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A rapid and enormously professional new-flanged 3,5-disubstituted triazole derivatives were synthesized by the one-pot five-component condensation reaction in the course of transesterification followed by the Biginelli/Click reaction in aqueous medium using magnetic CuFe2O4 NPs as heterogeneous catalyst beneath ultrasonic acceleration in aqueous medium. The synthesized 3,5-disubstituted triazole derivatives were finely characterized and the characterized desired target molecules were employed for the quantum chemical calculations for each reactant and product have been well thought-out using density functional theory. Furthermore, the molecular docking and ADMET revision of all the derivatives have been achieved as digestive enzyme and Cathepsin-B inhibitors and their connections with BSA to treat different diseases. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6-7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-a resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E. [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.

A new series of novel imidazo-[1',5':1,2]pyrimido[4,5-d]isoxazolo[2,3-a]pyrimidin-10-ones 5 has been accomplished by reaction of 3-amino-5-methyl-7aryl-7H-isoxazolo[2,3-a]pyrimidin-6-yl cyanides 2, with choloacetylchloride followed by treatment with aromatic primary amines and, then with formaldehyde. The key intermediate 2, is obtained by reaction of 3-amino-5-methylisoxazole 1 with aromatic aldehydes, and malononitrile by a three-component one-pot synthesis. The structures of newly synthesized compounds 2-5 have been established on the basis of spectral data, and evaluated for their in vitro antimicrobial activity. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum(PG) is a debilitating skin condition often accompanied by inflammatory bowel disease (IBD). Strikingly, ~40% of patients that present with PG have underlying IBD, suggesting shared but unknown mechanisms of pathogenesis. Impeding the development of effective treatments for PG is the absence of an animal model that exhibits features of both skin and gut manifestations. This study describes the development of the first experimental drug-induced mouse model of PG with concomitant intestinal inflammation. Topical application of pyrimidine synthesis inhibitors on wounded mouse skin generates skin ulcers enriched in neutrophil extracellular traps (NETs) as well as pro-inflammatory cellular and soluble mediators mimicking human PG. The mice also develop spontaneous intestinal inflammation demonstrated by histologic damage. Further investigations revealed increased circulating low density IL-1β primed neutrophils that undergo enhanced NETosis at inflamed tissue sites supported by an increase in circulatory citrullinated histone 3, a marker of aberrant NET formation. Granulocyte depletion dampens the intestinal inflammation in this model, further supporting the notion that granulocytes contribute to the skin-gut crosstalk in PG mice. We anticipate that this novel murine PG model will enable researchers to probe common disease mechanisms and identify more effective targets for treatment for PG patients with IBD. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a debilitating skin condition often accompanied by inflammatory bowel disease (IBD). Strikingly, ~40% of patients that present with PG have underlying IBD, suggesting shared but unknown mechanisms of pathogenesis. Impeding the development of effective treatments for PG is the absence of an animal model that exhibits features of both skin and gut manifestations. This study describes the development of the first experimental drug-induced mouse model of PG with concomitant intestinal inflammation. Topical application of pyrimidine synthesis inhibitors on wounded mouse skin generates skin ulcers enriched in neutrophil extracellular traps (NETs) as well as pro-inflammatory cellular and soluble mediators mimicking human PG. The mice also develop spontaneous intestinal inflammation demonstrated by histologic damage. Further investigations revealed increased circulating low density IL-1β primed neutrophils that undergo enhanced NETosis at inflamed tissue sites supported by an increase in circulatory citrullinated histone 3, a marker of aberrant NET formation. Granulocyte depletion dampens the intestinal inflammation in this model, further supporting the notion that granulocytes contribute to the skin-gut crosstalk in PG mice. We anticipate that this novel murine PG model will enable researchers to probe common disease mechanisms and identify more effective targets for treatment for PG patients with IBD.

Simple Summary: Although significant progress has been made in the treatment of myeloid malignancies, this issue remains a focus of interest for a large number of research teams. Current research is especially focused on elderly patients who are not suitable for intensive chemotherapy and bone marrow transplantation or patients who have achieved remission after such therapy but subsequently enter into relapse of the disease. Here, therapy with demethylating agents is indicated. However, we do not know of another treatment option in the case of resistance to such treatment. Therefore, knowledge of the causes and mechanisms of resistance to demethylating agents is an essential issue for improving the treatment of such patients. Three AML cell variants (M/A, M/A* from MOLM-13 and S/A from SKM-1) were established for resistance by the same protocol using 5-azacytidine (AZA) as a selection agent. These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2′-deoxycytidine (DAC), as well as in some molecular features. Differences in global DNA methylation, protein levels of DNA methyltransferases, and phosphorylation of histone H2AX were observed in response to AZA and DAC treatment in these cell variants. This could be due to changes in the expression of uridine-cytidine kinases 1 and 2 (UCK1 and UCK2) demonstrated in our cell variants. In the M/A variant that retained sensitivity to DAC, we detected a homozygous point mutation in UCK2 resulting in an amino acid substitution (L220R) that is likely responsible for AZA resistance. Cells administered AZA treatment can switch to de novo synthesis of pyrimidine nucleotides, which could be blocked by inhibition of dihydroorotate dehydrogenase by teriflunomide (TFN). This is shown by the synergistic effect of AZA and TFN in those variants that were cross-resistant to DAC and did not have a mutation in UCK2. [ABSTRACT FROM AUTHOR]

A new series of tetrahydropyrimidines were prepared by employing the Petrenko–Kritschenko reaction between 2-nitrobenzaldehyde and 1,3-dicarbonyl compounds in the presence of ammonium acetate at ambient temperature. The reaction afforded an unexpected heterocyclic skeleton instead of the usual piperidone ring. Physicochemical analyses including 1H, 13C NMR and HRMS were used to elucidate this structure. The stereochemistry was investigated by X-ray crystallography analysis and DFT calculations. The available results confirm the existence of an unusual structure containing two bulky groups at the cis position in the pyrimidine ring. Formation of such an exceptional structure is possible due to the π– π stacking stabilization of nitrophenyl groups. [ABSTRACT FROM AUTHOR]

Three AML cell variants (M/A, M/A* from MOLM-13 and S/A from SKM-1) were established for resistance by the same protocol using 5-azacytidine (AZA) as a selection agent. These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2′-deoxycytidine (DAC), as well as in some molecular features. Differences in global DNA methylation, protein levels of DNA methyltransferases, and phosphorylation of histone H2AX were observed in response to AZA and DAC treatment in these cell variants. This could be due to changes in the expression of uridine-cytidine kinases 1 and 2 (UCK1 and UCK2) demonstrated in our cell variants. In the M/A variant that retained sensitivity to DAC, we detected a homozygous point mutation in UCK2 resulting in an amino acid substitution (L220R) that is likely responsible for AZA resistance. Cells administered AZA treatment can switch to de novo synthesis of pyrimidine nucleotides, which could be blocked by inhibition of dihydroorotate dehydrogenase by teriflunomide (TFN). This is shown by the synergistic effect of AZA and TFN in those variants that were cross-resistant to DAC and did not have a mutation in UCK2.

New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection. [ABSTRACT FROM AUTHOR]

A reaction between two prebiotically plausible building blocks, hydantoin and glyoxylate, generates both the nucleobase orotate, a precursor of biological pyrimidines, and pyruvate, a core metabolite in the citric acid cycle and amino acid biosynthesis. The reaction proceeds in water to provide significant yields of the two widely divergent chemical motifs. Additionally, the reaction of thiohydantoin and glyoxylate produces thioorotate in high yield under neutral aqueous conditions. The use of an open‐chain thiohydantoin derivative also enables the potential pre‐positioning of a nucleosidic bond prior to the synthesis of an orotate nucleoside. The observation that diverse building blocks of modern metabolism can be produced in a single reaction pot, from common reactants under mild conditions, supports the plausibility of orthogonal chemistries operating at the origins of chemical evolution. [ABSTRACT FROM AUTHOR]

Chinese hamster ovary (CHO) cell lines are grown in cultures with varying asparagine and glutamine concentrations, but further study is needed to characterize the interplay between these amino acids. By following 13C‐glucose, 13C‐glutamine, and 13C‐asparagine tracers using metabolic flux analysis (MFA), CHO cell metabolism was characterized in an industrially relevant fed‐batch process under glutamine supplemented and low glutamine conditions during early and late exponential growth. For both conditions MFA revealed glucose as the primary carbon source to the tricarboxylic acid (TCA) cycle followed by glutamine and asparagine as secondary sources. Early exponential phase CHO cells prefer glutamine over asparagine to support the TCA cycle under the glutamine supplemented condition, while asparagine was critical for TCA activity for the low glutamine condition. Overall TCA fluxes were similar for both conditions due to the trade‐offs associated with reliance on glutamine and/or asparagine. However, glutamine supplementation increased fluxes to alanine, lactate and enrichment of glutathione, N‐acetyl‐glucosamine and pyrimidine‐containing‐molecules. The late exponential phase exhibited reduced central carbon metabolism dominated by glucose, while lactate reincorporation and aspartate uptake were preferred over glutamine and asparagine. These 13C studies demonstrate that metabolic flux is process time dependent and can be modulated by varying feed composition. [ABSTRACT FROM AUTHOR]

A new class of Indole connected cyanoaminopyrimidine scaffolds were synthesized by Multicomponent single-pot strategy with the reaction of indole-3-carbaldehyde, substituted acetophenone and cyanoguanidine in a basic alcoholic medium. The structural assignments were done for the obtained 2-Cyanoamino-6-aryl-4-(indol-3-yl)-1,2-dihydro-1Hpyrimidines (4a-4f) with the help of 1H,13C NMR, IR and Mass spectral data. The screened in vitro microbial activities of most of the compounds showed moderate to strong anti-microbial potential. [ABSTRACT FROM AUTHOR]

New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.

"The founder of green chemistry explains how chemicals manufacturing must change to support a sustainable future." In this review, Green chemistry is considered in the synthesis of heterocycles compounds containing Pyrimidine nuclei using different catalyzes, solvents, and techniques for the synthesis of pyrimidine derivatives that achieve sustainability. The mentioned fused heterocycles are classified according to the type of ring system. The yield of the target molecules reported in the review is given in the reaction's last step., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Summary: Proxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa) that has entered phase III clinical trials. In the present study, we intended to elucidate the antitumor efficacy of proxalutamide through the metabolomic profiling of PCa cells. Two AR-positive PCa cell lines and two AR-negative PCa cell lines were investigated. Cell viability assays based on ATP quantitation were conducted. LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide and enzalutamide). The results of this study showed that the inhibitory effect of proxalutamide on PCa cell proliferation was better than that of bicalutamide and enzalutamide, and proxalutamide preferentially affected AR-positive PCa cells over AR-negative cells. The metabolic composition of PCa cells changed significantly after proxalutamide administration, and these changes in response to proxalutamide were significantly different from those in the presence of the two other AR antagonists. In AR-positive cells, proxalutamide significantly decreased the intracellular levels of glutamine, glutamate, glutathione, cysteine, glycine, aspartate, uridine, cytidine and thymidine. However, the effects of the two other antagonists on these discriminant metabolites were ambiguous, and no changes in these metabolites were found in AR-negative cells. Our findings indicate that proxalutamide has inhibitory effects on glutamine metabolism, redox homeostasis and de novo pyrimidine synthesis in AR-positive PCa cells that enhance the cellular sensitivity to proxalutamide. [ABSTRACT FROM AUTHOR]

Pyrido[1,2-a]pyrimidin-4-one and their derivatives are found to be key intermediates in the synthesis of medicinally active compounds. Therefore an efficient and convenient procedure has been developed for the synthesis of some novel pyrido[1,2-a]pyrimidin-4-one derivatives like aryl-N-(2-(2-methyl-4-oxo-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl) carboxamide and alkyl-N-(2-(2-methyl-4-oxo-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl)carboxamide. The structures of the new compounds have been evaluated on the basis of FT-IR, ¹H NMR and Mass spectroscopy data. They have also been screened for their antimicrobial activities against various strains of bacteria and fungi. [ABSTRACT FROM AUTHOR]

A facile one-pot synthesis of trifluoromethylated pyrimidines has been achieved by the treatment of fluorinated 2-bromoenones with aryl- and alkylamidines. The assembly of pyrimidine core proceeds by the cascade reactions via aza-Michael addition–intramolecular cyclization–dehydrohalogenation/dehydration sequence. This strategy is featured by high selectivity and mild reaction conditions giving the target heterocycles in high yields (up to 99%). The unique influence of trifluoromethyl group on the reaction path is demonstrated. [ABSTRACT FROM AUTHOR]

A new family of pyrimidine modified tetrazole & azido derivatives (1‐16) was developed using the conventional and nucleophilic substitution methods. The 1H‐tetrazol‐1‐yl)pyrimidine (1‐10) compounds were prepared via traditional cycloaddition and condensation method. The compounds tetrazolo[1,5‐a]pyrimidine (11 a,12 a, and 13 a), azido‐(1H‐tetrazol‐1‐yl)pyrimidine (14 a and 15 a) and tetrazolo[1,5‐c]pyrimidine (16 a) were synthesized by simultaneously introducing conventional and nucleophilic substitution approaches. The latter technique was easy to process and reduce the synthesis time. The factors (solvent, temperature, steric effect, electron‐donating groups, and electron‐withdrawing groups) were found responsible for steering the azido‐tetrazole equilibrium in the compounds 11 a, 12 a, 13 a, and 16 a. All the prepared compounds were well characterized including single‐crystal X‐ray diffraction structures of 1, 3, 4, 6, 8, 10, 11 a, 12 a, 13 a, 14 a, 15 a, and 16 a. Thermal behaviour was investigated by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). The current work is significant to the development of a new class of pyrimidine modified tetrazole and azido derivatives in sense of easy reaction approach, good to excellent yields, safe process, and simple work‐ups. [ABSTRACT FROM AUTHOR]

2-Aminouracil is used in the synthesis of a new series of tri- and tetracyclic pyrimidine scaffolds as the precursor. Thiazolo[5,4-d]triazolo[4,3-a]pyrimidine has been synthesized by diazotization and heterocyclization of the aminopyrimidinone derivative with nitrous acid at low temperature. Some new pyrimidines have been formed in the course of acylation and cyclization of the same compound with acetic anhydride, formic acid, pyruvic acid, or phthalic anhydride. [ABSTRACT FROM AUTHOR]

Methyl 5-aroyl-6-aryl-4-methoxy-2-oxo(thioxo)hexahydropyrimidine-4-carboxylates were synthesized by four-component Biginelli reaction of methyl aroylpyruvate, aromatic aldehyde, urea (thiourea), and MeOH in the presence of NaHSO4. The products were obtained in moderate to high yields. [ABSTRACT FROM AUTHOR]

Herein, a rapid and highly efficient method for the synthesis of a new series of pyrimidine derivatives was demonstrated. The strategy was emanated from the reaction of hydrazinyl pyrimidine derivative (1) with different electrophilic species such as ethyl acetoacetate, ethyl 4,4,4‐trifluoro acetoacetate, and phenyl isothiocyanate following cyclocondensation mechanism to afford the corresponding derivatives (2‐6). Furthermore, condensation of hydrazine derivative (1) with different carbonyl compounds via conventional heating and microwave irradiation conditions was employed as a source of Schiff base derivatives bearing pyrimidine moiety (7‐12). The structural features of all newly synthesized compounds were characterized by elemental and spectroscopic evidences. Some of the synthesized compounds were evaluated for in vitro cytotoxicity. The preliminary screening results showed that most of the tested compounds have moderate cytotoxic activity against HepG2 and HCT‐116 cell lines. Finally, a molecular docking study was conducted to reveal the probable interaction with the thymidylate synthase enzyme. [ABSTRACT FROM AUTHOR]

Herein we report a comparative study of nickel‐catalyzed syntheses of pyrimidines via dehydrogenative multi‐component coupling of alcohols and amidines using two different classes of nickel catalysts (1 a/1 b and 2 a/2 b) differing with respect to their mode of action during catalysis. The catalysts 1 a and 1 b are two tetracoordinate Ni(II)‐complexes containing two apparently redox‐inactive tetraaza macrocyclic ligands while the catalysts 2 a and 2 b are square planar Ni(II)‐complexes featuring redox‐active diiminosemiquinonato type scaffolds. Catalyst 1 a and 1 b dehydrogenate alcohols via a two‐electron hydride transfer pathway involving energetically demanding nickel‐centered redox events while in the presence of 2 a and 2 b dehydrogenation of alcohols proceeds via a one‐electron hydrogen atom transfer (HAT) pathway via synergistic participation of metal and ligand centered redox processes avoiding high energy nickel centered redox events. Detailed substrate screening and control experiments were performed to unveil the reaction sequence and understand the advantages/disadvantages of these two pathways. [ABSTRACT FROM AUTHOR]

Herein we report an iron‐catalyzed multicomponent dehydrogenative functionalization of alcohols to pyrimidines under atmospheric conditions. Using a well‐defined Fe(II)‐complex featuring redox noninnocent 2‐phenylazo‐(1,10‐phenanthroline) ligand, as a catalyst, a wide array of 2,4,6‐trisubstituted pyrimidines were prepared via dehydrogenative coupling of primary and secondary alcohols with amidines under air at 100 °C. A few control experiments were carried out to understand and unveil the plausible reaction mechanism. [ABSTRACT FROM AUTHOR]

Leflunomide, an inhibitor of pyrimidine synthesis, is used for the treatment of rheumatic diseases, which are prevalent in women of childbearing age. Due to the very long half-life of the active metabolite, its mechanism of action and the teratogenicity observed in animal studies at doses similar to or lower than human therapeutic doses on a weight basis, it is recommended that women stop the treatment before conception and a drug elimination procedure be performed. However, unintended gestational exposures may occur, posing challenges in risk assessment. In order to address the safety of leflunomide in unintended exposures in pregnancy, we performed a critical review of human studies. We located 13 publications in Medline and Embase, which reported on 222 pregnancies with known outcomes exposed to leflunomide preconception and/or during pregnancy. Among the 169 live births, there were eight congenital malformations with no consistent pattern of anomalies. These studies collectively showed no significant difference in the rates of malformations between exposed and unexposed pregnancies. At present, accumulating human data do not point toward leflunomide as a potent human teratogen, which may inform risk assessment of unintended gestational exposure to leflunomide. [ABSTRACT FROM AUTHOR]

In current work, heteroannulation of 2‐amino‐6‐thioxouracil to new fused pyrimidine scaffolds is described, where pyrimidine 1 undergoes cyclocondensation with pyruvic acid derivative 2 and ninhydrin (6) to furnish thiopyranopyrimidine 5 and thienopyrimidine 8, respectively. Alkylation of aminopyrimidine 1 with benzyl chloride consumed two moles to form S‐ and N‐alkylated product 9. Subjecting compound 9 to aminolysis with aniline derivatives resulted in 4‐aminopyrimidine 10a,b through Dimorth rearrangement. Furthermore, the addition of cyclic enamine 10a,b to ninhydrin and benzoyl isothiocyanate produced pyrimidine derivatives 12a,b and 14. Finally, the addition of enamenic carbon of 10a,b to polarized systems 2 or 18 afforded the pyrido[2,3‐d]pyrimidines 17 and 21a‐d in moderate to good yield. [ABSTRACT FROM AUTHOR]

A useful and efficient procedure was obtained for the synthesis of 1,2,3‐triazole‐linked pyrimidines via click reaction of propynylated pyrimidine and aromatic azides in the presence of Mg‐Al‐LDH‐immobilized‐CuI with high‐to‐excellent yields. Moreover, the prepared catalyst was characterized by the FT‐IR spectroscopy, XRD, BET, SEM, and ICP techniques. The developed synthetic technique offers numerous advantages such as a clean reaction, easy workup, high reaction yields, and short reaction time. [ABSTRACT FROM AUTHOR]

A facile and general synthesis of 2,4,6‐triaryl pyrimidines has been developed. It involves a one‐pot [2+1+1+1+1] pseudo five‐component annulation of one methyl ketone, two aldehydes and two NH4OAc catalyzed by TfOH. One C−C and four C−N bonds are formed during the oxidative annulation process. The reaction shows good tolerance of many important functional groups in air and produces only water as the coproduct, making this methodology a highly versatile alternative to the existing methods for structuring pyrimidine framework. [ABSTRACT FROM AUTHOR]

Some novel pyrimidine derivatives are prepared via one‐pot reaction of triethoxymethane, aromatic ketone and ammonium acetate using catalytic system including nano‐magnetic pyridinium‐tribromide (TBP‐SCMNPs). The synthesized new catalyst was characterized by FE‐SEM, EDS, TEM, XRD, and TGA analysis. The highlighting points of using TBP‐SCMNPs are easy purification, reusability of the catalyst, good yields of products with short time reactions. [ABSTRACT FROM AUTHOR]

An efficient synthesis and fluorescent properties of a new series of fused pyrimidine derivatives are described. Condensation of aminopyrimidine derivative 1 with acetophenone leads to olefinic pyrimidine 2, various addition-cyclization reactions of which give the corresponding bicyclic pyrimidines 4, 6, and 8. Cycloaddition reaction of pyrimidine 1 to benzoyl isothiocyanate gives thiourea derivative 9. Intramolecular cyclization of compound 9 with NaOH or Br2 produces pyrimidine derivatives 10 or 12, respectively. Heteroannulation of pyrimidine 1 with ninhydrin or α-carbonyl carboxylic acid 15 gives the tetracyclic pyrimidine 14 and diazepine derivative 18, respectively. Fluorescence properties of pyrimidine derivatives have been tested. [ABSTRACT FROM AUTHOR]

A new set of 2-(2-benzimidazolyl) pyridine ligand based air and moisture stable ruthenium complexes were synthesized and characterized. The catalytic behaviors of these complexes were evaluated towards the multicomponent synthesis of highly substituted pyrimidines directly from various amidines, primary alcohols, and secondary alcohols. Among all the metal complexes, 2-hydroxypyridine and benzimidazole fragments containing complex A showed the best reactivity in this reaction. In addition, it was observed that the N–H proton of benzimidazole and the hydroxyl group of pyridine played a critical role in enhancing catalytic activity. Several control experiments and mechanistic studies were carried out to understand this multicomponent synthesis of pyrimidines using complex A. [ABSTRACT FROM AUTHOR]

Compound 1 condensed with benzaldehyde to produce styryl pyrimidine 2. Pyridopyrimidines 5, 8 and 10 resulted from [4 + 2] cycloaddition (condensation) of 1 with malononitrile, ethyl cyanoacetate and/or ethyl acetoacetate. Compound 1 was also concerted to pyridopyrimidine 14 through multistep reaction (hydrolysis, chlorination, isothiocyanate formation and intramolecular cyclization). Bromopyrimidine 15 transformed into thiazolopyrimidine 17. Cyclization of bromomethyl pyrimidine 15 resulted in imidazolopyrimidine 19. Upon reacting the compound 15 with ammonium acetate resulted in amination affording the amino derivative 20. Oxazolopyrimidine 21 was obtained as the result of the reaction of compound 1 with chloroacetic acid and p-nitrobenzaldehyde. Compound 21 was transformed into pyridopyrimidine 23 and pyridopyrimidine of type 25 when reacted with cyanoacetamide and/or phenylhydrazine, respectively. All of the tested compounds showed good microbial activity against pathogenic microorganisms especially pyridopyrimidine derivative 21. [ABSTRACT FROM AUTHOR]

A new series of mononuclear ruthenium(II) complexes of the type [Ru(PPh3)2(N,S-L1–3)2] 2H3O+.(Cl−)2.XH2O, [RuCl(dmso)3(N,S-L1–3)], and [Ru2(Cl−)2(N,S-L1–3)2].XH2O, where L1 is ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-pyrimidine-5-carboxylate (monastrol), and L2 and L3 are the 4-hydroxyphenyl and 4-bromophenyl analogs of monastrol have been prepared and characterized by elemental analysis, 1H, and 13C NMR spectroscopy. All the complexes were assayed for their anti-HIV-1 and HIV-2 activity in MT-4 cells, and cytotoxicity was also investigated in mock-infected in MT-4 cells by using MTT assay. All the complexes exhibited no anti-HIV activity, however complexes [RuCl(dmso)3(N,S-L1)] (7) and [RuCl(dmso)3(N,S-L2)] (8) showed cytotoxicity values of > 0.21 and > 2.14 µM, respectively against mock-infected MT-4 cells. In addition, complexes [Ru(PPh3)2(N,S-L3)2].2H3O+.2Cl−.H2O (4), 7, and [RuCl2(N,S-L1)] (10) have been selected for evaluation of their dual inhibition activity against dual-specificity tyrosine phosphorylation-regulated kinase (Dyrk1A). [ABSTRACT FROM AUTHOR]

An efficient synthesis of pyrimidines and pyridines has been developed from readily available aromatic ketones, aldehydes and ammonium salts under transition-metal-free conditions. In this strategy, ammonium salts were used as nitrogen sources and only water was generated as a nontoxic byproduct. A catalytic amount of NaIO4 played an important role in the selectivity control, whereas substituted pyridines were dominantly formed in its absence. [ABSTRACT FROM AUTHOR]

Theories about the origin of life require chemical pathways that allow formation of life’s key building blocks under prebiotically plausible conditions. Complex molecules like RNA must have originated from small molecules whose reactivity was guided by physico-chemical processes. RNA is constructed from purine and pyrimidine nucleosides, both of which are required for accurate information transfer, and thus Darwinian evolution. Separate pathways to purines and pyrimidines have been reported, but their concurrent syntheses remain a challenge. We report the synthesis of the pyrimidine nucleosides from small molecules and ribose, driven solely by wet-dry cycles. In the presence of phosphate-containing minerals, 5′-mono- and diphosphates also form selectively in one-pot reactions. The pathway is compatible with purine synthesis, allowing the concurrent formation of all Watson-Crick bases. [ABSTRACT FROM AUTHOR]

A novel and highly efficient heterogeneous gold(I)-catalyzed cyclization between ynals and amidines has been developed that proceeds smoothly under mild conditions and provides a general and practical method for the synthesis of a wide variety of 2,4-disubstituted pyrimidines with high atom-economy, good to high yield, and recyclability of the gold(I) catalyst. The present method is an attractive alternative to construct substituted pyrimidines. [ABSTRACT FROM AUTHOR]

Clinically relevant inhibitors of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in mammalian de novo pyrimidine synthesis, have strong antiviral and anticancer activity in vitro. However, they are ineffective in vivo due to efficient uridine salvage by infected or rapidly dividing cells. The pyrimidine salvage enzyme uridine-cytidine kinase 2 (UCK2), a ∼29 kDa protein that forms a tetramer in its active state, is necessary for uridine salvage. Notwithstanding the pharmacological potential of this target, no medicinally tractable inhibitors of the human enzyme have been reported to date. We therefore established and miniaturized an in vitro assay for UCK2 activity and undertook a high-throughput screen against a ∼40,000-compound library to generate drug-like leads. The structures, activities, and modes of inhibition of the most promising hits are described. Notably, our screen yielded non-competitive UCK2 inhibitors which were able to suppress nucleoside salvage in cells both in the presence and absence of DHODH inhibitors. [ABSTRACT FROM AUTHOR]

A metal free and divergent synthetic method has been successfully developed for the synthesis of sulfoximine tethered pyrimidines, amino pyrimidines, pyrazoles and isoxazoles. Two key sulfoximine tethered alkynone intermediates ((tert-butyldiphenylsilyl) imino)(2-oxo-4-phenylbut-3-yn-1-yl)(phenyl)-λ6-sulfanone (3a) and ((tert-butyldiphenylsilyl)imino)(2-oxopent-3-yn- 1-yl)(phenyl)-λ6-sulfanone (3b), have been reported for the first time and were used as the common building blocks to construct these heterocycles. Good functional group tolerability was observed and the products were isolated in excellent yield. [ABSTRACT FROM AUTHOR]

Targeting metabolic changes in glioblastoma: Glioblastoma (GBM) is the most aggressive brain cancer in adults. GBM stem cells (GSCs) contribute to tumor initiation and therapeutic resistance. Understanding the metabolic alterations in GSCs could help the development of new therapeutic strategies. Now, Wang et al. revealed that pyrimidine biosynthesis is up-regulated in GSCs and correlated with tumor grade in patients with GBM. This metabolic alteration was necessary for GSC maintenance, and combined targeting of pyrimidine synthesis and tumor-specific driver mutations using approved drugs improved survival and inhibited tumor growth compared to the single treatments in mouse models. Targeting metabolic reprogramming in combination with mutation-specific therapies might improve clinical outcome in patients with GBM. Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells. [ABSTRACT FROM AUTHOR]

• Synthesis of 2-(H)pyrimidines. • Novel selective reduction of 2-(phenylthio)pyrimidines. • High functionalization. • Wide substrate scope. A reaction method is described for selective reductive cleavage of 2-(phenylthio)pyrimidines using Pd(OAc) 2 and Et 3 SiH to produce 2-(H)pyrimidines. The reaction proceeds efficiently with a wide range of 2-(phenylthio)pyrimidines. Considering the ready availability of 2-(arylthio)pyrimidines derived from oxidative C S cross coupling of 3,4-dihydropyrimidin-1 H -2-thiones (DHPMs), this method unambiguously provides a shortcut to the preparation of 2-(H)pyrimidines with unprecedented diversity. [ABSTRACT FROM AUTHOR]

The syntheses of N-Alkylpyrimidine derivatives by reacting pyrimidin-2,4-diones with appropriate alkyl halide under microwave irradiation at 400 W were compared to the conventional synthesis route. These methodologies are regioselective and compatible with numerous substrates and furnish the corresponding N-alkylpyrimidines in good yields using a cheap catalyst HMDS/KI in MeCN. A comparison study between these two different modes of heating was investigated. [ABSTRACT FROM AUTHOR]

• N -sulfonyl-1,2,3-triazole was used as a 1-aza-[4C] synthon. • Excellent chemoselectivity was observed. • Fused pyrimidine and seven-membered 1 H -1,4-diazepine were synthesized effectively. A new synthetic application of N -sulfonyl-1,2,3-triazoles acting as a 1-aza-[4C] synthon via the 1,2-shift reaction of an α-imine rhodium carbene was developed for the synthesis of fused pyrimidine derivatives. The high reactivity of the strained three-membered 2 H -azirine ring facilitated the unusual cyclization of electron-deficient dienes with electron-deficient dienophiles. The compatibility was good with common functionalities tolerated. Excellent chemoselectivity was observed, and no reactions occurred between the rhodium carbene and 2 H -azirine. The products could be converted into seven-membered multi-functionalized 1 H -1,4-diazepine derivatives, illustrating the potential application of the protocol in medium-sized N -heterocycle synthesis. [ABSTRACT FROM AUTHOR]

A three‐component tandem reaction for the synthesis of multisubstituted pyrimidines from chalcone, benzyl alcohol and NH4OAc have been developed. This transformation represents an example for the simultaneous formation of two new C(sp2)−N bonds and a six‐membered ring using NH4OAc as nitrogen source under solvent‐free conditions. [ABSTRACT FROM AUTHOR]

An efficient pseudo four‐component procedure for the construction of chromeno[4,3‐d]pyrimidin‐5‐ones, a type of coumarin‐fused pyrimidines, from 4‐aminocoumarins, two molecules of aromatic aldehydes and ammonium iodide under metal‐free conditions is developed. The coumarin‐pyrimidine hybrids readily undergo sequential hydrolysis and alkylation to give all‐carbon substituted pyrimidines in excellent yields. One‐pot synthesis of pyrimidines from readily available 4‐aminocoumarins and other commodity chemicals is exemplified. [ABSTRACT FROM AUTHOR]

Abstract A total of 66 novel heterofused pyrimidine analogues (pyrazolo[3,4- d ]pyrimidine (7 - 43) and pyrido[2,3- d ]pyrimidine (51a - l & 52a - h)) were synthesized by employing suitable methods. The desired structures of all the synthesized compounds were confirmed based on FT-IR, 1H NMR, 13C NMR and HRMS experimental data. Further, 19F NMR and 1H-15N HMBC of the representative compound were presented. All the final compounds were screened for their in vitro antitubercular (Mycobacterium tuberculosis ; H 37 Rv), antibacterial (S. aureus , B. subtilis , E. coli and P. aeruginosa) and antifungal (C. neoformans, C. albicans and A. niger) activities. Compounds 51d , 51j , 51k , 51l , and 51g displayed good antibacterial and antifungal activity (MIC = 12.5 μg/ml) against bacterial and fungal strains, while moderate inhibition (MIC = 59 μM) was observed for 51l against H 37 Rv strain. Graphical abstract Image 1 Highlights • 66 Novel fused pyrimidines were synthesized and characterized. • In vitro anti-tubercular, anti-bacterial and anti-fungal screening were conducted. • Fluorinated pyrimidines 51d , 51j , 51k , 51l , and 51g showed significant antimicrobial activities. • Compound 51l displayed good anti-tubercular activity against H 37 Rv strain. [ABSTRACT FROM AUTHOR]

Abstract The polymer-supported synthetic protocol for preparation of thiazolidinedione-pyrimidine hybrids was developed and applied for rapid and effective synthesis of a library of variously substituted conjugates. Reported synthetic methodology is based on easy accessible building blocks and very simple chemical operations enabling effective development of potent experimental therapeutics of this type via a combinatorial manner. Synthesized model compounds were tested for their antitubercular activity against Mycobacterium tuberculosis H 37 Rv, antimicrobial activity against several Gram-positive and Gram-negative strains such as Staphylococcus aureus , Pseudomonas aeruginosa , Escherichia coli and Enterococcus faecalis and two fungal strains (Candida albicans and Aspergillus niger). Slight activity was found for some of them. Graphical abstract Image 1 Highlights • A gradual increase in the number of multidrug-resistant pathogens with reduced or no response to known antibacterial drugs. • The polymer-supported synthetic protocol for preparation of thiazolidinedione-pyrimidine hybrids. • Ability to introduce structural diversity from easily available building blocks with minimal synthetic operations. • The potency of developed methodology that could lead to new drug candidates in the future. [ABSTRACT FROM AUTHOR]

The "RNA first" model for the origin of life holds that RNA emerged spontaneously on early Earth and developed into life through its dual capabilities for genetics and catalysis. The model's central weakness is the difficulty of making its building blocks, in particular, the glycosidic bond joining nucleobases to ribose. Thus, the focus of much of the modern literature on the topic is directed toward solving this difficulty and includes elegant, though indirect, methods for making this bond. Here, we report that the glycosidic bond in canonical pyrimidine and purine ribonucleotides can be formed by direct coupling of cyclic carbohydrate phosphates with free nucleobases, all reported to be available by experimentally supported pathways that might have operated on early Earth. [ABSTRACT FROM AUTHOR]

A novel fused benzothiazolo‐pyrimidine based optical chemosensor 4‐imino‐2‐methylsulphanyl‐4H‐9‐thia‐1,4a‐diaza‐fluorene‐3‐cabonitrile (BTP‐1) was designed and synthesized efficiently for the selective recognition of Fe3+ and I− ions from the aqueous medium. Sensor BTP‐1 selectively recognizes Fe3+ ions through the quenching of fluorescence emission intensity at 454 nm and I− ions through a hyperchromic shift in UV‐Vis spectra. The recognition of both Fe3+ and I− ions was found free from the interference of other inspected cations and anions, respectively. [ABSTRACT FROM AUTHOR]