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Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of their anti-proliferative properties is of great pharmacological interest. Some 2-alkyl-4-amino-thieno[2,3-d]pyrimidines 2–5 were synthesized, and their cyto- and phototoxicity against BALB 3T3 cells were established by an in vitro 3T3 NRU test. The obtained results indicate that the tested compounds are not cytotoxic or phototoxic, and that they are appropriate to be studied for their anti-proliferative and anti-tumor properties. The anti-proliferative potential of the compounds was investigated on MCF-7 and MDA-MB-231 cancer cells, as well as a MCF-10A cell line (normal human mammary epithelial cells). The most toxic to MCF-7 was thienopyrimidine 3 with IC50 13.42 μg/mL (IC50 0.045 μM), followed by compound 4 (IC50 28.89 μg/mL or IC50 0.11 μM). The thienopyrimidine 4 revealed higher selectivity to MCF-7 and lower activity (IC50 367 μg/mL i.e., 1.4 μM) than compound 3 with MCF-10A cells. With respect to MDA-MB-231 cells, ester 2 manifested the highest effect with IC50 52.56 μg/mL (IC50 0.16 μM), and 2-ethyl derivative 4 revealed IC50 62.86 μg/mL (IC50 0.24 μM). It was estimated that the effect of the substances on the cell cycle progression was due to cell cycle arrest in the G2 stage for MDA-MB-231, while arrest in G1 was detected for the estrogen (ER)-positive MCF-7 cell line. The tested compound's effects on the change of the zeta potential in the tumorigenic cells utilized in this study were determined. The calculation which we performed of the physicochemical properties and pharmacokinetic parameters influencing the biological activity suggested high intestinal absorption, as well as drug-likeness. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase is the tyrosine kinase encoded by an X chromosome gene, was first mutated in a boy with Bruton's disease, known as X-linked agammaglobulinemia. Bruton's tyrosine kinase (BTK) is essential for the survival of leukemic cells in a variety of B cell malignancies. It controls the development and function of B cells (also referred as B-lymphocytes). It is one of the many non-receptor Tec (tyrosine kinase expressed in hepatocellular carcinoma) protein tyrosine kinases. One emerging moiety with potential efficacy in B-cell malignancies is pyrimidines, inhibiting Bruton's tyrosine kinase (BTK). About 20 years passed from the time a target was discovered and the beginning of therapeutic research before the drug received approval. Ibrutinib, a first of its kind medicine, through which B-cell cancers can be treated without the need of chemotherapy. In order to better comprehend the clinical and commercial potential of pyrimidines as BTK inhibitors, as well as the directions being pursued, we have highlighted the important milestones in their preclinical discovery and clinical development in this review. Moreover, it provides important insights related to SAR studies that might be applied to the research and development of future innovative medicines. [Display omitted] • Bruton's tyrosine kinase as a crucial modulator of B-cell receptor signaling. • Pyrimidine scaffolds against Bruton's tyrosine kinase for the last six years. • Mechanistic approaches and structure activity relationship. [ABSTRACT FROM AUTHOR]

A method was developed for the synthesis of new fused 3-alkyl-substituted derivatives of thieno[3,2-d]pyrimidin-4(3H)-ones based on 11-(2-furyl)-8,8-dimethyl-7,10-dihydro-8H-pyrano[3′′,4′′:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-one via nucleophilic substitution in the pyrimidine ring. A series of fused 4-amino-substituted 11-furylthieno[3,2-d]pyrimidine derivatives was also synthesized from the corresponding 4-chloro derivative. [ABSTRACT FROM AUTHOR]

Substituted prop-2-en-1-ones were obtained by the condensation reaction of 1-biphenyl-4-yl-ethanone with aromatic aldehydes in the presence of sodium hydroxide in an aqueous ethanol solution. Subsequent cyclization of the latter with hydrazine hydrate, phenylhydrazine, and thiosemicarbazide in an acidic medium leads to the corresponding pyrazolines. The reaction of amidine hydrochlorides with chalcones in a KOH–ethanol system leads to 2,4,6-trisubstituted pyrimidines. The luminescent and antibacterial properties of the resulting systems were studied. [ABSTRACT FROM AUTHOR]

In the realm of chemistry, increased energy consumption as a result of population development and industrialisation necessitates the usage of renewable energy sources. Nonrenewable energy sources emit not only greenhouse gases but also other toxic pollutants that harm all living creatures. This clearly necessitates the employment of an ecologically acceptable and cost-effective renewable energy source by the researchers. The Knoevenagel-Michael cyclocondensation of aldehyde derivatives, malononitrile, and barbituric acid/1,3-dimethylbarbituric acid via a three-condensation domino reaction can be used to create pyrano[2,3-d]pyrimidine scaffolds. This study establishes solar energy as a novel renewable energy source for the synthesis of pyrano[2,3-d]pyrimidine scaffolds under catalyst-solvent-free conditions, with excellent yields, reaction time savings, and atom economy. This reaction was carried out on a range of substrates with the use of a renewable energy source (sunlight) and a relatively simple experimental setup. The reaction was extremely fast, and there was no need for a solvent or chromatographic purification. According to a multigram scale reaction of model substrates, this reaction might be scaled up without affecting the outcome. Furthermore, the approach's broad applicability was proved by its usage to synthesis real-world pharmaceutical molecules. [ABSTRACT FROM AUTHOR]

In recent years, antimicrobial agents have been crucial in improving public health worldwide. However, due to improper usage, bacteria have developed resistance to these agents. This has led researchers to explore the use of heterocyclic compounds as alternative antimicrobial agents to combat resistance. Considering the success of heterocyclic derivatives in developing effective antimicrobial drugs, we conducted a 2D-QSAR (QSAR models using 2D-descriptors) study on novel pyrimidine derivatives and performed in silico simulations to evaluate their potential antibacterial activity against quinolone-resistant Escherichia coli. We used QSARINS V.2.2 (Insubria) software for the 2D-QSAR analysis and performed in silico absorption, distribution, metabolism, and excretion (ADME) and docking studies on 16 newly designed compounds. The best QSAR model had a high correlation coefficient ( R 2 = 0. 9 6 3 3 , Q LOO 2 = 0. 9 5 3 8 , Q LMO 2 = 0. 9 5 1 3) and showed no outliers. Based on these favorable results, we designed 16 new compounds and predicted their antibacterial activity using the best equation. Amongst the top six designed compounds, which had the best docking scores were subjected to practical synthesis. Compound 3cd was found to be good candidature from in-vitro anti-E. Coli activity. This compound may be targeting the DNA gyrases and thus, have inhibitory activity against E. Coli. This observation was also supported by 100 ns molecular dynamics and normal mode analysis results. The most promising compounds identified through these computational studies may be synthesized and tested as potential new drug candidates for treating bacterial infections. To summarize, we have developed a statistically robust and valid 2D-QSAR model with a set of 51 compounds of antibacterial pyrimidines using QSARINS V.2.2. The model is tested on newly designed fused pyrimidine derivatives for predicting bioactivity. Based on the QSAR model, binding affinity and ADMET prediction results, six designed compounds 3ae, 3af, 3be, 3bf, 3ca, and 3cd can act as a potent DNA gyrase inhibitor. These 4 compounds were synthesized with good yield and screened for antibacterial activity against E. coli. [ABSTRACT FROM AUTHOR]

A novel and highly efficient synthetic route to [1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives from 5-amino-1,3,4-thiadiazole-2-thiol, various aromatic aldehydes, and Meldrum's acid in the presence of acetic acid in dry ethanol has been reported. We designed the three-component reaction with the incorporation of Knoevenagel condensation followed by an intermolecular nucleophilic addition reaction in one pot under mild conditions. The structural diversities of these synthesized compounds have been confirmed spectroscopically, by IR, 1H-, and 13C NMR, and elemental analysis, which agree with the proposed structures. [ABSTRACT FROM AUTHOR]

Owing to its broad spectrum biological activity, pyrimidines have been extensively employed as building blocks for synthesizing various drug mimic molecules. In the present work, a novel 2-hydrazineyl-5-(2-phenylhydrazineylidene)pyrimidine-4,6(1H,5H)-dione 3 was prepared and was subsequently reacted with a variety of substituted benzaldehyde derivatives 4a–c, 6, and heteroaryl ketones namely, 2-acetylthiophene 8, acetophenone 10a, 2-acetylpyridine 10b, or 3-acetylindole 12 to give the respective hydrazones 5a–c, 7, 9, 11a,b, or 13. Moreover, the reaction of hydrazine 3 with commercially available active methylene compounds, namely, ethyl benzoylacetate 14, acetylacetone 16, and diethyl malonate 18, afford the respective pyrazole derivatives 15, 17, and 19. All reactions were preceded in good yields and the structures of the synthesized compounds were confirmed by elemental analysis, IR, 1H-NMR, 13C-NMR and mass spectral data. The anti-viral activity of the synthesized derivatives was investigated against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MD). The docking scores against (PDB: 6LU7), were calculated via Standard Precision (SP) method of the Glide docking module of Meastro. The docking score of the novel compounds ranged between −7.29 and −6.02 with good affinity toward Mpro. Pyrazolinone 19 demonstrated the lowest docking score (-7.293 kcal/mol) and glide emodel −72.978, showed three hydrogen bond interactions with GLU166, GLY143 and the catalytic dyad CYS145. Thus, compound 19 was chosen for further molecular dynamics simulation study for 20 ns. The results indicated that the protein was almost stabilized with average four to five hydrogen bonds with compound 19 during the simulation period. This means the potential inhibitory activity of the promising pyrazolinone 19 against SARS-CoV-2 Mpro. [ABSTRACT FROM AUTHOR]

A facile, environmentally benign and proficient route has been developed for the diverse synthesis of pyrrolo[2,3-d]pyrimidine derivatives followed by heterocyclization starting from Amino uracil, arylgyoxal and malononitrile/thiols. Readily available thiamin hydrochloride organocatalyst was used as a green promoting medium. As well as the reaction progress was taken place under aqueous media. This procedure also offers a base and metal free approach which endowed high yields with better functional group tolerating ability and mild reaction conditions. Further, methodology had a widescope with recyclability and reuse of thiamin hydrochloride. DFT/TD-DFT calculations with B3LYP/6-311G++ level of theory were used to study the optimized geometry and HOMO-LUMO energy of the synthesized compounds (4b and 6i). [ABSTRACT FROM AUTHOR]

To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify 41 different purine and pyrimidine (PuPy) metabolites in human urine to allow detection of most known disorders in this metabolic pathway and to determine reference intervals. Urine samples were diluted with an aqueous buffer to minimize ion suppression. For detection and quantification, liquid chromatography was combined with electrospray ionization, tandem mass spectrometry and multiple reaction monitoring. Transitions and instrument settings were established to quantify 41 analytes and nine stable-isotope-labeled internal standards (IS). The established method is precise (intra-day CV: 1.4–6.3%; inter-day CV: 1.3–15.2%), accurate (95.2% external quality control results within ±2 SD and 99.0% within ±3 SD; analyte recoveries: 61–121%), sensitive and has a broad dynamic range to quantify normal and pathological metabolite concentrations within one run. All analytes except aminoimidazole ribonucleoside (AIr) are stable before, during and after sample preparation. Moreover, analytes are not affected by five cycles of freeze-thawing (variation: −5.6 to 7.4%), are stable in thymol (variation: −8.4 to 12.9%) and the lithogenic metabolites also in HCl conserved urine. Age-dependent reference intervals from 3,368 urine samples were determined and used to diagnose 11 new patients within 7 years (total performed tests: 4,206). The presented method and reference intervals enable the quantification of 41 metabolites and the potential diagnosis of up to 25 disorders of PuPy metabolism. [ABSTRACT FROM AUTHOR]

In the present study, synthesis of a variety of 5-bromo-4-methyl-2-substituted pyrimidines endowed with pyrazolyl substituent appended in C4 position (7a-f) is described. These products are generated via treatment of 5-bromo-4-hydrazineyl-6-methyl-2-substituted pyrimidines (6a–f) and vinamidinum salt of (E)-N-(3-(dimethylamino)-2-phenylallylidene)-N-methylmethanaminium perchlorate (5) in good to excellent yields. The inhibitory and hydrogen-atom donating abilities of the synthesized products (7a-f) were assessed against nine pathogens including six bacterial strains (both Gram-negative and Gram-positive), three fungal strains and DPPH free radicals. Notable antioxidant properties were not observed with the products. IC50 values were in the range of 107.49–929.16 μg ml−1. The inhibition zone diameters of products at 10 mg ml−1 concentrations were recorded in the range of 10.51–18.44 mm via disk diffusion method. 5-Bromo-4-methyl-6-pyrazolylpyrimidine (7e) containing 2-(4-methylpiperazin) substituent showed better antioxidant and antimicrobial effects than other products. It was effective on all the tested microbial strains except Staphylococcus epidermidis. All the synthesized pyrazolyl pyrimidines, especially (7e) can be used to disinfect the environment and treat infectious diseases. [ABSTRACT FROM AUTHOR]

Triazolo[4,3-a]pyrimidine is one of the promising structural fragments for the development of drugs, including anticancer drugs. This work is devoted to the synthesis of a number of new 2-arylhydrazone derivatives of thiazolo[3,2-a]pyrimidine, which are synthetic precursors for triazolo[4,3-a]pyrimidines. The crystal structure of 6-acetyl-7-methyl-5-phenyl-2-(2-phenylhydrazineylidene)-5H-thiazolo[3,2-a]pyrimidin-3(2H)-one was established by SCXRD. In the reduction reaction of the compound, the following system was used: vanadium(V) oxide, and sodium borohydride in ethanol at room temperature, which led to the formation of only one pair of diastereomers (1R*)-1-((5S*,6R*,7R*)-(1-(hydroxymethyl)-7-methyl-1,5-diphenyl-1,5,6,7-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)ethan-1-ol. [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a]pyrimidine derivatives bearing imine groups (3a-e) were successfully synthesized in moderate to good yields using microwave-assisted heating. Corresponding amine derivatives (4a-e) were also obtained by the reduction reaction of the imine derivatives (3a-e). All synthesized products were characterized by FT-IR, ¹H NMR, 13C NMR, and LC-MS spectroscopic techniques. In silico ADMET, Lipinski, and drug-likeness studies of the compounds were conducted and all were found to be suitable drug candidates. The cytotoxicity of the potential drug molecules was screened against the breast cancer cell lines MCF-7 and MDA-MB-231 and the healthy model HUVEC by the sulforhodamine B method. According to the antiproliferative studies, compounds 3d and 4d showed remarkable inhibition of MCF-7 cells with IC50 values of 43.4 and 39.0 μM and of MDA-MB-231 cells with IC50 values of 35.9 and 35.1 μM, respectively. In particular, compound 3d selectively inhibited the proliferation of MCF-7 1.6-fold and MDA-MB-231 2.0-fold relative to healthy cells. Moreover, the apoptotic mechanism studies indicated that compound 4d induced apoptosis by moderately increasing the ratio of Bax/Bcl-2 genes. Imidazo[1,2-a]pyrimidine derivative 3d, a promising cytotoxic agent, may be helpful in the discovery of new and more efficient anticancer agents for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Structural-based drug design and solvent-free synthesis were combined to obtain three novel series of 5-arylethylidene-aminopyrimidine-2,4-diones (4, 5a–c, 6a,b), 5-arylethylidene-amino-2-thiopyrimidine-4-ones (7,8), and 6-arylpteridines (9,10) as dual BRD4 and PLK1 inhibitors. MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. The most active compounds were tested against normal Vero cells. Compounds 4 and 7 significantly inhibited BRD4 and PLK1, with IC50 values of 0.029, 0.042 µM, and 0.094, 0.02 µM, respectively, which are nearly comparable to volasertib (IC50 = 0.017 and 0.025 µM). Compound 7 triggered apoptosis and halted cell growth at the G2/M phase, similarly to volasertib. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates. [ABSTRACT FROM AUTHOR]

New series of 20 thieno[2,3‐d]pyrimidine derivatives have been synthesized. The National Cancer Institute evaluated all the newly synthesized compounds for their antiproliferative activity against a panel of 60 cancer cell lines. Compound 7b exhibited a remarkable antineoplastic activity at 10 µM dose and was therefore tested at five dose concentrations. The significant and broad‐spectrum antineoplastic action of compound 7b was observed against 37 of the tested cancer cell lines with a dose that inhibits 50% of the growth compared to control values in the micromolar range of 1.95–9.6 µM. The dose which inhibits the growth completely in the cytostatic range of 3.99–100 µM was also observed. Compound 7b effectively inhibited epidermal growth factor receptor (EGFR) with 50% inhibition concentration value (IC50) = 0.096 ± 0.004 compared to erlotinib with IC50 = 0.037 ± 0.002. Moreover, compound 7b revealed a powerful downregulation effect on total EGFR concentration and its phosphorylation. In addition, compound 7b inhibited phosphatidylinositol 3‐kinase, protein kinase B, and the mammalian target of rapamycin pathway phosphorylation. Furthermore, compound 7b raised total apoptosis by 21.93‐fold in the ovarian cancer cell line (OVCAR‐4) and caused an arrest in the cell cycle in the G1/S phase. It also raised the level of caspase‐3 by 4.72‐fold. Furthermore, to determine the binding manner of the most effective derivatives and validate their capacity to comply with the pharmacophoric properties necessary for EGFR inhibition, they were docked into the active site of the EGFR. [ABSTRACT FROM AUTHOR]

Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR‐2) inhibitors, a novel thieno[2,3‐d]pyrimidine derivative has been designed and its activity against VEGFR‐2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer‐induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug‐like nature of the designed candidate. According to the previous results, the thieno[2,3‐d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR‐2 (IC50 = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC50 values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI‐38). Finally, the thieno[2,3‐d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3‐d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase‐3, caspase‐9, Bcl‐2 associated X‐protein, and B‐cell lymphoma 2. [ABSTRACT FROM AUTHOR]

Far‐UVC radiation sources of wavelengths 222 nm and 233 nm represent an interesting potential alternative for the antiseptic treatment of the skin due to their high skin compatibility. Nevertheless, no studies on far‐UVC‐induced DNA damage in different skin types have been published to date, which this study aims for. After irradiating the skin with far‐UVC of the wavelengths 222 and 233 nm as well as broadband UVB, the tissue was screened for cyclobutane pyrimidine dimer‐positive (CPD+) cells using immunohistochemistry. The epidermal DNA damage was lower in dark skin types than in fair skin types after irradiation at 233 nm. Contrary to this, irradiation at 222 nm caused no skin type‐dependent differences, which can be attributed to the decreased penetration depth of radiation. UVB showed the relatively strongest differences between light and dark skin types when using a suberythemal dose of 3 mJ/cm2. As melanin is known for its photoprotective effect, we evaluated the ratio of melanin content in the stratum basale and stratum granulosum in samples of different skin types using two‐photon excited fluorescence lifetime imaging (TPE‐FLIM) finding a higher ratio up to skin type IV–V. As far‐UVC is known to penetrate only into the upper layers of the viable skin, the aforementioned melanin ratio could explain the less pronounced differences between skin types after irradiation with far‐UVC compared to UVB. [ABSTRACT FROM AUTHOR]

The reaction of enaminonitrile 2 with hydrazine hydrate yielded 5‐amino pyrazole derivative 4. Compound 4 reacted with ethyl acetoacetate, enaminone 8, chalcone 12, enaminonitrile 2, arylidene malononitrile 18, 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile 21 and phenacyl bromide to give the corresponding pyrazolopyrimidine derivatives 7, 11, 14, 17, 20, 23, and imidazopyrazole 25, respectively. The newly synthesized compounds were characterized by spectral and elemental analyses. The antimicrobial activities of the new compounds were tested against S. aureus, E. coli, and C. albicans. It was found that compound 23 exhibited the highest antimicrobial activity against the tested microorganisms. All tested compounds did not have antifungal activity against A. niger as a fungal strain. Utilizing drug‐likeness (ADME) and molecular docking the effectiveness of compound 23 towards G+ve and G‐ve bacteria has been studied. Accordingly, compound 23 is expected to have a high chance of oral bioavailability due to its compliance with Lipinski′s rule of five. In addition, it plays a critical role in the inhibition of bacterial S. Ribosome, dihydropteroate synthase, transpeptidase, and gyrase B. subunit proteins. [ABSTRACT FROM AUTHOR]

The current study involves the design and synthesis of a newly synthesized pyrrolo[2,3-d]pyrimidine derivatives to contain chlorine atoms in positions 4 and 6 and trichloromethyl group in position 2 using microwave technique as a new and robust approach for preparation of this type of pyrrolo[2,3-d]pyrimidine derivatives. The chemical structure of the synthesized pyrrolo[2,3-d]pyrimidine derivatives 3–19 was well-characterized using spectral and elemental analyses as well as single-crystal X-ray diffraction. All compounds were tested in vitro against seven selected human cancer cell lines, namely, MCF7, A549, HCT116, PC3, HePG2, PACA2 and BJ1 using MTT assay. It was found that compounds 14a, 16b and 18b were the most active toward MCF7 with IC50 (1.7, 5.7, and 3.4 μg/ml, respectively) relative to doxorubicin (Dox.) (26.1 μg/ml). Additionally, compound 17 exerted promising cytotoxic effects against HePG2 and PACA2 with IC50 (8.7 and 6.4 μg/ml, respectively) relative to Dox. (21.6 and 28.3 μg/ml, respectively). The molecular docking study confirmed our ELISA result which showed the promising binding affinities of compounds 14a and 17 against Bcl2 anti-apoptotic protein. At the gene expression level, P53, BAX, DR4 and DR5 were up-regulated, while Bcl2, Il-8, and CDK4 were down-regulated in 14a, 14b and 18b treated MCF7 cells. At the protein level, compound 14b increased the activity of Caspase 8 and BAX (18.263 and 14.25 pg/ml) relative to Dox. (3.99 and 4.92 pg/ml, respectively), while the activity of Bcl2 was greatly decreased in 14a treated MCF7 (2.4 pg/ml) compared with Dox. (14.37 pg/ml). Compounds 14a and 14b caused cell cycle arrest at the G1/S phase in MCF7. Compounds 16b and 18b induced the apoptotic death of MCF7 cells. In addition, the percentage of fragmented DNA was increased significantly in 14a treated MCF7 cells. [ABSTRACT FROM AUTHOR]

HRMS (ESI): I m i / I z i [M + H] SP + sp calcd for C SB 25 sb H SB 19 sb F SB 3 sb N SB 3 sb O SB 3 sb : 466.1373; found: 466.1396. HRMS (ESI): I m i / I z i [M + H] SP + sp calcd for C SB 23 sb H SB 19 sb F SB 3 sb N SB 3 sb O SB 3 sb : 442.1373; found: 442.1374. Keywords: site-selective cross-coupling reaction; pyrazolo[1,5- a ]pyrimidine; Suzuki-Miyaura reaction; arylation; alkynylation; amination EN site-selective cross-coupling reaction pyrazolo[1,5- a ]pyrimidine Suzuki-Miyaura reaction arylation alkynylation amination 2503 2516 14 07/31/23 20230817 NES 230817 Graph Fused nitrogen heterocycles make up an important class of organic molecules that play a crucial role in pharmaceutical and medicinal applications due to their broad range of biological properties. No significant effect was observed on the selectivity when Na SB 2 sb CO SB 3 sb was replaced by Cs SB 2 sb CO SB 3 sb or K SB 3 sb PO SB 4 sb (entries 13 and 14). [Extracted from the article]

This present study was conducted to provide evidence and an explanation for the apoptosis that occurs in the marine rotifer Brachionus plicatilis when facing 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) stress. Metabolomics analysis showed that aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, and arginine biosynthesis were the top three sensitive pathways to BDE-47 exposure, which resulted in the reduction in the amino acid pool level. Pyrimidine metabolism and purine metabolism pathways were also significantly influenced, and the purine and pyrimidine content were obviously reduced in the low (0.02 mg/L) and middle (0.1 mg/L) concentration groups while increased in the high (0.5 mg/L) concentration group, evidencing the disorder of nucleotide synthesis and decomposition in B. plicatilis. The biochemical detection of the key enzymes in purine metabolism and pyrimidine metabolism showed the downregulation of Glutamine Synthetase (GS) protein expression and the elevation of Xanthine Oxidase (XOD) activity, which suggested the impaired DNA repair and ROS overproduction. The content of DNA damage biomarker (8-OHdG) increased in treatment groups, and the p53 signaling pathway was found to be activated, as indicated by the elevation of the p53 protein expression and Bax/Bcl-2 ratio. The ROS scavenger (N-acetyl-L-cysteine, NAC) addition effectively alleviated not only ROS overproduction but also DNA damage as well as the activation of apoptosis. The combined results backed up the speculation that purine metabolism and pyrimidine metabolism alteration play a pivotal role in BDE-47-induced ROS overproduction and DNA damage, and the consequent activation of the p53 signaling pathway led to the observed apoptosis in B. plicatilis. [ABSTRACT FROM AUTHOR]

The present work describes an green and eco-friendly synthetic protocol, and vitro anti-proliferative activity of a new series of 3-arylidine imidazo[1,2-c]pyrimidines. The target molecules 4a--p were synthesized via one-pot cyclization of 6-amino-4-(4-chlorophenyl)-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile(1) with chloroacetyl chloride followed by condensation with a series of aromatic and heteroaromatic aldehydes in the presence of K2CO3-NPs at room temperature. The high yield (80-96%), mild reaction conditions (short reaction time and no heat needed), simple purification, and soft, cheap, high efficiency readily available and stability of K2CO3-NPs are evident features of the present approach. Pyrimidines 4c, 4 g and 4i demonstrated significant anti-proliferative activity against MCF-7 especially compound 4i was found to be the most effective among the tested compounds with IC50 values 3.83 mg/ml in MCF-7 cell line compared to the standard drug doxorubicin. In addition, compounds 4b, 4c, 4d, 4i, and 4n demonstrated high cytotoxic activity against HCT116, particularly compound (4b) was the most potent among the tested compounds with IC50 values 9.3 mg/ml in HCT116 cell line compared to doxorubicin. [ABSTRACT FROM AUTHOR]

Herein, a concise method for the Rh(III)-catalyzed, directing-group-assisted C–H/C–H cross-coupling of N-heterocycles (quinolines, indolines, indoles, pyridines, pyrimidines, pyrazoles) with other heteroarenes (benzoxazoles, benzofurans, and thiophenes) is disclosed for the synthesis of unsymmetrical heterobiaryl compounds in good to excellent yields. A plausible catalytic cycle has been delineated based on experimental and computational mechanistic studies. [ABSTRACT FROM AUTHOR]

Utilizing the Knoevenagel–Michael tandem cyclocondensation reaction of barbituric acid/1,3-dimethylbarbituric acid, malononitrile, and aryl aldehydes, a sustainable methodology for the photosynthesis of pyrano[2,3-d]pyrimidine scaffolds has been devised. The present study expounds on the development of a green radical synthetic approach toward this class of compounds. In this study, a novel halogenated dicyanobenzene-based photosensitizer was utilized in an aqueous solution, exposed to air at room temperature, and activated by a blue LED as a renewable energy source for the purpose of generating energy. The primary aim of this endeavor is to employ a recently developed, easily obtainable, and affordably priced halogenated cyanoarene-based donor–acceptor (D–A). The 3DPAFIPN [2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile]} photocatalyst, as a thermally activated delayed fluorescence (TADF), is capable of inducing single electron transfer (SET) upon irradiation with visible light, thereby offering a facile and efficient approach with a high degree of effectiveness, energy efficiency, and eco-friendliness. The aforementioned phenomenon facilitates the exploration of the temporal changes that have occurred in the interactions between the surroundings and chemical constituents. The present study aimed to investigate the turnover number (TON) and turnover frequency (TOF) for pyrano[2,3-d]pyrimidine scaffolds. Additionally, it has been demonstrated that gram-scale cyclization is a viable method for utilization in industrial applications. [ABSTRACT FROM AUTHOR]

C7‐Arylated pyrazolo[1,5‐a]azines are important structural motifs with profound applications in drug and material research. Here, we report a general and straighforward synthesis of these bi(hetero)aryls via palladium‐catalyzed direct C−H arylation, employing low‐cost and abundant (hetero)aryl chlorides as the aryl source. The catalytic system is robust and covers a wide substrate scope regarding heteroarenes as well as (hetero)aryl chlorides, with possible extension to the C−H arylation of [1,2,4]triazolo[1,5‐a]pyrimidines. This study also presents a rare example of using (hetero)aryl chlorides for the direct C−H arylation of six‐membered heteroarenes. [ABSTRACT FROM AUTHOR]

The reaction of N‐(4‐(phenyldiazenyl) phenyl) carbonohydrazonoyl dicyanide (2) with N‐methyl glucamine afforded 3‐amino‐3‐(methyl (2,3,4,5,6‐pentahydroxyhexyl)amino)‐2‐((4‐(phenyldiazenyl)phenyl)diazenyl)acrylonitrile (3). Additionally, compound 2 produced the pyrazole derivatives 4 and 6, respectively, by reactions with hydrazine hydrate and malononitrile. Moreover, when enaminonitrile 3 was treated with malononitrile, N,N‐Dimethylformamide ‐ dimethyl acetal, and thiourea, it generated the glucaminoid derivatives 9, 10, and 13, respectively. In pyridine, compound 19 was obtained when enaminonitrile 3 interacted with the carbon disulfide. While in sodium hydroxide in N,N‐Dimethylformamide, instead of pyridine, it afforded the methyl carbamodithioate 23. Finally, pyrimidinethione derivative 26 was produced when the enaminonitrile 3 and phenyl isothiocyanate interacted. All new compounds were well established by both spectral and elemental analyses. The antitumor activities were evaluated by testing their impact on the viability of four different cell lines: HepG2 (human hepatocellular liver carcinoma), WI‐38 (human lung fibroblast), VERO (African green monkey kidney epithelial), and MCF‐7 (human breast adenocarcinoma). The antitumor study showed that compound 23 has very strong antitumor activity against the HEPG‐2 cell line. The synthesized compounds were analyzed by docking studies that showed good binding scores against the diverse amino acids of the selected proteins B‐Cell Leukemia/Lymphoma‐2 (Bcl‐2). The conducted docking studies were found to be consistent with cytotoxic results. [ABSTRACT FROM AUTHOR]

The single‐stranded DNA/RNA binding protein WHIRLY1 is a major chloroplast nucleoid‐associated protein required for the compactness of nucleoids. Most nucleoids in chloroplasts of WHIRLY1‐knockdown barley plants are less compact compared to nucleoids in wild‐type plants. The reduced compaction leads to an enhanced optical cross‐section, which may cause the plastid DNA to be a better target for damaging UV‐B radiation. To investigate this hypothesis, primary foliage leaves, chloroplasts, and nuclei from wild‐type and WHIRLY1‐knockdown plants were exposed to experimental UV‐B radiation. Thereafter, total, genomic and plastid DNA were isolated, respectively, and analyzed for the occurrence of cyclobutane pyrimidine dimers (CPDs), which is a parameter for genome stability. The results of this study revealed that WHIRLY1‐deficient chloroplasts had strongly enhanced DNA damages, whereas isolated nuclei from the same plant line were not more sensitive than nuclei from the wild‐type, indicating that WHIRLY1 has different functions in chloroplasts and nucleus. This supports the hypothesis that the compaction of nucleoids may provide protection against UV‐B radiation. [ABSTRACT FROM AUTHOR]

Cancer, caused by the failure of the mechanism that controls cell growth and proliferation, is usually associated with severe health issues. Nowadays, chemotherapy still occupies an important place in clinical cancer treatment, but the multidrug resistance and low specificity of chemotherapeutics are the major obstacles that undermine effective cancer treatment. Pyrazole and pyrimidine/fused pyrimidine can be rewarded with significant anticancer activity and tampered with in a range of places whereby some of their derivatives have received approval to treat cancer. Notably, pyrazole-pyrimidine/fused pyrimidine hybrids, blending of pyrazole and pyrimidine/fused pyrimidine pharmacophores into in a new chemical entity, can act on different targets simultaneously in cancer cells and possess potent in vitro and in vivo activity against both drug-sensitive and drug-resistant cancers. Moreover, several pyrazole-pyrimidine/fused pyrimidine hybrids which are exemplified by ruxolitinib (pyrazole-pyrrolo[2,3-d]pyrimidine hybrid) have already applied in clinics for cancer therapy, demonstrating pyrazole-pyrimidine/fused pyrimidine hybrids are pharmacologically significant scaffolds for the exploration of novel anticancer agents. This review aims to shed light on the recent developments of pyrazole-pyrimidine/fused pyrimidine hybrids with anticancer potential, and their structure-activity relationships as well as mechanisms of action are also discussed, covering papers published from 2019 to present, to facilitate further rational design of more effective candidates. [ABSTRACT FROM AUTHOR]

Context: The design and synthesis of safe and highly active sulfonylurea herbicides is still a challenge. Therefore, following some principles of structure-activity relationship (SAR) of sulfonylurea herbicides, this work focuses on evaluating two sulfonylurea derivatives bearing electron-withdrawing substituents, namely, –(CO)OCH3 and –NO2 on the aryl group, on herbicidal activity. To understand the effects caused by the substituent groups, the molecular and electronic structures of the sulfonylureas were evaluated by density functional theory. Likewise, the crystalline supramolecular arrangements of both compounds were analyzed by Hirshfeld surface, QTAIM, and NBO, with the aim of verifying changes in intermolecular interactions caused by substituent groups. Finally, through a toxicophoric analysis, we were able to predict the interacting groups in their biological target, acetolactate synthase, and verify the interactions with the binding site. Methods: All theoretical calculations were conducted using the highly parameterized empirical exchange-correlation functional M06-2X accompanied by the diffuse and polarized basis set 6-311++G(d,p). The atomic coordinates were obtained directly from the crystalline structures, and from the energies of the frontier molecular orbitals (HOMO and LUMO), chemical descriptors were obtained that indicated the influence of the functional groups in the sulfonylureas on the reactivity of the molecules. The intermolecular interactions in the crystals were analyzed using the Hirshfeld, QTAIM, and NBO surfaces. Toxicophoric modeling was performed by the PharmaGist webserver and molecular docking calculations were performed by the GOLD 2022.1.0 software package so that the ligand was fitted to the binding site in a 10 Å sphere. For this, genetic algorithm parameters were used using the ChemPLP scoring function for docking and ASP for redocking. [ABSTRACT FROM AUTHOR]

Fused heterocyclic ring structures play an important role in the enhancement of pharmaceutical actions of the molecules and have been reported to have efficient medicinal applications in recent decades. Thiazolopyrimidines are fused heterocyclic molecules consisting of thiazole and pyrimidine ring systems that have significant importance in medicinal chemistry. Thiazolopyrimidines have been prepared by the reaction of 4,5-dihydrothiazol-2-amine with diketones, ethoxymethylene malonic esters, acetylene dicarboxylic esters and ethyl(chloroformyl)acetate. Herein, we have discussed a variety of synthetic approaches, e.g., condensation reaction, Biginelli condensation reaction, Knovenagel condensation reaction, ultrasonic assisted synthesis, multistep reaction, single step reaction, from chalcones, microwave-mediated synthesis, Pd-catalyzed coupling reaction, U-SH technique, and green synthesis, for the formation of isomeric forms of thiazolopyrimidines, including thiazolo[3,2-a]pyrimidine, thiazolo[5,4-d]pyrimidine, and thiazolo[4,5‐d]pyrimidine and their derivatives. [ABSTRACT FROM AUTHOR]

In this study, MnCoFe2O4@ovalbumin nanoparticles were synthesized using MnCoFe2O4 MNPs and egg white nano-ovalbumin. The surface of MnCoFe2O4 MNPs was activated with trisodium citrate anhydrou to improve the fabrication of nano-ovalbumin on MCF MNPs. The structure of these nanoparticles was properly characterized by Fourier-transform infrared spectroscopy (FT-IR), Scanning electron microscope, X-ray powder diffraction, Energy-dispersive X-ray spectroscopy, Transmission electron microscopy, Thermogravimetric, and Vibrating sample magnetometer. The catalytic activity of the MnCoFe2O4@ovalbumin nanoparticles was evaluated for the synthesis of pyrimido[4,5-d]pyrimidine derivatives via multi-component reaction of aldehyde, barbituric acid, urea, or thiourea under solvent-free condition. The desired products were prepared using an environmentally friendly method. Short reaction time, high efficiency, and easy work-up are some advantages of this procedure. This heterogeneous nanocatalyst can be easily recovered by a magnetic field and used at least six times without considerable loss of its activity. Also, MCF@OVL MNPs exhibited a CO2 adsorption capacity about 9.35 mmol/g at 25 °C. [ABSTRACT FROM AUTHOR]

In this work, the surface of Fe3O4 nanoparticles was functionalized with the glycine, furfural, and cobalt (II) nitrate hexahydrate to synthesize a novel support nanocatalyst (Fe3O4@gly@Furfural@Co(NO3)2). The characteristics of the nanocatalyst were confirmed by various techniques, such as energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectrometer, EDX mapping, scanning electron microscopy, X-ray diffraction, thermal gravimetric/derivative thermal gravimetric, vibrating sample magnetometer, and TEM. Finally, the performance of the nanocatalyst was investigated for the one-pot multicomponent synthesis of benzo[b]pyran and pyrano[2,3-d] pyrimidine derivatives. The good–excellent yield of the products was achieved in a green solvent under mild conditions at short reaction time. In addition, the green heterogeneous catalyst has features, such as environmental friendliness, easy separation from the reaction mixture by an external magnet, high catalytic activity, and reusability up to 6 stages without significant reduction of its catalytic activity. [ABSTRACT FROM AUTHOR]

C2‐functionalized pyrimidine derivative is a family of important nitrogen heterocyclic compounds due to their unique structure and multiple reaction sites. In this work, a novel method for the synthesis of C2‐functionalized pyrimidine derivatives through phenylalkynes and pyrimidine disulfides under ambient conditions is proposed. The reaction can be triggered by adding catalytic amounts of cesium fluoride, which is characterized by free‐catalyst and special activator. Importantly, this reaction has good compatibility with substrates substituted by electron‐donating and electron‐withdrawing groups at C4. Density functional theory (DFT) calculations also indicates that the production of C2‐functionalized pyrimidine derivatives is more favourable. [ABSTRACT FROM AUTHOR]

In this paper, thiazolo[3,2-a]pyrimidine-2,3-dicarboxylate and oxazolo[3,2-a]pyrimidine-2,3-dicarboxylate derivatives are produced in excellent yields via the multicomponent reaction of anilines, ethyl acetoacetate, aldehydes, urea or thiourea, activated acetylenic esters and triphenylphosphine in the presence of Ag/KF/CP@MWCNT as a high efficient catalyst in aqueous media at ambient temperature. The Ag/KF/CP@MWCNT is generated by water extract of rhizome Petasites hybridus as an environmentally media and moderate base. Also, Ag/KF/CP@MWCNT leads to increasing of yield of products and has notable reusability. Antioxidant ability of the resulted compounds is studied by DPPH (radical trapping of diphenyl-picrylhydrazine) and ferric reduction power tests. Also, the antimicrobial activity of some products is determined with the disk diffusion experiment on Gram-positive and Gram-negative bacteria. The advantages of this protocol include of short reaction time, high efficiency and easy separation of products and use of simple catalyst. Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Compounds bearing fused thiazole and pyrimidine units play important role in organisms because they have good biological potentials. Thiazolopyrimidines are an interesting group of heterocyclic compounds and among them the thiazolo[3,2-a]pyrimidine skeleton are a key constructions and have vital biological activities and are widely found in important drugs such as Alzheimer's disease, anticancer, antimicrobial, anti-inflammatory, antioxidant, anti-human cytomegalovirus activity, antiparkinsonian, antitumor and antiviral. [ABSTRACT FROM AUTHOR]

The present work describes one-pot synthesis of pyrano[2,3-d] pyrimidine derivatives using aromatic aldehyde, ethyl cyanoacetate and barbituric or thiobarbituric acid accelerated by microwave irradiation in the presence of agro-waste extract solvent medium with few drops of ethanol as a co-solvent presented. The reaction is optimized by various methods such as magnetic stirring, ultrasound, mechanochemical and microwave irradiation, but the microwave irradiation method excelled product formation faster rate with high yield and purity. The advantages of the present approach are the metal-free, chemical-less, and hazardous solvent-less employed and considered as an eco-friendly protocol for the synthesis of pyrano[2,3-d] pyrimidine derivatives developed. The final product isolated was recrystallized in ethanol and characterized by FT-IR, 1H-, 13C-NMR and LC-MS spectrometry. Further, some of the selected pyrano[2,3-d]pyrimidine derivatives (4a, 4b, 4d, 4f, 4m and 4o) are subjected to electrochemical behavior and anti-microbial activity studies. The anti-microbial activity tested derivatives showed comparable activities, and also electrochemical behavior of oxidation and reduction potentials observed by these compounds. [ABSTRACT FROM AUTHOR]

Using Silica Sulfuric Acid (SSA) as an eco-friendly, readily available, and reusable catalyst, herein we were prepared a new series of 3,4-dihydropyrimidin-2-(1H)ones and -thiones 4–16 (DHMPs). The condensation reaction of 2,5-dimethoxybenzaldehyde, 1,3-diphenylpropane-1,3-dione, and thiourea as one-pot reaction (known as Biginelli reaction) by using different catalysts. Silica sulfuric acid (SSA) showed the best catalytic activity (with yield 99%) using 0.11 mol at 15 min in the presence of ethylene glycol as green solvent. The targeted compounds of 3,4-dihydropyrimidin-2-(1H)ones and -thiones 4–16 have been fully characterized and tested as novel anti-cancer agents. The biological activity of the synthesized compounds 4–16, were evaluated in vitro as anti-cancer agents against both liver (Huh7 cell line) and lung cancer (A549) cells. Most of the tested compounds showed potential cytotoxic activity against liver cancer (Huh7) cell line, while they had moderate to week cytotoxic activity against lung cancer (A549) cell line. Most notably, compound 13 was the most effective cytotoxic agent against both liver and lung cancer cell lines, with less toxicity against non-cancer cell line MDCK, when compared to Doxorubicin as reference drug. Therefore, the mode of action of this compound using flow cytometry and molecular docking was investigated. The SAR study showed that the pyrimidines that contains chloride, florid or methoxy groups in their structures gave potent anti-cancer activity than that contains phenyl or naphthalene moieties, while the presence of sulfur as a substitution on the pyrimidine ring increased the anti-cancer activity than that observed in the presence of oxygen. [ABSTRACT FROM AUTHOR]

An efficient synthesis of new pyrazolo-, triazolo-, and thiazolopyrimidinyl-substituted derivatives of 1-phenylpyrazol-3-one on the basis of a product of the condensation of 4-acetylpyrazolone difluoroboron chelate with dimethylformamide dimethyl acetal has been developed. [ABSTRACT FROM AUTHOR]

Various approaches to the synthesis of 3-halopyrazolo[1,5-a]pyrimidines were studied. It is shown that the most effective strategy consists in the construction of the azoloazine core followed by halogenation with N-iodo- or N-bromosuccinimide. A series of 3-halopyrazolo[1,5-a]pyrimidines, which are bioisosteric analogs of natural purine nucleic bases and the drug Triazavirin®, were synthesized using this strategy. The obtained compounds are interesting as precursors of novel C-nucleosides, which can be synthesized by C-C-coupling with (pseudo)ribosides containing a keto group. [ABSTRACT FROM AUTHOR]

Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of improving biological activity and enhancing chemical or metabolic stability. Selective F substitution onto a therapeutic or diagnostic drug candidate can enhance several pharmacokinetic and physicochemical properties such as metabolic stability and membrane permeation. The increased binding ability of fluorinated drug target proteins has also been reported in some cases. An emerging line of research on F substitution has been addressed by using 18F as a radiolabel tracer atom in the extremely sensitive methodology of positron emission tomography (PET) imaging. This review aims to report on the fluorinated drugs approved by the US Food and Drug Administration (FDA) from 2016 to 2022. It cites selected examples from a variety of therapeutic and diagnostic drugs. FDA-approved drugs in this period have a variety of heterocyclic cores, including pyrrole, pyrazole, imidazole, triazole, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, triazine, purine, indole, benzimidazole, isoquinoline, and quinoline appended with either F-18 or F-19. Some fluorinated oligonucleotides were also authorized by the FDA between 2019 and 2022. [ABSTRACT FROM AUTHOR]

New thieno[2,3‐d]pyrimidine derivatives were designed and synthesized. The National Cancer Institute (NCI) evaluated the synthesized novel compounds against a panel of 60 tumor cell lines for their antiproliferative activity. Compounds 6b, 6f, and 6g showed potent anticancer activity at 10 µM dose, with mean GI of 20.86%, 76.41%, and 31.49%, respectively. Compound 6f was selected for five‐dose concentrations evaluation. Compound 6f scored a submicromolar range of GI50 values against 10 cancer cell lines, indicating broad‐spectrum and potent antiproliferative activity. Compound 6f TGI values were recorded in the cytostatic range of 4.02–95.1 µM. In comparison to sorafenib, the tested compounds 6b, 6f, and 6g inhibited VEGFR‐2 with IC50 values of 0.290 ± 0.032, 0.066 ± 0.004, and 0.16 ± 0.006 µM, correspondingly. Compound 6f significantly reduced the total VEGFR‐2 expression and its phosphorylation. Additionally, 6f reduced the phosphorylation of PI3K, Akt, and mTOR pathway proteins. Moreover, the migratory potential of HUVECs was significantly reduced, after 72 h of treatment with compound 6f, resulting in disrupted wound healing patterns which verified the angiogenesis suppression properties of compound 6f. Compound 6f increased the total apoptosis percentage by 21.27‐fold compared to sorafenib, which caused a 24.11‐fold increase in the total apoptosis percentage. This apoptotic activity was accompanied by a 7.81‐fold increase in the level of apoptotic caspase‐3. Furthermore, the cell cycle analysis revealed that the target derivative 6f reduced cellular proliferation and induced an arrest in HCT‐15 colon cancer cell cycle at the S phase. Molecular modeling was used to determine the binding profile and affinity of derivative 6f toward the VEGFR‐2 active site. [ABSTRACT FROM AUTHOR]

In this contribution, new derivatives of bicyclic fused rings with bridgehead nitrogen of 3-substituted imidazo/pyrimidine derivatives A1-A3 were synthesized by reacting 2-aminobenzothiazol, acetyl acetone, and different substituted aldehydes in a one-pot reaction. These compounds A1-A3 were then condensed with 4- bromobenzaldehyde and 4-(N,N-dimethylamino)benzaldehyde to form new chalcone derivatives A4-A9. Ring closure of these compounds A4-A9 with urea and malononitrile afforded new oxopyrimidine derivatives A10-A15 and cyanopyridine derivatives A16-A21, respectively. These compounds were characterized by FT-IR, 1H NMR, and 13C NMR spectroscopy. The second part of this work included some of the important applications conducted for these compounds to evaluate their biological activities against colon cancer, which showed excellent results against this disease. [ABSTRACT FROM AUTHOR]

Two series of compounds viz. spiro naphthyridine pyrimidine derivatives and N‐(quinolin‐8‐yl)acetamide derivatives which possess the quinoline core moiety were designed and synthesized. The spectral analysis viz. FT‐IR, 1H‐NMR, 13C‐NMR and mass was carried out to establish the structures for the synthesized compounds. In vitro anti‐tubercular activity was done against Mycobacterium tuberculosis H37Rv by following "microplate alamar blue assay (MABA)". The synthesized compounds showed good anti‐tuberculosis (TB) activity with the least minimum inhibitory concentration (MIC) value of 6.25 μg/mL. Computational molecular docking studies were performed out with Mycobacterium tuberculosis enoyl reductase (INHA) (PDB code: 4TZK) using AutoDock to predict the key binding interactions responsible for the activity and the Swiss ADME (absorption, distribution, metabolism, and excretion) tool computed the in silico drug likeliness properties. The synthesized title compounds create a way for the optimization and development of potential drugs against tuberculosis. [ABSTRACT FROM AUTHOR]

Focal adhesion kinase is upregulated in various types of cancer and has become an important research target for the development of more effective anticancer drugs. Herein, a dataset containing 31 pyrimidine-based derivatives as FAK inhibitors was used to develop new and effective FAK inhibitors through molecular modeling, three-dimensional quantitative structure–activity relationship analysis, molecular docking, and molecular dynamics simulation. The best comparative molecular similarity index analysis CoMSIA/HD model (Q2 = 0.699, R2 = 0.931, R2test = 0.815) passed all validation parameters, confirming its reliability and predictability. The contour maps showed that the hydrophobic and donor fields have a more significant impact on the bioactivities of the inhibitors. Consequently, four new FAK inhibitors (D1–D4) were developed with higher predicted inhibitory activity. The interaction mode between the new compounds (D1–D4) and the FAK receptor (PDB ID: 6I8Z) was investigated by molecular docking simulation, which showed good binding energy through the creation of hydrogen and hydrophobic bonds with the key residues of the protein, such as Cys502, Ile428, Leu553, Leu567, and Leu501. These new inhibitors had good oral bioavailability and were non-toxic based on their ADMET properties. Furthermore, the most suitable candidate, D3, the most active of the series, 36, and Defactinib as a reference drug were simulated by molecular dynamics for 100 ns, and their binding free energies were determined using the MM–PBSA method. The MD results confirmed the docking results and showed that compound D3 had satisfactory stability with ΔGbinding = −158.362 kJ mol−1 in the active site of the FAK receptor compared with Defactinib with ΔGbinding = −120.872 kJ mol−1. Finally, retrosynthesis tools suggested methods for the synthesis of compound D3 as the most potential therapeutic FAK inhibitor. In conclusion, this study provides theoretical guidelines for the development and synthesis of new FAK inhibitors. [ABSTRACT FROM AUTHOR]

Quadruple azidation of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine gave tetraazidopyrimido[5,4-d]pyrimidine (C6N16) with 86% yield. The title compound undergoes azide–tetrazole tautomerism in neutral organic solvents, but exists as a protonated C2-symmetric tetraazide dication in trifluoroacetic acid. On the other hand, in the solid state it occurs as a monotetrazole tautomer as revealed by its single crystal X-ray analysis. The newly obtained binary compound C6N16 is very sensitive towards both impact (<1 J) and friction (1 N). A detonation velocity of 7477 m s−1 with a 20.8 GPa detonation pressure was calculated using the EXPLO5 code (version V7.01.01). [ABSTRACT FROM AUTHOR]

Pyrimidine is a six‐membered diaza‐heterocycle i. e. 1,3‐diazine. It is found to be present in many biologically and pharmacologically active scaffolds like nucleotides, natural products, and drugs. The bioactivities of pyrimidine include anti‐tubercular, anti‐bacterial, anti‐fungal, anti‐viral, anti‐inflammatory, anti‐malarial, anti‐cancer, anti‐neoplastic and many more. In this review article we have summarized various synthetic approaches that involve the synthesis of these privileged building blocks by employing propargylic alcohols and their derivatives like propargylic esters and propargylic ynones as three carbon‐components. Here, we have confined ourselves to the developments appeared during the period of 23 years i. e. 2000–2022. [ABSTRACT FROM AUTHOR]

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work. [ABSTRACT FROM AUTHOR]

Fused pyrimidines scaffolds such as pyrimidopyrimidines, purines and xanthines are important structural motifs found in various natural products and drug molecules. They are used as anticancer, antiviral, antibacterial, antifungal, antioxidant, antitumor, anti‐diabetic, adenosine potentiating, and hepatoprotective agents. Due to their diverse biological applications, the synthesis of pyrimidopyrimidines, purines and xanthines has gained great importance among the researchers in recent years. Thus, the present study aims to review the synthetic methodologies published during the years 2000–2022 for the preparation of pyrimidopyrimidines, purines and xanthines nucleus. Mechanistic interpretation of some important cases has also been discussed. This survey will help researchers working in the fields of synthetic organic and medicinal chemistry to undertake and improve new approaches for the construction of titled compounds. [ABSTRACT FROM AUTHOR]

Chemically modified antisense oligonucleotides (ASO) currently in pre‐clinical and clinical experiments mainly focus on the 2′‐position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2′‐modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO's binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno‐modification at 5‐position of thymidine, as well as its Se‐oligonucleotides. Via X‐ray crystal structural study, we found that the Se‐modification was located in the major groove of nucleic acid duplex and didn't cause the thermal and structural perturbations. Surprisingly, our nucleobase‐modified Se‐DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential anti‐sense modification in the form of Se‐antisense oligonucleotides (Se‐ASO). [ABSTRACT FROM AUTHOR]

Pyrimidine, a six-membered heteroaromatic molecule, is a structural element found in several essential biomolecules, such as thiamine and nucleosides. Its significant biological activity is important in chemical and medicinal chemistry. Traditional methods for synthesizing pyrimidines often use hazardous solvents and toxic reagents, which can pose a risk to human health and the environment. However, many green chemistry methods have been developed in recent years. These methods use safer and more sustainable techniques, such as catalysts, multicomponent reactions, microwave-assisted synthesis, solventless approaches, mechanical procedures, ultrasonic synthesis, and ionic liquids. These methods produce pyrimidines with higher yields, less environmental impact, and financial gains. They also reduce waste and byproduct generation, shorten reaction times, and simplify workup methods. [ABSTRACT FROM AUTHOR]

Multi-component reactions (MCRs) have been receiving wide attention from chemists because they can be employed for the rapid assembly of compound arrays with high molecular diversity.[[1], [3]] In recent years, there has been increasing interest in the synthesis of pyrimidine derivatives, and there are good methods used to synthesize the pyrimidine ring, allowing access to a large number of multifunctionalized pyrimidine derivatives.[[5], [7]] Considerable activity has been devoted to their chemistry and biological activity.[9] Selenium-containing organic compounds have remarkable synthetic and biological functions.[[10], [12], [14]] The first synthesis of acyl isoselenocyanates, which were generated by the reaction of acyl chlorides and potassium selenocyanate, has been described by Douglass.[15] Recently, the syntheses of heterocycles from acyl isoselenocyanates were reported.[[16], [18], [20]] Herein, we describe a convenient synthesis of novel 3-aryl-4-phenyl-1-selenoxo-1,4-dihydro-9-oxa-2,4-diaza-phenanthren-10-ones using a reported method.[16] Thus, under reaction conditions similar to those previously described,[16] an aroyl chloride B 2 b was reacted with potassium selenocyanate B 3 b under solvent-free conditions at ambient temperature and then warmed at 90 °C for 5 min prior to the addition of 4-phenylamino-chromen-2-one B 1 b . The mass spectra of compounds B 4a-f b are fairly similar and display molecular ion peaks. For example, the mass spectrum of compound B 4a b (showing a molecular ion peak at I m/z i 474) is in line with the supposition that compound B 4a b is a condensation product of 6-methyl-4-phenylamino-pyran-2-one, 4-nitrobenzoyl chloride and potassium selenocyanate. The SP 13 sp C NMR spectrum of compound B 4a b showed 19 distinct signals consistent with the proposed structure. [Extracted from the article]