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The Microbicide Trials Network 042 study (MTN-042/DELIVER) is a two-arm, randomized, open-label Phase 3b trial that is evaluating the safety, adherence, and acceptability of the monthly ring and daily oral PrEP among HIV-uninfected pregnant people in four African countries. This analysis focuses on acceptability data captured qualitatively from a subset (n = 48) of the 150 people in the first cohort of the trial who were enrolled in late-stage pregnancy at 36 to 38 weeks gestational age and followed until after delivery. Single IDIs were conducted by trained interviewers at each clinic site using a semi-structured guide. Data excerpts of key codes pertaining to acceptability, pregnancy, and maternal health were summarized, reviewed and interpreted by multinational analyst teams. Although the product use period was relatively short, the data suggested several acceptability findings that may directly translate to longer durations of product use in pregnancy. The first was the overarching maternal sentiment that being able to protect both oneself and their baby was highly valued. The second was the importance of counseling support from providers not only because participants used methods that might generate side effects, but because pregnancy itself is a period with its own set of side effects. The third was that, similar to non-pregnant participants in other trials, here study products were generally liked and described as easy to use. Concerns about ring and oral PrEP use could be addressed with provider counseling and support and should form an essential component rollout among pregnant people.

BackgroundDisabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high.MethodsWe evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy.ResultsGenome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition.ConclusionsGain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).

Background: Identifying molecular biomarkers for predicting responses to anti-cancer drugs can enhance treatment precision and minimize side effects. This study investigated the novel cancer-targeting mechanism of combining SH003, an herbal medicine, with docetaxel in non-small cell lung cancer (NSCLC) cells. Also, the present study aimed to identify the genetic characteristics of cancer cells susceptible to this combination. Methods: Cell viability was analyzed by WST-8 assay. Apoptosis induction, BrdU incorporation, and cell cycle analysis were performed using flow cytometry. Metabolites were measured by LC–MS/MS analysis. Real-time PCR and western blotting evaluated RNA and protein expression. DNA damage was quantified through immunofluorescence. cBioPortal and GEPIA data were utilized to explore the mutual co-occurrence of TP53 and UMPS and UMPS gene expression in NSCLC. Results: The combination treatment suppressed de novo pyrimidine nucleotide biosynthesis by reducing the expression of related enzymes. This blockade of pyrimidine metabolism led to DNA damage and subsequent apoptosis, revealing a novel mechanism for inducing lung cancer cell death with this combination. However, some lung cancer cells exhibited distinct responses to the combination treatment that inhibited pyrimidine metabolism. The differences in sensitivity in lung cancer cells were determined by the TP53 gene status. TP53 wild-type lung cancer cells were effectively inhibited by the combination treatment through p53 activation, while TP53 mutant- or null-type cells exhibited lower sensitivity. Conclusions: This study, for the first time, established a link between cancer cell genetic features and treatment response to simultaneous SH003 and docetaxel treatment. It highlights the significance of p53 as a predictive factor for susceptibility to this combination treatment. These findings also suggest that p53 status could serve as a crucial criterion in selecting appropriate therapeutic strategies for targeting pyrimidine metabolism in lung cancer. [ABSTRACT FROM AUTHOR]

This work aimed to create and characterize some new bioactive chelates of bis azodye ligand, 5‐((2‐hydroxy‐4,6‐dioxo‐1,4,5,6‐tetrahydropyrimidin‐5‐yl)diazenyl)naphthalen‐1‐yl)diazenyl) pyrimidine 2,4,6 (1H,3H,5H)‐trione. Except for the Sm(III) chelate, which exhibited a (3M:1L) molar ratio, all chelates had a (2M:1L) stoichiometry. According to Fourier transform infrared spectroscopy (FT‐IR), azo groups were not included in chelating with all ions except Sm(III), where just one azo group was coordinated. With the Ni(II) and Zn(II) ions, the ligand behaved as OON‐tridentate moiety; with the Co(II) and Cu(II) ions, it behaved as ON‐bidentate moiety. Co(II) and Cu(II) chelates had square planar structure, and Ni(II) and Zn(II) chelates had square pyramidal geometry. The chelates had greater thermal stability than the uncoordinated ligand due to the chelate's structure. [Sm3(H4L)(OH)7(NO3)2.H2O].4.5EtOH exhibited the maximum thermal stability, which may be due to the large number of solvent molecules and the high number of chelate rings. With the exception of the Sm(III) chelate, all of the examined chelates were more cytotoxic against MCF‐7 and Hep‐G2 cells than their parent ligand. With the exception of the Zn(II) chelate, which demonstrated activity on Hep‐G2 rather than MCF‐7, the effects of each metal chelate on the two cells were nearly equivalent. All of the studied chelates, especially Zn(II) and Co(II), were potent as antioxidants more than the native ligand. To support experimental findings, density functional theory (DFT) studies were performed via the CAM‐B3LYP/LanL2DZ method, and the geometry of the ligand and its chelates had been validated. [ABSTRACT FROM AUTHOR]

The nature of π-hole spodium bonds in the HgLCl2⋯ZH3/CH2Y complexes (L = pyrrole 1, pyrazole 2, imidazole 3, pyridine 4, pyridazine 5, and pyrimidine 6; Z = N, P, As, and Sb; Y = O, S, Se, and Te) has been studied using theoretical calculations. The electrophilicity of the π-hole in the tri-coordinated HgII complexes varies with the type of N-heterocyclic ligand. The strength and nature of the π-hole spodium bond is closely related to the properties of the Lewis bases. In the case of HgLCl2⋯ZH3, the strength of the π-hole spodium bond weakens as the nucleophilicity of the base decreases, following the sequence HgLCl2⋯NH3 > HgLCl2⋯PH3 > HgLCl2⋯AsH3 > HgLCl2⋯SbH3. The Hg⋯Z spodium bonds change from a partially covalent interaction to a close-shelled noncovalent interaction. The nucleophilic ability of CH2Y decreases in the order CH2O > CH2S > CH2Se > CH2Te, while the strength of the π-hole spodium bond follows the order HgLCl2⋯OCH2 < HgLCl2⋯SCH2 < HgLCl2⋯SeCH2 < HgLCl2⋯TeCH2. The Hg⋯Y spodium bond undergoes a transition from a close-shelled noncovalent to a partially covalent interaction, resulting in an incremental increase in the degree of covalence. The Hg⋯Te spodium bond exhibits certain characteristics resembling those of a coordinate covalent bond. The inter-orbital interactions observed in the formation of the HgLCl2⋯YCH2 complexes appear to be significantly stronger compared to those observed in the HgLCl2⋯ZH3 complexation. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second most common cause of cancer‐related deaths and the third most common cancer worldwide. Because of its importance in DNA biosynthesis, thymidylate synthase (TS) has gathered attention as a promising target for cancer therapy. Herein, we have designed and synthesized 12 novel 5‐(N‐Benzyl indol‐3‐yl) pyrido[2, 3‐d] pyrimidine based derivatives and assessed their anticancer activity against HCT 116, MCF‐7, Hep G2, and PC‐3 cell lines. For compounds 5 a and 5 f TS inhibitory activity was also performed along with in silico studies. Further, all the synthesized compounds exhibited anticancer activity, but particularly, compounds 5 a and 5 f were showed excellent anticancer activity having IC50 values of 1.09±0.61, 5.54±0.81, 6.44±0.91, and 5.12±0.65 μM and 1.03±0.96, 3.09±0.52, 4.12±0.59, and 7.06±0.60 μM respectively with control Raltitrexed (IC50 1.02±0.51, 1.88±0.61, 1.30±0.89, and 2.09±0.67 μM respectively) and hTS inhibitory activity with IC50 of 18.91±1.09 and 16.19±0.96 nM with control Raltitrexed (IC50 12.25±1.21 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 5 a and 5 f to the catalytic site of TS. Additionally, ADME characteristics were also in the acceptable range for these compounds. Based on the anticancer activity, SAR was also performed for lead optimization. [ABSTRACT FROM AUTHOR]

The starting compound 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (1) is reacted with each of diketone and β-ketoester, forming pyridopyrazolo[1,5-a]pyrimidines 4a,b and 14a,b, respectively. The compounds 4 and 14 reacted with each of aromatic aldehyde and arenediazonium salt to give the respective arylidenes and arylhydrazo derivatives, respectively. The structure of the new products was established using spectroscopic techniques. The cytotoxic activity of selected targets was tested in vitro against three cancer cell lines MCF7, HepG2 and HCT116. The data obtained from enzymatic assays of TrKA indicated that compounds 7b and 16c have the strongest inhibitory effects on TrKA with IC50 = 0.064 ± 0.0037 μg/ml and IC50 = 0.047 ± 0.0027 μg/ml, respectively, compared to the standard drug Larotrectinib with IC50 = 0.034 ± 0.0021 μg/ml for the HepG2 cancer cell line. In cell cycle analysis, compounds 7b, 15b, 16a and 16c caused the greatest arrest in cell cycle at the G2/M phase. In addition, compound 15b has a higher apoptosis-inducing effect (36.72%) than compounds 7b (34.70%), 16a (21.14) and 16c (26.54%). Compounds 7b, 16a and 16c were shown fit tightly into the active site of the TrKA kinase crystal structure (PDB: 5H3Q). Also, ADME study was performed on some selected potent anticancer compounds described in this study. Highlights: A series of new pyrido[4ʹ,3ʹ:3,4]pyrazolo[1,5-a]pyrimidine derivatives were synthesized. The anticancer activity of the new compounds were tested in vitro. Compounds 7b and 16c showed broad spectrum potent anticancer activity. Compound 15b induced cell cycle arrest at G2/M phase in HepG-2 cell line. Compound 7c, the most promising agent, can be absorbed very easily by the gastrointestinal tract with potential BBB permeability. [ABSTRACT FROM AUTHOR]

This article explores the synthesis and properties of two 2'-deoxyadenosine mimics, dSA and dSO2A, which contain a thieno[3,2-d]pyrimidine ring. The authors aimed to investigate the enzymatic reactions, photophysical properties, and potential incorporation into oligonucleotides of these mimics. The synthesized adenosine mimics demonstrated high enzymatic stability and exhibited different absorption and fluorescence properties compared to natural adenosine. However, while one mimic successfully formed oligonucleotides, the other decomposed under basic conditions. Overall, this study suggests that dSA can be utilized as a stable adenosine congener with fluorescence properties in ON technologies. [Extracted from the article]

This article explores the development of new nucleoside analogues for treating viral infections and cancer. Specifically, it focuses on fluorinated carbocyclic systems, which have shown promise in medicinal and biological chemistry. The authors discuss the synthesis of various analogues with unsaturation and stereoinversion, as well as different reaction methods. The article also highlights the relevance of nucleoside analogues in the context of the COVID-19 pandemic and the development of mRNA vaccines and antiviral medications. The researchers successfully synthesized a small library of fluorinated carbocyclic nucleoside analogues, achieving C2'-C3' unsaturation using Corey-Winter or Eastwood olefination. They also discovered an unusual C1'-C2' alkene scaffold as a side-product, enabling the synthesis of a 1',2'-didehydro 6'-fluorinated carbauridine and carbacytidine. NMR data was used to investigate the conformations of the analogues in solution, revealing that C2'-C3' unsaturation favored a 6'-endo envelope conformation. Biological evaluation of these nucleoside motifs is currently ongoing. [Extracted from the article]

The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC50 < 0.3 μM) and no toxicity on fibroblasts (IC50 > 25 μM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 μM at 72 hpf. [ABSTRACT FROM AUTHOR]

The design of novel 4′-thionucleoside analogues bearing a C2′ stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2′ center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1′,2′-anti thioaminal furnished the desired β-D-4′-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1′,4′-trans isomers, causing a significant decrease in their reaction rate relative to 1′,4′-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4′-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles. [ABSTRACT FROM AUTHOR]

The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation. [ABSTRACT FROM AUTHOR]

–Objective: In this paper, a series of piperazine pyrimidines and morpholine pyrimidines have been synthesized effectively, and their biological activities have been evaluated. Methods: We examined the cytotoxicity tests of the compounds against two human tumor cells (HCT-116, HeLa), as well as one human normal cells (L02), in order to determine their anticancer activity. Results: The compound (IV) outperformed the others, and flow cytometry was used to further examine how it works against cancer. Additionally, the (IV) molecule showed strong anticancer efficacy but was marginally less effective in apoptosis assays than the control 5-FU. Discussion: The compound (IV) chemical treated HCT-116 cells and HeLa cells in the cell cycle research had a larger percentage of cells in the G1 phase. The induction of apoptosis by interfering with the cell cycle may be the anticancer mechanism of this substance. Additionally, molecular docking investigated potential interactions between the substances and the Topo II active site. Conclusions: The groundwork for the creation and structural modification of new pyrimidine medications is laid out in this study. [ABSTRACT FROM AUTHOR]

Objective: To synthesize new dihydropyrazolo[1,5-a]pyrimidine derivatives and screen for the antibacterial and antifungal screening. Methods: We have synthesized a new series of 7-(1,3-diphenyl-1-H-pyrazol4-yl)-2-(methylthio)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile compounds and screened compounds for antibacterial and antifungal activity. Gram-positive (Bacillus megaterium, Micrococcus spp.) and Gram-negative bacteria were tested for antibacterial activity (E.coli, S. typhi). Antifungal activity was tested on Ganoderma spp., A. niger, A. flavus, and Penicillium spp.Results: Some compounds have shown significant antimicrobial activity. Discussion: As per the results the compound possesses good biological activity due to presence of core pyrazolo[1,5-a]pyrimidine moiety. Conclusions: The synthesis of new 7-(1,3-diphenyl-1-Hpyrazol-4-yl)-2-(methylthio)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile compounds was successfully completed and characterized by relevant techniques. Compounds are screened for the biological activities with moderate to good results. The MIC of the synthesized compound is compared to marketed available standard drugs. [ABSTRACT FROM AUTHOR]

In this study, we designed and synthesized several novel fused [1,2,3]triazolo [4′,5′:3,4]pyrrolo[1,2‐a]thieno[2,3‐d]pyrimidine derivatives using in a single [3 + 2] reaction cycloaddition reaction of 3‐(3‐iodoprop‐2‐yn‐1‐yl)thieno[2,3‐d]pyrimidin‐4(3H)‐one (4) followed by C‐C bond coupling with various aryl azides in a PEG‐400 medium. All of the newly synthesized compounds were evaluated in vitro for EGFR kinase inhibitory action as well as anti‐breast cancer activity against MDA‐MB‐231 and MCF‐7 breast cancer cell lines. When compared to the reference molecule, erlotinib, the majority of the compounds demonstrated adequate efficacy. The most promising compounds, 5g and 5i, demonstrated excellent anticancer activity against both cancer cell lines, with IC50 values ranging from 04.17 ± 0.55 to 8.65 ± 0.89 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.467 ± 0.063 and 0.412 ± 0.081 μM). The in silico studies of five potent compounds 5f, 5g, 5h, 5i, and 5k were also carried out to identify the interactions against the EGFR receptor and found that the energy calculations were covenant with the obtained IC50 values. [ABSTRACT FROM AUTHOR]

In this work, we report an effective, one‐pot syntheses of benzo[4,5]imidazo[1,2‐a]pyrimidine and pyrano[4,3‐b]pyran derivatives using L‐glutamine functionalized nanoparticles (Fe3O4@SiO2@L‐glutamine NPs) under microwave irradiation. The organo‐nanocatalyst underwent characterization through diverse techniques, including FT‐IR, p‐XRD, SEM, TEM, EDX, XPS, TGA, and VSM. Microwave irradiation and multicomponent reactions synergistically yield excellent product yields (≈80%–95%) in shorter reaction times (≈6–15 min) with a broader substrate scope. The organo‐nanocatalyst displays notable catalytic efficacy, evidenced by high turnover numbers (TON) and turnover frequencies (TOF) across syntheses. This innovative protocol showcases exceptional efficiency, cost‐effectiveness, and environmental friendliness, with advantages like minimal reaction conditions, easy catalytic recovery, recyclability, operational simplicity, and the use of eco‐friendly solvents. [ABSTRACT FROM AUTHOR]

Cellular purines, particularly adenosine 5′-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5′-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis. [ABSTRACT FROM AUTHOR]

To address the increasing levels of carbon dioxide (CO2) in the atmosphere, various heterocyclic N/B‐based intramolecular frustrated Lewis pairs (IFLPs) have been experimentally and theoretically investigated. Reports have shown them to be a potential catalyst for CO2 sequestration, however, a comparative rationale of these IFLPs has not been reported. Thus, in the present work, we have proposed an uninvestigated IFLP based on i. e., 2‐boranyl‐1,3,5‐triazine (BT) and compared with previously reported borylated imidazole (Im) and pyrimidine (Prm) for CO2 abduction. The density functional theory (DFT) base calculations have been carried out to probe the reaction mechanism and thorough natural bond orbital analysis has been carried out to get deeper insights into the catalytic behavior of the proposed IFLPs. Further, the effect of substituting the hydrogens at the ring and the B atom of the considered IFLP, by −CH3, −Cl and −OH, on the catalytic behavior has been studied. The results show that the borylated triazines can be a potential catalyst for CO2 sequestration. Also, the catalytic behavior of the presented IFLPs can be modulated by appropriated substitutions. [ABSTRACT FROM AUTHOR]

The pyrimidine ring is present in various biomolecules such as DNA and RNA bases, aminoacids, vitamins, etc. Additionally, many clinically used drugs including methotrexate and risperidone contain the pyrimidine heterocyclic scaffold as well. Pyrimidine derivatives present diverse biological activities including antioxidant and anticancer activities and can be considered as privileged scaffolds in drug discovery for the treatment of various diseases. Piperidine pyrimidine amides have gained significant attention due to their enzymatic inhibitory activity. Based on our experience and ongoing investigation on cinnamic acid derivatives, their hybrids and substituted pteridines acting as lipoxygenase inhibitors, antioxidants, anti-cancer, and anti-inflammatory agents a series of novel piperidine pyrimidine cinnamic acids amides have been designed and synthesized. The novel hybrids were studied for their antioxidant and anti-inflammatory potential. They exhibit moderate antioxidant activity in the DPPH assay which may be related to their bulkiness. Moreover, moderate to good lipid peroxidation inhibition potential was measured. With regards to their lipoxygenase inhibitory activity, however, two highly potent inhibitors out of the nine tested derivatives were identified, demonstrating IC50 values of 10.7 μM and 1.1 μM, respectively. Molecular docking studies to the target enzyme lipoxygenase support the experimental results. [ABSTRACT FROM AUTHOR]

Environment-benign one-pot three-component cycloadditions of diazo compounds, nitrosoarenes and vinyl pyrimidines, or vinyl purines, or vinyl imidazoles, or vinyl triazoles or vinyl indole have been developed. This catalyst- and additive-free strategy could efficiently introduce the isoxazolidine skeleton into nucleoside analogues, oxazole molecules and indole derivatives to provide diverse classes of isoxazolidinyl pyrimidine nucleoside analogues, isoxazolidinyl purine nucleoside analogues, isoxazolidinyl imidazoles, isoxazolidinyl triazoles and isoxazolidinyl indole with moderate to good yields for most substrates. [ABSTRACT FROM AUTHOR]

In the current study, N1‐N4‐bis (3‐(trimethoxysilyl) propyl) butane‐1,4‐diammonium trinitromethanide on titanium dioxide {TiO2−Bis [TMS−NH2+ C(NO2)3−]} was synthesized and characterized using a variety of techniques including energy dispersive X‐ray analysis (EDX), fourier transform infrared spectroscopy (FT‐IR), thermo gravimetric analysis (TGA), field emission scanning electron microscopy (FESEM), and X‐ray diffraction (XRD). Then TiO2−Bis [TMS−NH2+ C(NO2)3−] was used as an efficient nano‐catalyst in the one‐pot synthesis of 1,2,4‐triazolo[4,3‐a] pyrimidine derivatives at 120 °C under the solvent‐free conditions with good to excellent yields. Easy separation of the products from the catalyst, short period of the reaction times, and reusability of the catalyst are among the most important features of the reported method. [ABSTRACT FROM AUTHOR]

Due to their extensive applications in pharmaceuticals and natural substances, organic synthesis and heterocyclic compounds have been at the forefront of research for many years. Pyrimidine is one of the heterocyclic compounds that have various derivatives with promising biological and pharmacological properties. This review article covers the synthesis and biological effects of pyrimidine derivatives, such as pyrano[2,3‐d]pyrimidines, pyrido[2,3‐d]pyrimidines, and furo[2,3‐d]pyrimidines. The compounds discussed in this review have a wide range of biological activities. Recent advances in green chemistry have led to the development of eco‐friendly synthetic methods for producing these bioactive heterocycles. This review aims to present various synthetic methods and biological effects of these compounds and provide new opportunities for organic chemists to develop potent nitrogen‐ and oxygen‐containing heterocycles for future applications. The review highlights examples of successful syntheses and applications of pyrimidine derivatives in the fields of antibacterial, antifungal, anticancer, enzyme inhibition, and antiviral research. [ABSTRACT FROM AUTHOR]

Two new series of 4,5-difunctionalized 1-bromobenzyl[1,2,3]triazole (2a, 3a, 4a, 5a, and 6a) and 4,5-difunctionalized 1-(2-oxo-2-(p-tolylamino)ethyl-[1,2,3]triazole (2b, 3b, 4b, 5b, and 6b) were synthesized using related 1-(azidomethyl)-4-bromobenzene 1a and p-tolylcarbamoyl azide 1b respectively. The substituted [1,2,3]triazolo[4,5-d]pyrimidine-7-one derivatives (7a, 7b, 8a, and 8b) were synthesized by the reaction of [1,2,3]triazolo derivatives 2a and 2b with carbon disulfide in the presence of 10% sodium hydroxide/dimethylformamide and/or by the reaction with formic acid respectively. The S-glucoside derivatives (9–12) of newly synthesized [1,2,3]triazolo[4,5-d]pyrimidines were also synthesized. By using several spectroscopic methods, including IR, 1H NMR, 13C NMR, and elemental analysis, the chemical structures of the novel derivatives were confirmed. The synthetic compounds' cytotoxicity and in vitro anticancer activity were examined vs. human breast carcinoma (MCF-7), human laryngeal carcinoma (HEP-2), and human colorectal carcinoma (HCT-116) cell lines. According to the findings, HEP-2 and HCT-116 cells are more sensitive to the tested compounds than the other cell lines. In the HEP-2 and MCF-7 cell lines, respectively, compounds 5b and 11 showed potential anticancer activity when compared to the effect of the commonly used anticancer medication, doxorubicin. The selectivity of compounds against the cancer cell line was confirmed by testing their cytotoxicity on VERO (African Green Monkey kidney) normal cells. The anticancer activity of those compounds is suggested to be due to nuclear damage generated by a high generation of reactive oxygen species (ROS). In addition, the induction of apoptosis by significantly upregulating the apoptotic genes PAR-4 and BAX while substantially downregulating the anti-apoptotic genes BCL-2 and BCL-xl. Molecular docking research was undertaken to predict the probable binding poses of the most effective drugs in the active site of CDK-2. The more active compounds (2a, 3a,b, 4a,b, 5a,b, 6b, 11, and 12) have been docked on the CDK-2 enzyme to demonstrate their mode of action as anticancer medicines. The compounds exert many interactions and showed high binding to the CDK-2 receptor. Finally, a hypothetical pharmacophore model was created using the Molecular Operating Environment (MOE) software and five compounds that are structurally similar to the synthesized ones with known anticancer action. [ABSTRACT FROM AUTHOR]

Changes in vibrational spectra are among the most important manifestations of the interaction between transition metal dichalcogenides and nucleic acid bases (NAB). Infrared and Raman spectra were calculated using the DFT/M06-2X method for the most stable stacked and covalently bonded complexes of pyrimidine bases with MoS2. Obtained spectra were analyzed to determine the spectral markers of the interactions between the pyrimidine bases and MoS2. We found that interaction with MoS2 leads to significant changes in both frequencies and intensities of NAB vibrations. The correlation between the changes and interaction energies of the NAB molecules with MoS2 was demonstrated. In general, changes in the vibrational frequencies in complexes with covalent bonds are significantly greater than ones in stacked ones. For the bonded complexes, the most significant changes are observed for those fragments of the NAB molecules that are directly involved in the formation of the covalent bonds. Calculations predict the decrease of the IR intensity and Raman activities of the NAB molecules in the spectra of stacked complexes and their increase in the spectra of covalently bonded complexes. [ABSTRACT FROM AUTHOR]

Fibromyalgia patients vary in clinical phenotype and treatment can be challenging. The pathophysiology of fibromyalgia is incompletely understood but appears to involve metabolic changes at rest or in response to stress. We enrolled 54 fibromyalgia patients and 31 healthy controls to this prospective study. Symptoms were assessed using the Fibromyalgia Impact Questionnaire (FIQ) and blood samples were collected for metabolomics analysis at baseline and after an oral glucose tolerance test and a cardiopulmonary exercise test. We identified key symptoms of fibromyalgia and related them to changes in metabolic pathways with supervised and unsupervised machine learning methods. Algorithms trained with the FIQ information assigned the fibromyalgia diagnosis in new data with balanced accuracy of 88% while fatigue alone already provided the diagnosis with 86% accuracy. Supervised analyses reduced the metabolomic information from 77 to 13 key markers. With these metabolites, fibromyalgia could be identified in new cases with 79% accuracy. In addition, 5‐hydroxyindole‐3‐acetic acid and glutamine levels correlated with the severity of fatigue. Patients differed from controls at baseline in tyrosine and purine pathways, and in the pyrimidine pathway after the stress challenges. Several key markers are involved in glutaminergic neurotransmission. This data‐driven analysis highlights fatigue as a key symptom of fibromyalgia. Fibromyalgia is associated with metabolic changes which also reflect the degree of fatigue. Responses to metabolic and physical stresses result in a metabolic pattern that allows discrimination of fibromyalgia patients from controls and narrows the focus on key pathophysiological processes in fibromyalgia as treatment targets. [ABSTRACT FROM AUTHOR]

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, β-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 μM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research. [ABSTRACT FROM AUTHOR]

This article discusses the use of microwave-assisted ionic liquid catalysis in the synthesis of pyrano[2,3-d]pyrimidine derivatives. The authors highlight the advantages of microwave irradiation in organic synthesis, such as uniform and selective heating and high yields. They also emphasize the benefits of ionic liquids, which have unique characteristics and can replace conventional bases in synthetic organic transformations. The authors present a protocol for the synthesis of pyrano[2,3-d]pyrimidine derivatives using ethyl methyl imidazolium hydroxide as a catalyst, resulting in short reaction times and high yields. They suggest that this method can be applied to the synthesis of other heterocyclic systems. [Extracted from the article]

To explore novel natural product‐based nitrogen‐containing heterocyclic compounds with antiproliferative activity, 20 L‐carvone‐derived pyrimidine‐urea compounds 4a–4t were synthesized through the multi‐step reaction of L‐carvone, and structurally characterized by Fourier transform infrared (FT‐IR), hydrogen‐1 nuclear magnetic resonance (1H‐NMR), Carbon‐13 nuclear magnetic resonance (13C‐NMR), and High‐resolution mass spectrometry (HRMS). Besides, the in vitro antiproliferative activity of the target compounds against HepG2, Hela, and MCF‐7 cells was evaluated by methyl thiazolyl tetrazolium (MTT) assay. According to the results, the target compounds showed certain inhibitory activities against the tested cancer cell lines, and five compounds (4b, 4h, 4k, 4l, and 4t) exhibited better inhibition activities against Hela cells than the positive control (5‐FU). Among them, compound 4b held significant antiproliferative activities against Hela and HepG2 cells, and thus deserved further study as a leading compound of new anticancer drugs. In addition, an effective and reasonable three‐dimensional quantitative structure‐activity relationships (3D‐QSAR) model was built by the Comparative molecular field analysis (CoMFA) method to analyze the relationship between the structures of the target compounds and their antiproliferative activities (expressed as pIC50) against Hela cells, and proven to have good predictive ability. Molecular docking was carried out to study the possible binding modes of compound 4b and Survivin, and it was found that compound 4b could be well embedded into the active site, along with the formation of several hydrogen bonds and hydrophobic interactions. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. METHODS: Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. RESULTS: Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. CONCLUSION: The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

BACKGROUND: Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. METHODS: We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged 12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). CONCLUSIONS: Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.

Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.

BackgroundAtopic dermatitis is a chronic inflammatory skin disease that can negatively impact work productivity and daily activities. Ruxolitinib cream, a Janus kinase inhibitor, demonstrated efficacy and safety in patients with atopic dermatitis in two phase III studies (TRuE-AD1 and TRuE-AD2).ObjectiveThis post hoc analysis sought to describe the effects of ruxolitinib cream on work productivity and activity impairment from pooled data from the phase III studies, to estimate indirect costs due to atopic dermatitis, and to estimate the incremental cost savings with ruxolitinib cream versus vehicle cream.MethodsPatients in both studies were ≥ 12 years old with atopic dermatitis for ≥ 2 years, an Investigator's Global Assessment score of 2 or 3, and a 3-20% affected body surface area at baseline. Patients were randomized 2:2:1 to receive ruxolitinib cream (0.75% or 1.5%) or vehicle cream for 8 weeks. Patient self-reported productivity in the efficacy-evaluable population was assessed at weeks 2, 4, and 8 using the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem version 2.0. Statistical significance for the two doses versus vehicle was calculated using an analysis of covariance. Work Productivity and Activity Impairment overall work impairment scores were converted to a model of costs per employed patient due to lost productivity and incremental cost savings from ruxolitinib cream treatment using a human capital approach.ResultsOf 1249 patients enrolled (median age, 32 years; female sex, 61.7%), 1208 were included in the efficacy-evaluable population. Patients applying 0.75% or 1.5% ruxolitinib cream had significant changes in overall work impairment (- 17.9% [0.75% strength] and - 15.0% [1.5% strength] vs - 5.7% for vehicle; p < 0.0001 for both) and daily activity impairment (- 20.6% [0.75% strength] and - 21.5% [1.5% strength] vs - 10.6% for vehicle; p < 0.0001 for both). These corresponded to estimated lost productivity costs in 2021 US dollars of $1313 (0.75% strength) and $1242 (1.5% strength) versus $2008 (vehicle) over the 8-week trial period. Compared with a patient receiving vehicle, incremental annual indirect cost savings were estimated to be $5302 with 0.75% ruxolitinib cream and $4228 with 1.5% ruxolitinib cream.ConclusionsRuxolitinib cream therapy is associated with improved work productivity and daily activity compared with vehicle and is estimated to reduce the indirect cost burden on the patient.Clinical trial registrationClinicalTrials.gov identifiers: NCT03745638 (registered 19 November, 2018) and NCT03745651 (registered 19 November, 2018).

DksA is a conserved RNA polymerase-binding protein known to play a key role in the stringent response of proteobacteria species, including many gastrointestinal pathogens. Here, we used RNA-sequencing of Escherichia coli, Salmonella bongori and Salmonella enterica serovar Typhimurium, together with phenotypic comparison to study changes in the DksA regulon, during Salmonella evolution. Comparative RNA-sequencing showed that under non-starved conditions, DksA controls the expression of 25%, 15%, and 20% of the E. coli, S. bongori, and S. enterica genes, respectively, indicating that DksA is a pleiotropic regulator, expanding its role beyond the canonical stringent response. We demonstrate that DksA is required for the growth of these three enteric bacteria species in minimal medium and controls the expression of the TCA cycle, glycolysis, pyrimidine biosynthesis, and quorum sensing. Interestingly, at multiple steps during Salmonella evolution, the type I fimbriae and various virulence genes encoded within SPIs 1, 2, 4, 5, and 11 have been transcriptionally integrated under the ancestral DksA regulon. Consequently, we show that DksA is necessary for host cells invasion by S. Typhimurium and S. bongori and for intracellular survival of S. Typhimurium in bone marrow-derived macrophages (BMDM). Moreover, we demonstrate regulatory inversion of the conserved motility-chemotaxis regulon by DksA, which acts as a negative regulator in E. coli, but activates this pathway in S. bongori and S. enterica. Overall, this study demonstrates the regulatory assimilation of multiple horizontally acquired virulence genes under the DksA regulon and provides new insights into the evolution of virulence genes regulation in Salmonella spp.

BackgroundPathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease. In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease.MethodsFirst, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot. Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083. We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry. We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis. Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice.ResultsIn vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways. We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease. VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced. Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity.ConclusionsAltogether, these findings suggest that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology. Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease.

A new series of hydrazone derivatives incorporating spirocyclic aminopyrimidine with aryl alkanesulfonates were synthesized. The targeted products were obtained in excellent yields via an acid catalyzed reaction of spirocyclic hydrazinopyrimidine with aryl aldehyde sulfonates. The structures of the synthesized hydrazones were studied by the different spectroscopic tools, in addition to the high resolution mass analysis. The antiproliferative activities of the compounds were tested in vitro against the National Cancer Institute (NCI) 60 cell panel by the Developmental Therapeutics Program. Amongst the tested hydrazone compounds, the methansulfonate derivatives showed the highest activities against lung, brain, kidney, and breast cancers. [ABSTRACT FROM AUTHOR]

An efficient one‐pot synthesis of some new series of benzo[5,6]chromeno[2,3‐d]pyrimidine derivatives is reported by the three‐component condensation reaction of 2,3‐dihydroxynaphthalene, 2‐thiobarbituric acid and aromatic aldehydes using sulfuric acid as the catalyst in glacial acetic acid under reflux condition. This transformation apparently proceeds through Michael addition, intra‐molecular heterocyclization and dehydration sequences. This protocol provides cleaner reaction profiles, good to high yields, operational simplicity, easy workup, readily accessible starting materials and not requires column chromatography for isolation of target products in pure form. [ABSTRACT FROM AUTHOR]

Recently, 5-[(4-ethoxyphenyl)imino]methyl-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amine has been synthesized, characterized, and evaluated for its antibacterial activity against Enterococcus faecalis in combination with antineoplastic activity against gastric adenocarcinoma. In this study, new 5-iminomethylpyrimidine compounds were synthesized which differ in the substituent(s) of the aromatic ring attached to the imine group. The structures of newly obtained pyrimidine Schiff bases were established by spectroscopy techniques (ESI-MS, FTIR and 1H NMR). To extend the current knowledge about the features responsible for the biological activity of the new 5-iminomethylpyrimidine derivatives, low-temperature single-crystal X-ray analyses were carried out. For all studied crystals, intramolecular N–H∙∙∙N hydrogen bonds and intermolecular C–H∙∙∙F interactions were observed and seemed to play an essential role in the formation of the structures. Simultaneously, their biological properties based on their cytotoxic features were compared with the activities of the Schiff base (III) published previously. Moreover, computational investigations, such as ADME prediction analysis and molecular docking, were also performed on the most active new Schiff base (compound 4b). These results were compared with the highest active compound III. [ABSTRACT FROM AUTHOR]

Herein, we report a commercially available natural saponin acting as a surfactant and serving as a micellar catalyst, enabling Suzuki–Miyaura cross-coupling effectively with highly challenging heteroaromatic substrates in water at room temperature. Utilizing this green and sustainable protocol, a broad spectrum of pyridine and pyrimidine substrates, and notably the notoriously unstable 2-pyridyl boronic acid were successfully cross-coupled in moderate to high yields. [ABSTRACT FROM AUTHOR]

2-Aminobenzimidazoles react with acetylene in the KOBut/DMSO superbase system (80°C, 20 min) to give benzimidazo[1,2-a]imidazoles and benzimidazo[1,2-a]pyrimidines formed by the self-assembly of the starting compounds with two or three molecules of acetylene. Vinyl derivatives of 1,3-dihydro-2H-benz[d]imidazole-2-imine were also isolated. [ABSTRACT FROM AUTHOR]

A series of 4-(1H-pyrazol-5-yl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine derivatives have been depicted by one-pot three component synthesis. The synthesis involved the reaction of 4-hydroxy-2H-chromen-2-one with 1H-pyrazole-5-carbaldehydes and urea/thiourea. The reaction was conducted in the presence of L-proline as a catalyst and ethanol as the solvent. This approach exhibits notable benefits like high yields, environmental compatibility, an easy procedure, short reaction periods, and mild reaction conditions. The synthesized compounds were examined for their cytotoxicity potential in HeLa and MCF-7 cells. Among all, 4-(1,4-dimethyl-1H-pyrazol-5-yl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione showed promising activity with IC50 values 8.0 and 8.5 µM towards MCF-7 and HeLa cells, respectively. In addition, the docking studies revealed that 4-(1,4-dimethyl-1H-pyrazol-5-yl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione had a favorable binding energy of –9.4 kcal/mol in inhibiting the human Aldo-keto reductase 1C3. [ABSTRACT FROM AUTHOR]

A series of novel (Z)-N′-(1-(aryl)ethylidene)-6-cyano-5-imino-3-methyl-7-(methylthio)-5Hthiazolo[3,2-a]pyrimidine-2-carbohydrazide derivatives was synthesized. All the synthesized compounds were investigated for antimalarial efficacy against Plasmodium falciparum parasite. It was found that, of all tested compound with 4-Cl and 2,4-Cl substituents in aromatic ring exhibited an excellent activity. Molecular docking analysis of the significantly active compounds was performed using PfDHFR enzyme. Compound with 4-Cl substituent demonstrates a binding energy of –9.0 kcal/mol, while that with 2,4-Cl substituent exhibits a binding energy of –9.3 kcal/mol. An analysis of their physicochemical and pharmacokinetics properties related to ADMET was also carried out for all the synthesized molecules. [ABSTRACT FROM AUTHOR]

Aims During fermentation, the accumulation of acidic products can induce media acidification, which restrains the growth of Bifidobacterium animalis subsp. lactis Bb12 (Bb12). This study investigated the nutrient consumption patterns of Bb12 under acid stress and effects of specific nutrients on the acid resistance of Bb12. Methods and results Bb12 was cultured in chemically defined medium (CDM) at different initial pH values. Nutrient consumption patterns were analyzed in CDM at pH 5.3, 5.7, and 6.7. The patterns varied with pH: Asp + Asn had the highest consumption rate at pH 5.3 and 5.7, while Ala was predominant at pH 6.7. Regardless of the pH levels (5.3, 5.7, or 6.7), ascorbic acid, adenine, and Fe2+ were vitamins, nucleobases, and metal ions with the highest consumption rates, respectively. Nutrients whose consumption rates exceeded 50% were added individually in CDM at pH 5.3, 5.7, and 6.7. It was demonstrated that only some of them could promote the growth of Bb12. Mixed nutrients that could promote the growth of Bb12 were added to three different CDM. In CDM at pH 5.3, 5.7, and 6.7, it was found that the viable cell count of Bb12 was the highest after adding mixed nutrients, which were 8.87, 9.02, and 9.10 log CFU ml−1, respectively. Conclusions The findings suggest that the initial pH of the culture medium affects the nutrient consumption patterns of Bb12. Specific nutrients can enhance the growth of Bb12 under acidic conditions and increase its acid resistance. [ABSTRACT FROM AUTHOR]

The increase in the prevalence of antibiotic‐resistant pathogens leads to a decrease in the number of antimicrobial agents for the treatment of infections and prompts researchers to search for new effective antimicrobial drugs. This study reports the synthesis of novel triphenylphosphonium‐functionalized substituted pyrimidines and in vitro evaluation of their antibacterial and antibiofilm activity. Most of the synthesized derivatives showed high antibacterial activity (MIC = 0.39–1.56 μg/mL) against the methicillin‐resistant strain of S. aureus 222. Compounds 2a and 11 exhibited a high level of antibiofilm activity against S. aureus 222 and E. coli 311. The triphenylphosphonium‐containing pyrimidines 11 and 2a reduced S. aureus 222 biofilm formation by 99.1% and 95.8%, respectively. In addition, compound 2a was the most active against E. coli 311 biofilm formation (the biomass decreased by 98.4%). [ABSTRACT FROM AUTHOR]

This work describes the design and synthesis of three series of hybrids of thienopyrimidines and sulfonamides. Dihydrofolate reductase enzyme was selected as a target for the in-silico screening of the synthesized thienopyrimidine–sulfonamide hybrid as an antibacterial, while squalene epoxidase was selected as an antifungal target protein. All screened compounds showed promising binding affinity ranges, with perfect fitting not exceeding 1.9 Å. The synthesized compounds were tested for their antimicrobial activity using agar well diffusion and minimum inhibitory concentration tests against six bacterial strains in addition to two Candida strains. Compounds 8iii and 12ii showed varying degrees of inhibition against Staphylococcus aureus and Escherichia coli bacterial strains, whereas the best antifungal activity against Candida was displayed by compound 8iii. Compound 12ii, the cyclohexathienopyrimidine coupled with sulfadiazine at position 3, has the best antibacterial activity, which is consistent with molecular docking results at the active site of the oxidoreductase protein. Interestingly, compound 12ii also has the highest docking binding energy at the antifungal squalene epoxidase active site. Investigating the physicochemical properties of the synthesized hybrids revealed their high tolerability with cell membranes, and moderate to poor oral bioavailability, and that all are drug-like candidates, among which 4i, the cyclohexathieno[2,3-d] pyrimidine core with sulphaguanidine incorporated at position 4, recorded the best score (1.58). [ABSTRACT FROM AUTHOR]

Pyridopyrimidine are heterocyclic molecules enclosing fused pyridine and pyrimidine rings. Owing to its fascinating core structure and pharmacological applications a series of 7-([1,1′-biphenyl]-4-yl)-5-arylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones were synthesized and characterized using IR, 1H, 13C NMR and Mass spectral techniques. The antibacterial, antioxidant and anticancer activities were investigated for the synthesized compound 5a-5f. Compounds with electron-donating groups showed excellent free radical scavenging activity. Halogen-substituted compounds showed more potent antimicrobial and anticancer activity than other derivatives in comparison with their respective standards. Based on the IC50 value obtained from anticancer activity, 5c was further analyzed for apoptosis by AO/EB staining method. The findings suggested early apoptosis in the MCF-7 cell line. Molecular Docking studies of the synthesized compounds were performed with Kinase 1 inhibitors (PDB id: 2YEX), 5c exposed good docking results with minimum binding energy. Further, these compounds were acknowledged as orally active drug candidates from in-silico ADMET studies. Computational analysis supports biological findings indicating compound 5c as a promising anticancer agent against the human breast cancer MCF-7 cell line. [ABSTRACT FROM AUTHOR]

A straightforward and effective strategy for the synthesis of novel 7-cyano-4-imino-3-phenyl-6-(pyrrolidin-1-yl)-2-substituted-3,4-dihydroselenopheno[3,2-d]pyrimidines have been accomplished through a base-promoted cascade addition/cyclization sequence employing phenyl isothiocyanate followed by the S-alkylation of the obtained fused Se-containing heterocyclic framework with various alkyl halides. Free radical scavenging activity of the synthesized selenium-containing structures was studied against DPPH, as well. Antioxidant activities as IC50 values were ranged from 12.19 to 91.08 µM. Unfused 3-amino-2,4-dicyano-5-(pyrrolidin-1-yl)selenophene was much more powerful antioxidant agent than ascorbic acid. Moreover, the promising antioxidant potentials were observed with selenopheno[3,2-d]pyrimidines. Taking into account the best antioxidant activity of S-benzylated derivative amongst pyrimidine-fused heterocycles and significant relationship between antioxidant activity of compounds and many of their biological potencies, using benzyl halides bearing electron donating groups on phenyl ring can probably improve their antioxidant capacities to make them more effective anti-cancer, anti-diabetic, anti-inflammatory and anti-neurodegenerative agents. [ABSTRACT FROM AUTHOR]

The exponential development of resistance to conventional chemical insecticides adds another important motive for the creation of novel insecticidal active agents. One of the keys to meeting this challenge is the exploration of novel classes of insecticidal molecules with different modes of action. Herein, a novel series of spiro pyrimidine derivatives was prepared using some green synthetic methodologies such as microwave irradiation, and sonication under ultrasound waves. Spiro pyrimidine aminonitrile 1 is a key starting material for the synthesis of targets 2–9 by reaction with different carbon electrophiles and nitrogen nucleophiles. The structures of all the newly synthesized compounds were approved using spectral data. The toxicological efficiency and biological impacts of the synthesized spiro pyrimidine derivatives were assessed against Culex pipiens L. larvae. The toxicity of synthesized compounds showed remarkable variations against the C. pipiens larvae. Where, 3, 4 and 2 were the most efficient compounds with LC50 values of 12.43, 16.29 and 21.73 µg/mL, respectively. While 1 was the least potent compound with an LC50 value of 95.18 µg/mL. As well, other compounds were arranged according to LC50 values as follows 5 > 7 > 6 > 9 > 8. In addition, 3 and 4 exhibited significant prolongation of the developmental duration and greatly inhibited adult emergence. Moreover, many morphological deformities were observed in all developmental stages. Furthermore, cytotoxicity of the most effective compounds was assessed against the normal human cells (WI-38) as non-target organisms, where compounds 2, 4 and 3 showed weak to non-toxic effects. The study of binding affinity and correlation between chemical structure and reactivity was carried out using molecular docking study and DFT calculations to investigate their mode of action. This study shed light on promising compounds with larvicidal activity and biological impacts on the C. pipiens life cycle. [ABSTRACT FROM AUTHOR]

Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment. [ABSTRACT FROM AUTHOR]

The photocatalytic activity of graphitic carbon nitride (g-C 3 N 4) depends to a large extent on its morphology and electronic band structure. In order to design a photocatalyst with suitable structural property and high efficiency of photo-generated carrier separation, herein, the pyrimidine doped g-C 3 N 4 is prepared by a conventional one-pot copolymerization of urea and 2,4,6-Triaminopyrimidine (TAP). Such TAP organic molecule can not only regulate the electronic structure of conjugated system and distort heptazine units, but also affect the polymerization of precursor urea. As expected, the optimized photocatalyst shows a high photocatalytic hydrogen evolution activity of 453 μmol·h−1 under visible light irradiation, which is 4.41 times over that of pure g-C 3 N 4. Such enhanced photocatalytic performance is attributed to the introduction of pyrimidine ring which facilitates the electrons delocalization in the in-plane structure, enlarges the specific surface area, and broadens the visible light absorption range. • The electron delocalization is promoted on pyrimidine doped graphitic carbon nitride. • Homogeneous carbon doping is achieved on a heptazine ring. • The specific surface area of the modified sample is up to 150.07 m2 g−1. [ABSTRACT FROM AUTHOR]

The current research is directed to construct a novel category of linear annulated chromeno[3',2':5,6]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidines. The chemical reactivity of the recently synthesized aldehyde 1 was examined toward a diversity cyclic methylene ketones, cyclic enamines and cyclic enols. Friedländer condensation of aldehyde 1 with 1,3-cyclohexanediones gave the multi-linear chromenopyrido- pyrimidothiazoloquinolines 2 and 3. Also, treating aldehyde 1 with some pyrazolones furnished annulated chromenopyridopyrazolopyridothiazolopyrimidines 4-6. Further, 1,3-thiazolidine-2,4-dione and barbituric acid condensed with aldehyde 1 giving chromenopyridothiazolopyridothiazolopyrimidine 7 and chromenopyridopyrimido-thiazolopyridopyrimidine 8, respectively. Moreover, reacting aldehyde 1 with cyclic enamines (6-amino-2-thiouracil and 6-amino-1,3-dimethyluracil) and cyclic enols (4-hydroxycoumarin and 1-ethyl-4-hydroxyquinolin-2(1H)-one) furnished polyfused heterocycles 9-12, respectively. During in vitro investigation of the antimicrobial efficiency, the synthesized compounds showed considerable activity against yeast and fungal strains, as well as moderate to high activity against Gram-positive and Gram-negative bacteria. Polyfused compounds 4-6 showed significant efficiency against all types of tested microorganisms. [ABSTRACT FROM AUTHOR]