 MCC cell lines. Following incubation of the cells with these compounds, cell viability, reactive oxygen species (ROS) production and apoptosis induction were evaluated. Cells were then subjected to combined treatment with inhibitors and cisplatin (CDDP), and viability and ROS levels were further analyzed. Our results clearly illustrate that cells treated with NNMT inhibitors underwent significant reductions in viability, increased ROS production and activation of apoptotic pathways. Given the association of NNMT with cancer aggressiveness, inhibiting its catalytic activity might present a novel strategy for counteracting cancer growth and chemoresistance, providing the rationale for an effective anti-cancer therapy based on the use of specific NNMT inhibitors. Full article

Zika virus (ZIKV) caused Zika outbreaks and continues to post threats to public health. ZIKV infection may cause congenital abnormalities during pregnancy and neurological manifestations in adults. The recurrent public health threat of Zika in various geographical areas demonstrates a need for the development of effective therapeutics. Currently, there are no approved therapies for Zika. ZIKV is a single-stranded, positive-sense RNA virus, whose genome encodes three structural proteins and seven non-structural proteins. The surface envelope (E) protein is essential for host–cell recognition and viral entry; therefore, inhibition of E-mediated viral entry is a key strategy underlying antiviral treatments. Here, molecular docking-based virtual screening was used to screen small-molecule compound libraries to identify potential ZIKV entry inhibitors. Among the compounds identified, Pyrimidine-Der1 exhibited efficient inhibition of reporter ZIKV infection. The microscale thermophoresis assay confirmed its binding with the ZIKV E protein. This compound has effective inhibition of authentic ZIKV infection in a plaque inhibition assay against R103451, PAN2016, and FLR human strains (IC₅₀: ~3–5 μM). Additionally, it efficiently inhibited ZIKV infection at viral entry and fusion steps of the virus life cycle in a time-of-addition assay. Overall, Pyrimidine-Der1 is a promising ZIKV entry inhibitor, warranting further optimization and evaluation. Full article

Imidazothiazoles are important and attractive scaffolds for the design of potential biologically active small molecules. Dialkylenamines are convenient building blocks and are often used as intermediate reagents for the synthesis of various heterocyclic systems such as pyrimidine, pyridine, pyrazole, etc. In the present paper, the simple and effective synthesis of (Z)-6-((dimethylamino)methylene)-2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one (2) is reported. The proposed method, based on the reflux of 2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one with N,N-dimethylformamide dimethyl acetal, leads to an 80% yield of title compound 2. The structure of the synthesized compound 2 was confirmed using ¹H, ¹³C NMR, and LC-MS spectra. The applied protocol demonstrates practical advantages such as the absence of a solvent, a simple work-up, and the possibility of scale-up. Full article

Benefit/risk management of skin exposure to sunlight, especially ultraviolet (UV) rays, is mainly driven by photoaging, cancer incidence, and the requirement for vitamin D3 synthesis. Antioxidant phytocompounds are considered to be a valuable source of molecules to protect skin from UV-induced damage, but their impact on other UV-related metabolic pathways is rarely described. In this study, an indigoid-rich Persicaria tinctoria extract (PTE) was evaluated on three consequences of UV exposure: DNA damage and inflammation, vitamin D3 content, and melanogenesis. A moderate UV exposure was applied on skin models, corresponding to approximately 1 h exposure in the spring in western Europe. UV-induced DNA damage and inflammation were measured through the quantification of cyclobutane pyrimidine dimers (CPDs) and cytokines. Response to heat stress was quantified through the release of prostaglandin. Then, the impact of PTE on vitamin D3 and melanin synthesis was observed. PTE decreased by −56% in the number of cells presenting CPDs. PTE decreased the production of pro-inflammatory cytokine IL-6 (−59%) and stimulated the release of the protective cytokine IL-1Ra (+49%). It decreased PGE₂ release by −27%. In skin explants, PTE boosted the vitamin D3 concentration (+345%). Several genes involved in melanogenesis were up-regulated by PTE (MC1R × 2.46, MITF × 1.69, TYR × 2.06, MLPH × 1.53). It promoted melanin content by +126% and by +86% when associated with SPF 30. The extract decreased the amount of protective eumelanin, leading to visible skin tanning of reconstructed human epidermis (L*-15%, ITA −125%). As a new finding, PTE minimized DNA damage and inflammation caused by a daily dose of UV, and surprisingly, promoted vitamin D3 and eumelanin synthesis, suggesting that it represents an opportunity to reconcile skin protection and the physiological need for sunlight. Full article

In order to find the biochemical effects of Aeromonas hydrophila and its therapeutic chemical, enrofloxacin (ENR), on American shad (Alosa sapidissima A. Wilson), four groups were set up: a control group (C), an A. hydrophila group (A), an A. hydrophila + 70 mg·L⁻¹ enrofloxacin (ENR) group (E1), and an A. hydrophila + 140 mg·L⁻¹ ENR group (E2). Histological, enzymatic activities, transcriptome, and proteomics have been performed. MDA, PPO, AKP, TNF-α, and AMPK were significantly increased, while AhR and EROD were decreased in the liver of American shad after treatment with A. hydrophila. AhR and EROD showed a significant decrease in E1 group; MDA, PPO, AKP, and AMPK were significantly increased, while AhR and EROD decreased in E2 group. A. hydrophila significantly increased ferroptosis, TGF-β signaling pathway, etc. Ferroptosis, pyrimidine metabolism, and glycerolipid metabolism significantly increased in E1 group, while protein processing in endoplasmic reticulum significantly increased in E2 group. A total of 126 shared metabolites were found in the comparisons of A vs. C and E2 vs. C, and the main enriched pathway were organic oxygen compounds, lipids, and lipid-like molecules. Except for fluorobenzoate degradation, the pathways of ascorbate and aldarate metabolism, pyrimidine metabolism significantly increased in A and E2 groups, which further resulted in vacuolization, cell shedding, and necrosis in the liver. A. hydrophila led to a significant decrease in lipid metabolism, leading to oxidative stress and energy expenditure. The addition of ENR in aquaculture significantly enhanced liver metabolic abnormalities caused by A. hydrophila. Excessive use of ENR leads to oxidative stress in American shad, affecting its immune system as well as lipid, carbohydrate, and energy metabolism. Full article

A pyrimidine-based compound (PP) was recently found to be a promising anticancer agent for colorectal and breast cancers. However, this compound exhibited low selectivity and poor water solubility. To address these challenges, albumin gel nanoparticles were used, where the gel matrix is formed by cross-linking of BSA molecules, allowing for a high concentration of this hydrophobic drug to be carried with no cytotoxicity to non-tumor cells. Functionalization with hyaluronic acid (HA) was employed to target CD44-overexpressing cancer cells, specifically triple-negative breast cancer (MDA-MB-231) and colorectal cancer cell lines (HCT 116). The gel nanoparticles present mean sizes below 250 nm, very low polydispersity, small aggregation tendency, and excellent colloidal stability in PBS buffer for a storage period of 30 days. Moreover, the drug-loaded particles showed high encapsulation efficiencies (above 85%) and sustained release profiles. Drug-loaded BSA/HA particles (PP-HA-BSA-NPs) revealed advantageous activity, presenting around 55% and 23% cell viability at a IC₅₀ drug concentration for triple-negative breast cancer (the most aggressive breast cancer subtype) and colorectal cancer (second leading cause of cancer-related deaths), respectively. In conclusion, these nanoparticles outperform the ones without HA, demonstrating target capabilities, while retaining the drug’s anticancer activity and reducing the drug’s toxicity. These results are promising for future in vivo assays and clinical translational applications. Full article

Two series of tricyclic thieno[3,2-d]pyrimidines were synthesized, achieving yields of up to 97%. The tricyclic thieno[3,2-d]pyrimidines examined in this study are synthetic analogs of the deoxyvasicinone alkaloids, where the thiophene ring substitutes for the benzene ring. A systematic investigation was conducted on the scaffold-hopping strategy of these alkaloids, emphasizing the selective synthesis and anticancer properties of thieno[3,2-d]pyrimidines. The anticancer evaluation was performed on human cancer cell lines, specifically cervical HeLa and colon HT-29 carcinoma cells. Additional bioassays included cell migration analyses, cell cycle progression, apoptosis, and molecular docking analyses. Furthermore, molecular docking studies showed that the most active small molecule 6e is likely to disrupt the cell cycle process through targeting CDKs (Cyclin-dependent kinases), leading to the inhibition of tumor cell proliferation. Full article

The corticotropin-releasing factor (CRF) and its type 1 receptor (CRF₁R) play a key role in the regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Dysregulation of the HPA axis is associated with congenital adrenal hyperplasia (CAH) and depression. Non-peptide CRF₁R-selective antagonists displayed antidepressant effects on animal models and are used for the management of CAH. To develop novel non-peptide CRF₁R antagonists, we have previously designed and synthesized a series of substituted pyrimidines. Among these analogs, molecule 43 (M43) binds to CRF₁R with the highest affinity. Based on this finding, we selected M43 for further pharmacological characterization in the present study. The results suggest that M43 is a potent CRF₁R antagonist, blocking the ability of the CRF-related agonist, Tyr⁰-sauvagine, to stimulate (1) cAMP accumulation in HEK 293 cells expressing CRF₁R and (2) the proliferation rate of RAW 264.7 macrophages. Computational studies suggest that the antagonist properties of M43 are mostly attributed to its ability to interact with residues in the allosteric pocket of CRF₁R, comprised of the third, fifth, and sixth transmembrane domain residues, which block activation-associated structural rearrangements of the receptor. Our data will be used to design novel non-peptide CRF₁R antagonists for clinical use. Full article