Search

Purpose: To investigate the anti-inflammatory, anti-cancer, anti-parkinsonian, anti-microbial, analgesic, and anti-hyperglycemic properties of a variety of poly-fused pyrimidine derivatives. Methods: A novel series of fused pyrimidine derivatives 1-6 were synthesized by reacting amino pyrazole derivatives with active methylene derivatives to give the corresponding compounds 1-6. Anti-parkinsonian activity was investigated with benzotropene as a reference drug, anti-inflammatory effect in mice was evaluated using carrageenan in paw edema with indomethacin as reference drug, antimicrobial activity was assessed using nutritional agar with ciprofloxacin and ketoconazole as reference drugs, analgesic activity was evaluated using valdecoxib as reference drug, anti-hyperglycemic activity was investigated using alloxan and sucrose models (SLM) with pioglitazone as reference drug and anticancer activity was investigated using the MTT micro-cultured tetrazolium assay method with doxorubicin as reference drug. Results: Pyrimidine derivatives 1-6 possess significant active anti-parkinsonian, anti-inflammatory, antimicrobial, analgesic, anti-hyperglycemic and anticancer activities in comparison to the reference drugs used for each model. Compared to Benzotropene®, compounds 1 and 3 showed a significantly stronger anti-parkinsonian activity (p < 0.03). Compound 3 showed a significantly stronger anti-inflammatory effect than Indomethacin® (p < 0.05). Compounds 5 and 6 exhibited significant anti-microbial activity compared to ciprofloxacin® (p < 0.05). Compounds 4 and 6 exhibited significantly improved analgesic activity as compared to Valdecoxib® (p < 0.01). Compounds 1 and 3 exhibited significantly higher antihyperglycemic effects in SLM model when compared to pioglitazone® (p < 0.02). Compound 5 demonstrated the highest activity against human colon cancer cell line (HT-29) and human prostate cancer cell line (DU145), and also, significantly improved level of efficacy against human lung cancer cell line (A549) compared to Doxorubicin® (p < 0.02). Conclusion: Using the six pyrimidine derivatives 1 - 6 as a lead molecule, a novel class of clinically beneficial anti-cancer, anti-inflammatory, anti-microbial, analgesic, and anti-hyperglycemic drugs may be produced. [ABSTRACT FROM AUTHOR]

A series of new 8-decylthio-10-methylthio-pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives was prepared and characterized by FTIR, 1H NMR, 13C NMR, and HRMS. The bioassay results revealed that the title compounds had moderate to excellent insecticidal activities against Aphis fabae at a concentration of 500 mg/L. Among them, 8-(decylthio)-2-((4-chlorophenoxy)methyl)-5-propyl-10-(methylthio)-5,6-dihydropyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine (4l) exhibited the highest insecticidal activity, with 95% mortality. Moreover, 8-(decylthio)-2-((2,4-dichlorophenoxy)methyl)-5-propyl-10-(methylthio)-5,6-dihydropyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine (4i) showed broad-spectrum postemergence herbicidal activities against Abutilon theophrasti, Amaranthus spinosus, Chenopodium album, Digitaria sanguinalis, Echinochloa crusgalli, and Setaria viridis, which were equivalent to the positive control flumetsulam. However, all new synthesized compounds displayed weak fungicidal activity against four kinds of phytopathogenic fungi including Botrytis cinerea, phytophythora capsici, Elsinoe fewcetti, and Diaporthe medusaea. Compound 4l with remarkable insecticidal activity, and compound 4i with excellent herbicidal activity could be promising lead compounds for further investigation. [ABSTRACT FROM AUTHOR]

This article provides a review of recent advances in the synthesis and biological activities of functionalized pyrimidines. It discusses the synthesis and pharmacological activities of pyrimidines in the areas of anticancer, antidiabetes, and antioxidant properties. The article also highlights the potential applications of novel pyrimidine compounds in various fields, including their antioxidant, anti-inflammatory, antibacterial, and antiviral activities. The authors acknowledge the support of Mohanlal Sukhadia University in India. [Extracted from the article]

This document presents a method for synthesizing pyrano[2,3-d]pyrimidines using tris(hydroxymethyl)aminomethane (THAM) as a catalyst. The reactions were carried out in a water/ethanol solution at room temperature and resulted in high yields of the desired compounds. The THAM catalyst could be reused multiple times with only a slight decrease in yield. The article suggests that this simple and environmentally friendly method may encourage further research and synthesis of these heterocyclic systems. The research was supported by the Research Council of the Apadana Institute of Higher Education. [Extracted from the article]

New cytisine-thienopyrimidine hybrid molecules were synthesized by reacting cytisine with 4-chlorothieno [2,3-d]pyrimidines in the presence of Et3N. The solvent effect on the course of the reaction was studied. The structures of the obtained compounds were elucidated using IR, 1H and 13C NMR spectroscopy and TLC-MS spectrometry. X-ray crystal structure analyses of the synthesized compounds were performed. [ABSTRACT FROM AUTHOR]

The essential aim of the present study is designed to utilize 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (1) to build some novel heterocyclic systems containing benzofurans as well as furo[3,2-g]chromenes. Ring opening ring closure reactions of compound 1 with N-phenyl-2-cyanoacetamide produced 8-amino-furochromenopyridine-7-carboxamide 2, which cyclized with some electrophilic reagents giving furochromenopyridopyrimidines (63–73% yields). The reaction of carbonitrile 1 with pyrazolone derivatives yielded furochromenopyrazolopyridines 10 and 11 in good yields. Also, benzo[h]furochromeno naphthyridine 13 was synthesized from recyclization of carbonitrile 1 with 1-ethyl-4-hydroxyquinolin-2(1H)-one (12). On a different mechanism, recyclization of carbonitrile 1 with some 1,3-binucleophiles afforded pyrido[2,3-d]pyrimidines (14 and 15), pyrimido[1,2-a]pyrimidine 17 and pyrimido[2,1-c][1,2,4]triazine 19 in suitable yields (62–71%). Finally, the reaction of carbonitrile 1 with 1,3-cyclohexanedione and 1,4-cyclohexanedione in 2:1 molar ratio yielded polyfused systems 20 and 21, respectively. Based on spectral and analytical results, the structures of the all products were inferred. [ABSTRACT FROM AUTHOR]

The pyrimidine scaffold represents one of the privileged structures in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. A series of 2-amino pyrimidines were synthesized by the reaction of ketene dimethyl thio-acetals with guanidinium nitrate in presence of sodium ethoxide in ethanol under reflux condition. Spectral analysis of the final compounds has been carried out using IR, 1H NMR, 13C NMR spectroscopy and HRMS. Further, the structure of one of the derivatives 4-ethoxy-6-(naphthalen-1-yl) pyrimidin-2-amine (2d) was confirmed by single crystal X-ray diffraction technique. X-ray diffraction analysis for 2d has been reported. The crystal structure of 2d is stabilized by intermolecular N–H...N, C–H...π and π...π weak interactions. To check whether pyrimidine could be ligands for two kinases involved in cancer, docking studies were performed. Few of the compounds showed strong binding affinity with IGF1R and EGFR. [ABSTRACT FROM AUTHOR]

In this investigation, a novel group of compounds, 2-mercapto-benzofuro-pyrimidine derivatives, were synthesized from 2-hydroxy-5-nitro-1-benzonitrile (1) as the starting material. This was treated with various haloketones to provide the corresponding 1-(3-amino-5-nitro-1-benzofuran-2-yl) ethan-1-one (2a-d), which was then treated with ammonium thiocyanate and acetyl chloride to yield N-[(2-acetyl-5-nitro-1-benzofuran-yl) carbamothioyl]acetamide (3a-d). Further, it was reflux with sodium hydroxide yields 4-methyl/aryl-8-nitro[1] benzofuro[3,2-d]pyrimidine-2-thiol(4a-d). To obtain the appropriate acids, continue stirring compounds (4ad) with chloroacetic acid to obtain [(4-methyl-8-nitro[1]benzofuro[3,2-d]pyrimidin-2-yl)sulfanyl]acetic acid (5a-d). The structures of all the newly synthesized compounds have been established by spectral studies such as Fourier-transform infrared, Proton nuclear magnetic resonance and Mass spectra. Furthermore, all the new compounds were screened antibacterial and antifungal activity against human pathogenic viz. gram +Ve and gram -Ve organisms by agar well diffusion method. In addition, molecular docking was performed for all synthesized compounds using high inhibition organisms selected protein of both genetic and non-genetic algorithm techniques, where result are demonstrate in an excellent docking energy. [ABSTRACT FROM AUTHOR]

Purines and pyrimidines are essential components as they are the building blocks of vital molecules, such as nucleic acids, coenzymes, signalling molecules, as well as energy transfer molecules. Purine and pyrimidine metabolism defects are characterised by abnormal concentrations of purines, pyrimidines and/or their metabolites in cells or body fluids. This phenomenon is due to a decreased or an increased activity of enzymes involved in this metabolism and has been reported in humans for over 60 years. This review provides an overview of neurological presentations of inborn errors of purine and pyrimidine metabolism. These conditions can lead to psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscular symptoms. Clinical signs are often nonspecific and thus overlooked, but some diseases are treatable and early diagnosis may improve the child's future. Although these metabolic hereditary diseases are rare, they are most probably under-diagnosed. When confronted with suggestive clinical or laboratory signs, clinicians should prescribe genetic testing in association with a biochemical screening including thorough purine and pyrimidine metabolites analysis and/or specific enzyme evaluation. This is most likely going to increase the number of confirmed patients. • Genetic defects in purine and pyrimidine metabolism cause neurological conditions. • These metabolic hereditary diseases are rare but likely under-diagnosed. • Some pathologies are treatable and early diagnosis may improve the child's future. • Each disorder includes the involved genes, clinical signs, and biochemical tests. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) infection causes respiratory disease. Recently, infection of IAV H5N1 among mammals are reported in farmed mink. Therefore, to discover antivirals against IAV, we screened a compound library by using the RNA‐dependent RNA polymerase (RdRp) assay system derived from H5N1 IAV including a drug‐resistant PA mutant (I38T) and a viral polymerase activity enhancing PB2 mutant (T271A). Upon screening, we found vidofludimus can be served as a potential inhibitor for IAV. Vidofludimus an orally active inhibitor for dihydroorotate dehydrogenase (DHODH), a key enzyme for the cellular de novo pyrimidine biosynthesis pathway. We found that vidofludimus exerted antiviral activity against wild‐type and drug‐resistant mutant IAV, with effective concentrations (EC50) of 2.10 and 2.11 μM, respectively. The anti‐IAV activity of vidofludimus was canceled by the treatment of uridine or cytidine through pyrimidine salvage synthesis pathway, or orotic acid through pyrimidine de novo synthesis pathway. This indicated that the main target of vidofludimus is DHODH in IAV RdRp expressing cells. We also produced recombinant seasonal IAV H1N1 virion and influenza B virus (IBV) RdRp assay system and confirmed vidofludimus also carried highly antiviral activity against seasonal IAV and IBV. Vidofludimus is a candidate drug for the future threat of IAV H5N1 infection among humans as well as seasonal influenza virus infection. [ABSTRACT FROM AUTHOR]

Objectives: To synthesize a novel series of 3-(Aryl/Heteroaryl)-5-Methyl-7-Phenyl [1,2,4]triazolo[4,3a]Pyrimidines (5a-i). Materials and Methods: Synthesis was carried out though the microwave assisted synthesis, Spectroscopic approaches such as IR, 1HNMR and MASS spectroscopy were used to characterize the produced substances. Antimicrobial screening was done by Cup Plate Method for the antibiotic zone determination and Minimum Inhibitory Concentration was determined by the tube dilution method. Experimental Work: The oxidation of substituted pyrimidinylhydrazones in dichloromethane with iodobenzene diacetate was used in the synthesis. Substituted pyrimidinylhydrazones was obtained by the condensation of 1-(1,4-dihydro-6-methyl-4-phenylpyrimidine-2-yl)-hydrazine containing a variety of aromatic/heteroaromatic aldehydes. 3-(Aryl/Heteroaryl)-5-Methy l-7-Phenyl-[1,2,4]triazolo[4,3a]Pyrimidines (5a-i) were investigated in vitro for antibacterial activity against gram-positive bacteria such as Bacillus subtilis and Staphylococcus aureus, as well as gram-negative bacteria such as Escherichia coli and Pseudomonas putida. Results: 3-(4-fluorophenyl)-5-Methyl-7-Phenyl-[1,2,4]Triazolo[4,3a]Pyrimidine (5a) and 3-(4-Nitrophenyl)-5-Methyl-7-Phenyl-[1,2,4]Triazolo[4,3a]Pyrimidine (5e) found effective when compared to known marketed drugs Streptomycin and Chloramphenicol as both compounds are having the substitution of most electronegative groups which shows strong interaction with targeted DNA Gyrase enzyme of the bacteria. Conclusion: Microwave found to be an eco-friendly method for cyclization of pyrimidinylhydrazone to triazolopyrimidine. This method was found to be clean, safe and operationally simple which give triazolopyrimidine products with high yield. [ABSTRACT FROM AUTHOR]

According to the recent studies bezylcarboxamide fragment attached to the thiophene ring of thieno[2,3-d]pyrimidine is beneficial for antimicrobial activity of the compounds. Therefore we focused our efforts on constructing of the simple molecules such as N-(benzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamides to get deeper insight into their antimicrobial activity. As the optimal procedure for preparation of target compounds we choose 1,1'-carbonyldiimidazole promoted interaction of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid with the series of substituted benzyl amines. The obtained amides showed good activity against the strains of S. aureus and B. subtilis, which was higher for the derivative without substituents in benzene ring or the compounds with small substituents like methyl or methoxyl groups in the para-position of the benzene ring. Docking studies showed that despite the good values of the scoring functions, the conformational analysis of the ligands' poses in the active site revealed their ability for only partial inhibition of TrmD of P. aeruginosa. [ABSTRACT FROM AUTHOR]

The use of ultraviolet-C (UV-C) irradiation in marine biofouling control is a relatively new and potentially disruptive technology. This study examined effects of UV-C exposure on the biofilm-forming diatom, Navicula incerta. UV-C-induced mutations were identified via Illumina HiSeq. A de novo genome was assembled from control sequences and reads from UV-C-exposed treatments were mapped to this genome, with a quantitative estimate of mutagenesis then derived from the frequency of single nucleotide polymorphisms. UV-C exposure increased cyclobutane pyrimidine dimer (CPD) abundance with a direct correlation between lesion formation and fluency. Cellular repair mechanisms gradually reduced CPDs over time, with the highest UV-C fluence treatments having the fastest repair rates. Mutation abundances were, however, negatively correlated with CPD abundance suggesting that UV-C exposure may influence lesion repair. The threshold fluence for CPD formation exceeding CPD repair was >1.27 J cm−2. Fluences >2.54 J cm−2 were predicted to inhibit repair mechanisms. While UV-C holds considerable promise for marine antifouling, diatoms are just one, albeit an important, component of marine biofouling communities. Determining fluence thresholds for other representative taxa, highlighting the most resistant, would allow UV-C treatments to be specifically tuned to target biofouling organisms, whilst limiting environmental effects and the power requirement. [ABSTRACT FROM AUTHOR]

Background: The pyrimidine salvage pathway plays a critical role in tumor progression and patient outcomes. The roles of pyrimidine salvage pathway-related genes (PSPGs) in cancer, however, are not fully understood. This study aims to depict the characteristics of PSPGs across various cancers.Methods: An integrative pan-cancer analysis of six PSPGs (CDA, UCK1, UCK2, UCKL1, UPP1, and UPP2) was conducted using TCGA data, single-cell RNA sequencing datasets, and patient samples. Single-cell transcriptome analysis and RT-qPCR were used to validate the relation between UPP1 and cytokines. Flow cytometry was performed to validate the role of UPP1 in immune checkpoint regulation. The correlation between UPP1 and tumor associated neutrophils (TAN) were investigated and validated by single-cell transcriptome analysis and tissue microarrays (TMAs).Results: PSPGs showed low mutation rates but significant copy number variations, particularly amplifications in UCKL1, UPP1, and UCK2 across various cancers. DNA methylation patterns varied, with notable negative correlations between methylation and gene expression in UPP1. PSPGs were broadly up-regulated in multiple cancers, with correlations to clinical staging and prognosis. Proteomic data further confirmed these findings. Functional analysis revealed PSPGs' associations with tumor proliferation, metastasis, and various signaling pathways. UPP1 showed strong correlations with the tumor microenvironment (TME), particularly with cytokines, immune checkpoints, and various immune cells. Single-cell transcriptome analysis confirmed these associations, highlighting UPP1's influence on cytokine expression and immune checkpoint regulation. In esophageal squamous cell carcinoma (ESCC), UPP1-high tumor cells were significantly associated with immunosuppressive cells in the TME. Spatial analysis using TMAs revealed that UPP1+ tumor cells were predominantly located at the invasive margin and closely associated with neutrophils, correlating with poorer patient prognosis.Conclusion: Our study depicted the multi-dimensional view of PSPGs in cancer, with a particular focus on UPP1's role in the TME. Targeting UPP1 holds promise as a potential strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

Isonicotinohydrazide is the first‐line medication in the prevention and treatment of tuberculosis. Antitubercular, antibacterial, antifungal, antiviral, anti‐inflammatory, antimalarial activity, anticancer, antineoplastic activity, and anti‐HIV activity are all demonstrated by drugs with a pyrimidine ring. The current study focuses on the synthesis of N‐(4‐(substituted‐phenyl)‐6‐(substituted‐aryl) pyrimidin‐2‐yl)‐2‐(2‐isonicotinoylhydrazinyl) acetamide from isonicotinohydrazide. Newly synthesized compounds were characterized by spectral studies (IR, 1H‐NMR, 13C‐NMR, and mass spectroscopy). They were screened for their antituberculosis, antimalarial, and antiprotozoal activities and compared with standard drugs. Molecular docking of isonicotinohydrazide‐bearing pyrimidine motifs was also done for some of the active compounds. [ABSTRACT FROM AUTHOR]

CTNNB1, encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

PurposeAurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion.MethodsKey inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles.ResultsIn total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration.ConclusionsThis trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.

PurposeAdagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.Materials and methodsPatients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.ResultsTwenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).ConclusionAdagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

This article discusses the synthesis of a potential anti-HIV agent called 2'-deoxy-2'-β-fluoro-4'-azido-5-fluorouridine (1). The authors describe the design and synthesis of this nucleoside analogue, which is structurally modified to mimic physiological nucleosides. The compound was successfully synthesized in nine steps starting from 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-d-arabinofuranoside. In vitro biological evaluation showed that the compound exhibited good antiviral activity against HIV-1 infection. This research contributes to the development of novel nucleoside analogues for the treatment of viral infections. [Extracted from the article]

The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds. To achieve this, a dataset of pyrimidine and uracil compounds from ChEMBL were collected and curated. A workflow was developed for data-driven machine learning QSAR using an intuitive dataset design and forwards selection of molecular descriptors. The model was thoroughly externally validated against available data. Blind validation was also performed by synthesis and antiproliferative evaluation of new synthesized uracil-based and pyrimidine derivatives. The most active compound among new synthesized derivatives, 2,4,5-trisubstituted pyrimidine was predicted with the QSAR model with differences of 0.02 compared to experimentally tested activity.

The relevance of the asymmetric Biginelli reaction (ABR) has been increased in this century, due to the pharmacological application of its products. This review focuses predominantly on articles published in the period from 2015 to 2024 on asymmetric synthetic advances in the formation of dihydropyrimidinones (DHPMs), dihydropyrimidinethiones (DHPMTs), and related compounds. The relevant bibliography on general processes in the Biginelli reaction and some methods of separation of isomers have also been referenced.

1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism of the 1,2,3-triazine/1,2,3,5-tetrazine-amidine reaction as well as its intrinsic reactivity remains underexplored. By using 15N-labeling, kinetic investigations, and kinetic isotope effect studies, complemented by extensive computational investigations, we show that this reaction proceeds through an addition/N2 elimination/cyclization pathway, rather than the generally expected concerted or stepwise Diels-Alder/retro Diels-Alder sequence. The rate-limiting step in this transformation is the initial nucleophilic attack of an amidine on azine C4, with a subsequent energetically favored N2 elimination step compared with a disfavored stepwise formation of a Diels-Alder cycloadduct. The proposed reaction mechanism is in agreement with experimental and computational results, which explains the observed reactivity of 1,2,3-triazines and 1,2,3,5-tetrazines with amidines.

We report long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized chronic lymphocytic leukemia (CLL) studies. Patients (≥65 years) with previously untreated CLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5-0.8 mg/kg ≤12 cycles (n = 133). With up to 8 years of follow-up (range, 0.1-96.6 months; median, 82.7 months), significant PFS benefit was sustained for ibrutinib vs chlorambucil (hazard ratio [HR], 0.154; 95% confidence interval [CI], 0.108-0.220). At 7 years, PFS was 59% for ibrutinib vs 9% for chlorambucil. PFS benefit was also observed for ibrutinib- vs chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated immunoglobulin heavy chain variable region (HR, 0.112; 95% CI, 0.065-0.192). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 31 patients because of AEs; these AEs resolved or improved in 85% (67 of 79) and 90% (28 of 31) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials were registered at www.clinicaltrials.gov as #NCT01722487 and #NCT01724346.

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) 10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.

Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.

Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma.SignificanceWe demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.

Brilacidin, a mimetic of host defense peptides (HDPs), is currently in Phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inactivating the virus. In this study, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on the host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, an HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on the host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.

IntroductionTreatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50 - 100 × 109/L) are reported.Patients and methodsPatients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety.ResultsOf 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were -20.5% (-55.8% to 38.5%, n=51) and -39.8% (-98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3).ConclusionA starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

Following our recent work on the benzene molecule [P.-F. Loos, Y. Damour, and A. Scemama, J. Chem. Phys. 153, 176101 (2020)], motivated by the blind challenge of Eriksen et al. [J. Phys. Chem. Lett. 11, 8922 (2020)] on the same system, we report accurate full configuration interaction (FCI) frozen-core correlation energy estimates for 12 five- and six-membered ring molecules (cyclopentadiene, furan, imidazole, pyrrole, thiophene, benzene, pyrazine, pyridazine, pyridine, pyrimidine, s-tetrazine, and s-triazine) in the standard correlation-consistent double-ζ Dunning basis set (cc-pVDZ). Our FCI correlation energy estimates, with an estimated error smaller than 1 millihartree, are based on energetically optimized-orbital selected configuration interaction calculations performed with the configuration interaction using a perturbative selection made iteratively algorithm. Having at our disposal these accurate reference energies, the respective performance and convergence properties of several popular and widely used families of single-reference quantum chemistry methods are investigated. In particular, we study the convergence properties of (i) the Møller–Plesset perturbation series up to fifth-order (MP2, MP3, MP4, and MP5), (ii) the iterative approximate coupled-cluster series CC2, CC3, and CC4, and (iii) the coupled-cluster series CCSD, CCSDT, and CCSDTQ. The performance of the ground-state gold standard CCSD(T) as well as the completely renormalized CC model, CR-CC(2,3), is also investigated. We show that MP4 provides an interesting accuracy/cost ratio, while MP5 systematically worsens the correlation energy estimates. In addition, CC3 outperforms CCSD(T) and CR-CC(2,3), as well as its more expensive parent CCSDT. A similar trend is observed for the methods including quadruple excitations, where the CC4 model is shown to be slightly more accurate than CCSDTQ, both methods providing correlation energies within 2 millihartree of the FCI limit. [ABSTRACT FROM AUTHOR]

Toxoplasmosis is a common protozoan infection that can have severe outcomes in the immunocompromised and during pregnancy, but treatment options are limited. Recently, nucleotide metabolism has received much attention as a target for new antiprotozoal agents and here we focus on pyrimidine salvage by Toxoplasma gondii as a drug target. Whereas uptake of [³H]-cytidine and particularly [³H]-thymidine was at most marginal, [³H]-uracil and [³H]-uridine were readily taken up. Kinetic analysis of uridine uptake was consistent with a single transporter with a Km of 3.3 ± 0.8 µM, which was inhibited by uracil with high affinity (Ki = 1.15 ± 0.07 µM) but not by thymidine or 5-methyluridine, showing that the 5-Me group is incompatible with uptake by T. gondii. Conversely, [³H]-uracil transport displayed a Km of 2.05 ± 0.40 µM, not significantly different from the uracil Ki on uridine transport, and was inhibited by uridine with a Ki of 2.44 ± 0.59 µM, also not significantly different from the experimental uridine Km. The reciprocal, complete inhibition, displaying Hill slopes of approximately -1, strongly suggest that uridine and uracil share a single transporter with similarly high affinity for both, and we designate it uridine/uracil transporter 1 (TgUUT1). While TgUUT1 excludes 5-methyl substitutions, the smaller 5F substitution was tolerated, as 5F-uracil inhibited uptake of [³H]-uracil with a Ki of 6.80 ± 2.12 µM (P > 0.05 compared to uracil Km). Indeed, we found that 5F-Uridine, 5F-uracil and 5F,2’-deoxyuridine were all potent antimetabolites against T. gondii with EC50 values well below that of the current first line treatment, sulfadiazine. In vivo evaluation also showed that 5F-uracil and 5F,2’-deoxyuridine were similarly effective as sulfadiazine against acute toxoplasmosis. Our preliminary conclusion is that TgUUT1 mediates potential new anti-toxoplasmosis drugs with activity superior to the current treatment. [ABSTRACT FROM AUTHOR]

This study reports synthesizing and characterizing imidazolium‐based ionic liquids (ILs) using substituted benzoates as anions. Thermal stability of ILs described using thermogravimetric analysis (TGA). One inherent property of ILs is aggregates or cluster formation due to supramolecular interactions. The supramolecular interaction in synthesized ILs has been studied through Electrospray ionization mass spectrometry (ESI‐MS). The potential of ILs as organic catalysts is investigated in multicomponent reaction (MCR) using urea, malononitrile, and different aromatic aldehydes to prepare phenyl pyrimidines derivatives. The results demonstrate that catalysis with ILs effectively reduces reaction time and enhances yield. ILs entities are hypothesized to form new assemblies with reactive moieties of reactants through supramolecular interactions. The ILs can be reused and recycled. [ABSTRACT FROM AUTHOR]

The study focused on developing new triazolopyrimidine derivatives as potential DNA Gyrase inhibitors and antimicrobial agents. The compounds were designed, synthesized, and evaluated for their biological activities, safety, and ADMET properties. Encouragingly, the initial results showed promising potency and acceptable ADME parameters, forming a strong basis for further drug development research. The newly synthesized compounds were verified through spectra, mass, and elemental analysis. Notably, several compounds exhibited significant activity against both Gram‐positive and Gram‐negative bacteria, with MIC values ranging from 100 μg/ml to 250 μg/ml. importantly, the compounds were found to be safe, with no reported adverse effects or toxicities. Among the tested compounds, compound 2 m stood out as an excellent DNA Gyrase inhibitor, with an IC50 value of 0.89 μM, comparable to the reference drug ciprofloxacin with an IC50 value of 0.91 μM. Molecular docking studies confirmed that the compounds′ binding mode and docking scores were similar to ciprofloxacin, validating their antibacterial activity via DNA Gyrase inhibition. The research provides valuable insights into the potential of these newly synthesized triazolopyrimidine derivatives as DNA Gyrase inhibitors and antimicrobial agents. Their promising antibacterial activity and safe profile make them potential candidates for further development as antimicrobial agents. [ABSTRACT FROM AUTHOR]

Pyrimidine derivatives have attracted much attention in medicinal chemistry because of their diversified biological properties and potential therapeutic applications. The Suzuki‐Miyaura, Sonogashira, and Buchwald‐Hartwig coupling reactions provide flexible methods for synthesizing structurally diverse pyrimidine derivatives. These reactions can modify the pyrimidine structure to incorporate different functional groups and substitution patterns, improving the pharmacological activities and maximizing the drug‐like properties. Using other coupling partners, such as aryl and heteroaryl moieties, has produced novel pyrimidine‐based scaffolds with enhanced bioactivity profiles. This comprehensive review examines the biological activities of pyrimidine derivatives, concentrating on how their diversification via coupling reactions utilizing synthetic techniques has affected their pharmacological properties. Investigating various biological effects and exploring novel artificial techniques present great opportunities for creating next‐generation medicines with improved efficacy and selectivity. [ABSTRACT FROM AUTHOR]

Two series of substituted thieno[3,2-d]pyrimidine derivatives as EZH2 inhibitors were synthesized via structural modifications of tazemetostat. The antiproliferative activity of compounds against SU-DHL-6, WSU-DLCL-2, K562, H358 and H1703 cancer cell lines and the toxicity against HEK293T cells were evaluated. The most promising compound 12e had a remarkable antitumor activity against SU-DHL-6, WSU-DLCL-2 and K562 cells (IC50 = 0.55 μM, 0.95 μM and 1.68 μM, respectively) and low toxicity against HEK-293T cells (CC50 = 15.09 μM). The preliminary structure–activity relationship (SAR) studies indicate that piperidine-2,6-dione was more suitable for a P1 moiety and benzyl-linked morpholine for a P5 moiety, which were beneficial for improving the antitumor activities. The biological evaluation showed that 12e can significantly affect lymphoma cell morphology, and induce the apoptosis of SU-DHL-6 cells in a concentration-dependent manner and inhibit their migration. These findings indicated that 12e would be an attractive chemical tool for the further optimization and evaluation of new EZH2 inhibitors. [ABSTRACT FROM AUTHOR]

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1WT) as a potential diagnostic and prognostic biomarker for non–small cell lung cancer (NSCLC), but how IDH1WT modulates NSCLC progression remains elusive. Here, we report that IDH1WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1WT interacts with and stabilizes PHGDH and fragile X–related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1WT-PHGDH and IDH1WT-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine–depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1WT in serine metabolism, highlighting IDH1WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC. Editor's summary: Tumor-initiating cells (TICs) have high metabolic plasticity and have been suggested as the cause for tumorigenesis and relapse in many cancers including non–small cell lung cancer (NSCLC). Here, Zhang et al. have examined the role of serine synthesis in TICs IDH1 wild-type NSCLC and identified that inhibiting this pathway sensitizes cells and xenografts to standard of care. Their study suggests a potential metabolic target for treated NSCLC that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

A novel series of oxazolyl‐pyrimidine derivatives (11 a–j) have been synthesized and structures were confirmed by spectral data. The synthesized compounds were assessed for cytotoxic profile towards human cervix cancer (SiHa), lung cancer (A549), breast cancer (MCF‐7), and colon cancer (Colo‐205) cell lines by employing MTT assay and using etoposide as the positive control. The heteroaryl compounds having the terminal pyridyl (11 a) and thiazolyl (11 b) groups showed superior cytotoxic potency against cervix and lung cancer cell lines and varying methoxy substituted derivatives 11 c–11 e have excellent to good cytotoxic properties. Compound 11 a and 11 b have IC50 values in the range of 0.01±0.0034 to 0.17±0.059 μM and 0.10±0.038 to 0.66±0.077 μM respectively in the tested cell lines. The selected compounds 11 a and 11 b were studied by molecular docking to assess the binding interactions, binding energies, and possible mechanisms. The in‐silico ADME properties were calculated and all the compounds have the desired properties of drug‐like molecules. The toxicity results indicate that all the compounds are free from toxicity except 11 j, which has high tumorigenic properties. The optimized structure, energies of frontier molecular orbitals, molecular electrostatic potential, and NLO parameters for compound 11 a were determined using DFT/B3LYP level with a 6‐311++G(d,p) basis set. [ABSTRACT FROM AUTHOR]

Hot‐water‐soluble starch (HWSS) was employed as binder for fabrication of a composite from magnetite and Ag nanoparticles (NPs). Electron microscopy images showed a good dispersion of magnetite NPs in the matrix of HWSS. This observation indicates that HWSS tends to coat the maximum surface of magnetite by encapsulation of individual magnetite NPs, leading to disassembly of their aggregates. The HWSS‐coated magnetite NPs were employed as nano‐support for immobilization of fine Ag NPs generated in situ via reduction of Ag+ cations by glucose. Monitoring of the formation and growth of Ag NPs by UV–Vis spectroscopy made it possible to set up an optimal condition for fabrication of the nano‐composite and to verify the supremacy of HWSS‐coated magnetite NPs over bare magnetite NPs as support in this new protocol. Valuable insights into the texture of the nano‐composite were obtained by VSM, FT‐IR and XRD studies. The bio‐derived nano‐composite displayed an interesting magnetic property and an efficient catalytic activity in the three‐component synthesis of pyrano[2,3‐d]pyrimidines. It is a robust heterogeneous catalyst and can be simply retrieved from reaction mixtures by magnetic separation method. [ABSTRACT FROM AUTHOR]

In the present study a series of ethyl 4-(substituted)-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carboxylate and ethyl 4-(substituted)-8-methoxy-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carboxylate have been synthesized and evaluated for their preliminary antibacterial, antifungal, antimycobacterial, antioxidant and antimalarial activity. Among all the synthesized derivatives some of the compounds exists good biological activity which is similar to that of standard drugs. These facts make the compounds interesting candidates for further evaluation of their efficacy in the treatment microbial, tubercular and malarial disease. [ABSTRACT FROM AUTHOR]

An efficient and facile protocol for the synthesis of pyrimidine, pyridine and pyrazole ring systems was reported, Reaction of isothiocyanate with enaminone to give pyrimidinthione 4, the reactions of pyrimidinthione 4 with several active species such as ethyliodide, benzaldehyde, p-anisidine, acetylacetone were studied, the reactions of isothiocyanate 1 with active species such as ethyl cyanoacetate to form thioamide then oxazine, thiourea togivethiosemicarbazide, hydrazine, and phenylhydrazine resulted in pyrimidines. Novel compounds were tested for biological activity against Gram+ bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram– bacteria (E. Coli and Klebsiella pneumonia) using Gentamycin as reference standard drug, Results showed novel compounds as potent antibacterial agents against all bacterial strains except (Klebsiella pneumonia bacteria). [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a]pyrimidine derivatives are a class of biologically active parent nucleus structures containing both imidazole and pyrimidine rings, which are important intermediates for the synthesis of a variety of drugs. This class of structures has attracted a lot of attention of researchers, and more and more synthetic strategies have been developed and reported. Currently, the main synthetic strategies are one-pot multi-component methods, microwave radiation, ultrasonic irradiation and other auxiliary Knoevenagel condensation and Michael addition methods to obtain these compounds, with the aim of achieving high yields, low time consumption and environmental friendliness. This review comprehensively summarizes the various synthetic methods as well as mechanism recently reported for the construction of this remarkable backbone structure and further used for the development of new chemical synthesis strategies and drug development as it has a wide range of applications in medicinal chemistry. In order to provide some impetus to the research of synthetic methods for this structure. [ABSTRACT FROM AUTHOR]

The given text provides information on the synthesis and biological evaluation of fused compounds for potential cancer treatment. The compounds were tested for their cytotoxic activity against MCF-7 and A-549 cell lines, with some compounds showing superior activity against MCF-7 and moderate activity against A-549. Additionally, the compounds were tested for their tyrosine kinase EGFR inhibitory activity, with some compounds showing promising potency comparable to the reference drug erlotinib. The synthesis of the compounds involved several steps and the use of specific reagents and solvents. The document provides information on the synthesis and characterization of various chemical compounds. The compounds are derivatives of 1,2,3-triazolo[4',5':4,5]pyrido[2,3-d]pyrimidine and contain different substituents on the phenyl and triazole rings. The compounds are obtained through column chromatography and their physical and spectroscopic properties are reported. The information provided can be useful for researchers studying the synthesis and properties of similar compounds. This document describes the synthesis and evaluation of a series of novel compounds with potential anticancer activity. The compounds, which are fused [1,2,3]-triazolo[4¿,5¿:4,5]pyrido[2,3-d]pyrimidine linked 1,2,3-triazoles, were tested for their inhibitory activity against the tyrosine kinase EGFR proteins. Two compounds, [Extracted from the article]

This article discusses the design, synthesis, and molecular docking of a new pyrimidine compound with potential antitumor activity. The researchers synthesized five compounds and tested their cytotoxicity in vitro. The results showed that compounds with single alkynyl groups had better activity than those with double alkynyl groups. Molecular docking simulations revealed the main forces involved in the compounds' interactions with proteins. The study provides valuable insights for the development of new drugs and suggests that further optimization is needed to reduce toxicity and increase effectiveness. The research was funded by Anhui University of Science and Technology and the cell experimental data was provided by the Affiliated People's Hospital of Jiangsu University. [Extracted from the article]

In this study, new benzothiazole–pyrimidine hybrids (5a–c, 6, 7a–f, and 8–15) were designed and synthesised. Two different functionalities on the pyrimidine moiety of lead compound 4 were subjected to a variety of chemical changes with the goal of creating various functionalities and cyclisation to further elucidate the target structures. The potency of the new molecules was tested against different tuberculosis (TB) strains. The results indicated that compounds 5c, 5b, 12, and 15 (MIC = 0.24–0.98 µg/mL) are highly active against the first-line drug-sensitive strain of Mycobacterium tuberculosis (ATCC 25177). Thereafter, the anti-tubercular activity was evaluated against the two drug-resistant TB strains; ATCC 35822 and RCMB 2674, where, many compounds exhibited good activity with MIC = 0.98–62.5 3 µg/mL and 3.9–62.5 µg/mL, respectively. Compounds 5c and 15 having the highest anti-tubercular efficiency towards sensitive strain, displayed the best activity for the resistant strains by showing the MIC = 0.98 and 1.95 µg/mL for MDR TB, and showing the MIC = 3.9 and 7.81 µg/mL for XDR TB, consecutively. Finally, molecular docking studies were performed for the two most active compounds 5c and 15 to explore their enzymatic inhibitory activities. [ABSTRACT FROM AUTHOR]

Nanotechnology-based strategies can overcome the limitations of conventional cancer therapies. Hence, novel series of pyrimidine Schiff bases (4–9) were employed in the synthesis of selenium nanoparticle forms (4NPs–9NPs). All selenium nano-sized forms exerted greater inhibitions than normal-sized compounds, far exceeding 5-fluorouracil activity. Compound 4 showed effective anti-proliferative activity against MCF-7(IC50 3.14 ± 0.04 µM), HepG-2(IC50 1.07 ± 0.03 µM), and A549(IC50 1.53 ± 0.01 µM) cell lines, while its selenium nanoform 4NPs showed excellent inhibitory effects, with efficacy increased by 96.52%, 96.45%, and 93.86%, respectively. Additionally, 4NPs outperformed 4 in selectivity against the Vero cell line by 4.5-fold. Furthermore, 4NPs exhibited strong inhibition of CDK1(IC50 0.47 ± 0.3 µM) and tubulin polymerase(IC50 0.61 ± 0.04 µM), outperforming 4 and being comparable to roscovitine (IC50 0.27 ± 0.03 µM) and combretastatin-A4(IC50 0.25 ± 0.01 µM), respectively. Moreover, both 4 and 4NPs arrested the cell cycle at G0/G1 phase and significantly forced the cells towards apoptosis. Molecular docking demonstrated that 4 and 4NPs were able to inhibit CDK1 and tubulin polymerase binding sites. [ABSTRACT FROM AUTHOR]