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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]

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]

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]

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]

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]

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 method was developed for the synthesis of new fused amines, thieno[3,2-d]pyrimidine derivatives, starting from the corresponding chloride and various amines. Isomeric triazolo[4,3-c]- and -[1,5-c]-pyrimidines were obtained. The absence of azidotetrazole transformation of fused tetrazolo[1,5-c]pyrimidine was revealed. [ABSTRACT FROM AUTHOR]

A novel series of 2-(4-chlorobenzylamino)-4-(cyclohexylmethylamino)-pyrimidine-5-carboxamide derivatives are synthesized and their structures are confirmed by 1H and 13C NMR, and MS spectral data. The compounds are screened for their antitubercular activity, and those with aryl moiety 7o, 7q, and 7r demonstrate potent activity against Mycobacterium tuberculosis. Docking studies suggest a mode of interaction of the products with the binding site of enoyl-CoA hydratase demonstrating that the target compounds were potential anti-TB agents. [ABSTRACT FROM AUTHOR]

Synthesis of new 8-alkyl-5-aryl-1,3-dimethyl-5,7-dihydro-2H-pyrimido[5′,4′:5,6]pyrano[2,3-d]- pyrimidine-2,4,6(1H,3H)-triones by the high yield reaction of 7-amino-5-aryl-1,3-dimethyl-2,4-dioxo-1,3,4,5- tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitriles with aliphatic carboxylic acids in the presence of POCl3 is presented. It is probable that synthesis of these new products proceeds via the tandem intramolecular Pinner–Dimroth rearrangement. The products are characterized by FT-IR, 1H, and 13C NMR spectra and evaluated for their antibacterial activity against gram +ve bacteria (Staphylococcus aureus and Staphylococcus epidermidis) and gram–ve bacteria (Escherichia coli and Pseudomonas aeruginosa) using the disc diffusion method. [ABSTRACT FROM AUTHOR]

The cross coupling of 5'-ethynyllappaconitine with benzoic acid chlorides under the conditions of the Sonogashira reaction in benzene leads to the corresponding 5-alkynones. By condensation of the obtained 5'-alkynones with amidines, compounds with hybrid structure containing fragments of a diterpene alkaloid and pyrimidine were synthesized. The yields of the target compounds were 67-90%. The possibility of carrying out the cross coupling - condensation reaction as a one-pot synthesis is demonstrated. [ABSTRACT FROM AUTHOR]

In all organisms, carbamoylphosphate (CP) is a precursor common to the synthesis of arginine and pyrimidines. In Escherichia coli and most other Gram-negative bacteria, CP is produced by a single enzyme, carbamoylphosphate synthase (CPSase), encoded by the carAB operon. This particular situation poses a question of basic physiological interest: what are the metabolic controls coordinating the synthesis and distribution of this high-energy substance in view of the needs of both pathways? The study of the mechanisms has revealed unexpected moonlighting gene regulatory activities of enzymes and functional links between mechanisms as diverse as gene regulation and site-specific DNA recombination. At the level of enzyme production, various regulatory mechanisms were found to cooperate in a particularly intricate transcriptional control of a pair of tandem promoters. Transcription initiation is modulated by an interplay of several allosteric DNA-binding transcription factors using effector molecules from three different pathways (arginine, pyrimidines, purines), nucleoid-associated factors (NAPs), trigger enzymes (enzymes with a second unlinked gene regulatory function), DNA remodeling (bending and wrapping), UTP-dependent reiterative transcription initiation, and stringent control by the alarmone ppGpp. At the enzyme level, CPSase activity is tightly controlled by allosteric effectors originating from different pathways: an inhibitor (UMP) and two activators (ornithine and IMP) that antagonize the inhibitory effect of UMP. Furthermore, it is worth noticing that all reaction intermediates in the production of CP are extremely reactive and unstable, and protected by tunneling through a 96 Å long internal channel. [ABSTRACT FROM AUTHOR]

A series of half sandwich η5-cyclopentadienyl Rh(III) and Ir(III) complexes bearing the general formula [Cp*LCl]Cl·2H2O (L = neutral bidentate pyridyl pyrimidine based ligands, Cp* = η5-C5Me5) have been synthesized. The neutral bidentate coordination of ligand with Rh(III) and Ir(III) via N atoms was confirmed by various analytical and spectroscopic techniques. The effect of position and electron releasing strength of substituents at ancillary ligands on DNA binding of metal complexes was checked by UV-Vis. absorption spectroscopy and hydrodynamic method. Molecular docking study was performed for the preferred orientation of stable DNA-metal complex associates to get an insight of binding site and binding affinity between these molecules, and binding energy data were evaluated to check the strength of association. The probable application of metal complexes as compelling chemical nuclease agent was assessed by gel electrophoresis. The cytotoxic nature of metal complexes was checked on a simple zoological organism-artemia cyst. [ABSTRACT FROM AUTHOR]

Due to their similarity to natural counterparts, nucleic acid derivatives (nucleobases, nucleosides, and nucleotides, among others) are interesting molecules for pharmaceutical, biomedical, or food industries. For this reason, there is increasing worldwide demand for the development of efficient synthetic processes for these compounds. Chemical synthetic methodologies require numerous protection-deprotection steps and often lead to the presence of undesirable by-products or enantiomeric mixtures. These methods also require harsh operating conditions, such as the use of organic solvents and hazard reagents. Conversely, enzymatic production by whole cells or enzymes improves regio-, stereo-, and enantioselectivity and provides an eco-friendly alternative. Because of their essential role in purine and pyrimidine scavenging, enzymes from purine and pyrimidine salvage pathways are valuable candidates for the synthesis of many different nucleic acid components. In recent years, many different enzymes from these routes, such as nucleoside phosphorylases, nucleoside kinases, 2′-deoxyribosyltransferases, phosphoribosyl transferases, or deaminases, have been successfully employed as biocatalysts in the production of nucleobase, nucleoside, or nucleotide analogs. Due to their great activity and stability at extremely high temperatures, the use of enzymes from thermophiles in industrial biocatalysis is gaining momentum. Thermophilic enzymes not only display unique characteristics such as temperature, chemical, and pH stability but also provide many different advantages from an industrial perspective. This mini-review aims to cover the most representative enzymatic approaches for the synthesis of nucleic acid derivatives. In this regard, we provide detailed comments about enzymes involved in crucial steps of purine and pyrimidine salvage pathways in thermophiles, as well as their biological role, biochemical characterization, active site mechanism, and substrate specificity. In addition, the most interesting synthetic examples reported in the literature are also included. [ABSTRACT FROM AUTHOR]

An approach to the synthesis of new 6-(1,3-benzoxazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-ones and their 4-thioanalogs was developed. Some of the synthesized compounds exhibited antimicrobial activity against strains of Bacillus subtilis bacteria and Candida albicans fungi. [ABSTRACT FROM AUTHOR]

A series of 5-(arylmethylidene)-2,4,6-pyrimidine-2,4,6(1H,3H,5H)-triones were synthesized and tested for antimicrobial activity against Staphylococcus and Streptococcus bacteria strains. [ABSTRACT FROM AUTHOR]

New aryl substituted uracil and thiouracil glycosides are synthesized by glycosylation at N1 in the pyrimidine nucleus using glycopyranosyl halides in basic medium. In addition C-linked hydrazinyl acyclic sugar derivatives exhibiting different sugar moieties, attached at C6, are also prepared. Antiviral activity of the newly synthesized compounds is studied against Hepatitis B virus (HBV). The antiviral tests data indicated high activity of compounds 6b, 6c and 12a-12c with mild cytotoxic effects. The influence of glycosyl moieties attached to the substituted pyrimidine system in addition to the substitution at the aryl fragment on activity is discussed. [ABSTRACT FROM AUTHOR]

Abstract: In this research layered double hydroxides functionalized with (3r,5r,7r)-1-(3-(triethoxysilyl)propyl)-1,3,5,7-tetraazaadamantan-1-ium chloride (LDHs-TPTAACl) as a novel, green, efficient and recyclable heterogeneous ionic liquid were synthesized and characterized by various methods, such as FT-IR, TGA, SEM, EDX, TEM and XRD. The mentioned catalyst was applied as a new ionic liquid catalyst for the one-pot three-component synthesis of a new class of pyrido[2,3-d]pyrimidine derivatives through combination of aromatic aldehydes, 2,4-thiazolidinedione and N,N-dimethyl-6-amino uracil using water as solvent in high to excellent yield and short reaction times. The LDHs-TPTAACl catalyst could be simply recycled and reused up to five continuous runs with no substantial structural change and loss of activity.Graphical Abstract: [ABSTRACT FROM AUTHOR]

An improved seven-step synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine from dimethyl malonate with 31% overall yield is described. The procedure is operationally simple and practical for the synthesis of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine building block. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, boron trifluoride supported on coconut shell nano-particles (nano-BF2O-coc) was prepared from nano-crystalline coconut shell through mechanical method using ultrasonication. The resultant was utilized to obtain nano-crystalline BF3 supported on coconut shell nano-particles (nano-BF2O-coc). The novel nanostructure has been characterized using Fourier transform infrared spectroscopy, transmission electron microscopy, field-emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy (EDX) techniques. The catalytic activity of the solid acid catalyst has been successfully examined in a one-pot, three-component condensation reaction of barbituric acid, ethyl cyanoacetate or malononitrile, and aldehydes in refluxing ethanol to furnish pyrano[2,3-d]pyrimidine derivatives.Graphical abstract: [ABSTRACT FROM AUTHOR]

Melting of a mixture of 5-substituted 2,4-dimethyl-1,6-dihydropyrimidin-6-ones with cinnamic aldehyde, 1-methylindoline-2,3-dione and 6-methoxy-2-chloroquinoline-3-carbaldehyde in the presence of ZnCl2 led to the formation of substituted pyrimidines with conjugated bonds in the position 2. The structure of synthesized compounds as 2-isomers was confirmed by 2D 1H NMR NOESY data. [ABSTRACT FROM AUTHOR]

Drimenic acid was synthesized in six steps from norambreinolide. Reaction of drimenic acid with oxalyl chloride produced iso-drimenic acid chloride, which reacted with heterocyclic amines (2-aminopyrimidine, 2-aminopyrazine, 4-aminopyrimidine, N-aminocarbazole, and 3-amino-1,2,4-triazole) to form amides of iso-drimenic and albicanic acids. The structures of the amides were elucidated by spectral methods and an X-ray structure analysis. [ABSTRACT FROM AUTHOR]

5-Substituted 2,6-dimethylpyrimidin-4(3H)-ones were synthesized, and their structure was proved by X-ray analysis. Their reactions with aromatic aldehydes regioselectively afforded (Z)-2-(2-arylethenyl)- pyrimidin-4(3H)-ones whose structure was determined by one- and two-dimensional (NOESY) 1H NMR and X-ray analysis. [ABSTRACT FROM AUTHOR]

The amount of photolesions produced in DNA after exposure to physiological doses of ultraviolet radiation (UVR) can be estimated with high sensitivity and at low cost through an immunological assay, ELISA, which, however, provides only a relative estimate that cannot be used for comparisons between different photolesions such as cyclobutane pyrimidine dimer (CPD) and pyrimidine(6-4)pyrimidone photoproduct (64PP) or for analysis of the genotoxicity of photolesions on a molecular basis. To solve this drawback of ELISA, we introduced a set of UVR-exposed, calibration DNA whose photolesion amounts were predetermined and estimated the absolute molecular amounts of CPDs and 64PPs produced in mouse skin exposed to UVC and UVB. We confirmed previously reported observations that UVC induced more photolesions in the skin than UVB at the same dose, and that both types of UVR produced more CPDs than 64PPs. The UVR protection abilities of the cornified and epidermal layers for the lower tissues were also evaluated quantitatively. We noticed that the values of absorbance obtained in ELISA were not always proportional to the molecular amounts of the lesion, especially for CPD, cautioning against the direct use of ELISA absorbance data for estimation of the photolesion amounts. We further estimated the mutagenicity of a CPD produced by UVC and UVB in the epidermis and dermis using the mutation data from our previous studies with mouse skin and found that CPDs produced in the epidermis by UVB were more than two-fold mutagenic than those by UVC, which suggests that the properties of CPDs produced by UVC and UVB might be different. The difference may originate from the wavelength-dependent methyl CpG preference of CPD formation. In addition, the mutagenicity of CPDs in the dermis was lower than that in the epidermis irrespective of the UVR source, suggesting a higher efficiency in the dermis to reduce the genotoxicity of CPDs produced within it. We also estimated the minimum amount of photolesions required to induce the mutation induction suppression (MIS) response in the epidermis to be around 15 64PPs or 100 CPDs per million bases in DNA as the mean estimate from UVC and UVB-induced MIS. [ABSTRACT FROM AUTHOR]

The review summarizes information on cyclopropane as an independent pharmacophore group and as a fragment for modification of pharmacological activity level of medicines used in practice. The advantages of a cyclopropane fragment over its bioisosteres are that, on the one hand, this fragment imposes conformational rigidity on the molecules of physiologically active compounds and, on the other hand, the replacement of acyclic terminal and “linker” groups with a cyclopropane fragment increases the metabolic stability of the target structures and extends the scope of their therapeutic action. [ABSTRACT FROM AUTHOR]

Novel pyrano[2,3- d] pyrimidine derivatives were synthesized via the three-component reaction of thiophene-2-carbaldehyde, malononitrile and barbituric or thiobarbituric acid in the presence of MnO nanoparticles. This method has been found to be eco-friendly and economical. Compound 1 was used as a precursor for the synthesis of new pyranopyrimidine derivatives 2-5. Moreover, 7-amino-2,3,4,5-tetrahydro-4-oxo-5-(thiophen-2-yl)-2-thioxo-1H-pyrano[2,3-d]pyrimidine-6-carboxamide 4 was then converted into another set of novel compounds 6-8. On the other hand, a series of Mn(II) complexes with pyrano[2,3- d]pyrimidine derivatives have been prepared. The synthesized compounds and its complexes were characterized by elemental analysis, magnetic and spectroscopic methods (IR, XRD, SEM, TEM, C, HNMR) as well as thermal analysis. The spectrophotometric determinations suggest a distorted octahedral geometry for all complexes. The organic compounds and its chelates as inhibitors exhibited remarkable effects on the enzyme activity of an extracellular toxic protease, KB76 from Brevibacterium otitidis as well as against different bacterial and fungal strains. Graphical abstract: [ABSTRACT FROM AUTHOR]

New triazolo[1,5-a]pyrimidines containing aroyl and acetyl or ester groups in the pyrimidine ring were synthesized in a process related to the Biginelli-like reaction, using hydrates of arylglyoxals, β-dicarbonyl compounds, and 1H-1,2,4-triazol-5-amine. Reaction was carried out in either sequential or one-pot procedure. [ABSTRACT FROM AUTHOR]

De novo synthesis of the nucleotide CTP is catalyzed by the essential pyrimidine biosynthesis enzyme CTP synthase (CTPs), which forms large-scale filamentous structures consisting of CTPs termed cytoophidia in prokaryotes and in eukaryotes. Recent studies have shown that cytoophidia are abundant in neuroepithelial stem cells in Drosophila optic lobes and that overexpression of CTPs impairs optic lobe development. Whether CTPs and cytoophidia also play a role in the development of the mammalian cortex remains elusive. Here, we show that overexpression of CTPs by in utero electroporation in the embryonic mouse brain induces formation of cytoophidia in developing cortical neurons and impairs neuronal migration. In addition, the increase of cytoophidia accelerates neuronal differentiation and inhibits neural progenitor cell proliferation by reducing their mitotic activity. Furthermore, we discovered that the cytoophidia diffused during the early G1-phase of the cell cycle. Together, our findings show, for the first time, that CTPs play a significant role in the development of the mammalian cortex. [ABSTRACT FROM AUTHOR]

One-step three-component cyclocondensation of 2,6-disubstituted pyrimidin-4(3H)-ones with 1,3-dicarbonyl compounds and some aromatic and heterocyclic aldehydes on heating or under microwave irradiation afforded new functionally substituted 5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-ones. Conventional heating was found to be more advantageous. The effects of the 2-substituent in the initial pyrimidin-4(3H)-one and the nature of the dicarbonyl component on the product structure and yield were analyzed. [ABSTRACT FROM AUTHOR]

An efficient and green protocol for the synthesis of novel benzylpyrazolyl pyrido[1,2- a]pyrimidine derivatives via three-component reaction of aryl aldehydes, 2-hydroxy-4 H-pyrido[1,2- a]pyrimidine-4-ones, and 3-methyl-1-phenyl-1 H-pyrazol-5-one has been reported using a magnetically separable and reusable heterogeneous copper ferrite (CuFeO) nano-catalyst under solvent-free conditions. CuFeO nanoparticles were characterized by FT-IR, powder X-ray diffraction and transmission electron microscopy. Graphical Abstract: An efficient one-pot synthesis of highly functionalized benzylpyrazolyl pyrido[1,2- a]pyrimidine derivatives using CuFeO nanoparticles under solvent-free conditions. [ABSTRACT FROM AUTHOR]

Phototherapy with psoralens as photosensitizers is the commonly used method for the treatment of vitiligo. Considering the structure similarity between psoralens and thieno[2,3- d]pyrimidinones, a series of novel sulfonamide derivatives containing tricyclic thieno[2,3- d]pyrimidinone were synthesized and evaluated for melanin synthesis in murine B16 cells. All new compounds were characterized by H NMR, C NMR, IR and HRMS (ESI). Among them, 6 compounds demonstrated excellent activity than positive control (8-methoxylpsoralen, 8-MOP) with more than 1.5-fold potency. Compound 11w with dichloro substitution at meta-positions in the benzenesulfonyl moiety was the most potent one (658.3 ± 8.7%), exhibiting 5.0-fold stronger activity than 8-MOP (130.9 ± 8.6%). The difluoro analog compound 11o increased melanin synthesis in murine B16 cells with a 4.35-fold potency as compared to 8-MOP. These compounds may serve as lead compounds for further drug discoveries for the treatment of vitiligo. [ABSTRACT FROM AUTHOR]

The alkylation of ambident anions of 2-(methylsulfanyl)-6-(polyfluoroalkyl)pyrimidin-4(3 H)-ones with 4-bromobutyl acetate leads to concurrent formation of O- and N-(4-acetoxybutyl) derivatives. Polar aprotic solvents favor formation of the O-isomer, and weakly polar dioxane favors N-alkylation. The reaction of 2-(methylsulfanyl)-6-(trifluoromethyl)pyrimidin-4(3 H)-one with an equimolar amount of 1,2-dibromoethane in polar acetonitrile gives a mixture of N, N-, O, O-, and N, O-bridged bis-pyrimidines, as well as N- and O-[2-(methylsulfanyl)ethyl] derivatives, whereas in the presence of 10 equiv of 1,2-dibromoethane the N, O-isomer is formed as the only product. The reaction in weakly polar tetrahydrofuran yields N, N- and N, O-bispyrimidines. [ABSTRACT FROM AUTHOR]

The nitration of 1,3-dimethylpyrrolo[3,2- d]pyrimidine-2,4-diones under different conditions led to the formation of their 6(7)-mono- and 6,7-dinitro derivatives which were reduced to the corresponding amines. The latter reacted with α- and β-dicarbonyl compounds, as well as with ortho-quinones to give a number of new polycyclic heteroaromatic systems. [ABSTRACT FROM AUTHOR]

An efficient method for the synthesis of pyrazolo $$[1{,}5\hbox {-}a]$$ pyrimidines by the tandem reactions of dienones with pyrazole-3-amine through an aza-Michael addition/nucleophilic addition/1,3-hydrogen transfer process in the presence of potassium hydroxide is described. This protocol offers access to 7-arylethyl-5-arylpyrazolo $$[1{,}5\hbox {-}a]$$ pyrimidines in good to excellent yield. Meanwhile for 4-substituted dienones, different products, 7-arylethylene-5-arylpyrazolo $$[1{,}5\hbox {-}a]$$ pyrimidines, are given through an aza-Michael addition/nucleophilic addition/oxidation process. A gram-scale reaction has been performed to demonstrate the potency of optimized procedure for the scale-up process. Graphical Abstract : SYNOPSIS7-Arylethyl-5-arylpyrazolo $$[1{,}5\hbox {-}a]$$ pyrimidines were efficiently synthesized by the reactions of 4-unsubstituted dienones with pyrazole-3-amine. In contrast, 7-arylethylene-5-arylpyrazolo $$[1{,}5\hbox {-}a]$$ pyrimidines could be afforded by the reactions of 4-substituted dienones with pyrazole-3-amine. [ABSTRACT FROM AUTHOR]

Background: Heterocyclic pyrimidine nucleus, which is an essential base component of the genetic material of deoxyribonucleic acid, demonstrated various biological activities. A series of bis-pyrimidine Schiff bases were synthesized and screened for its antimicrobial and anticancer potentials. The molecular docking study was carried to find the interaction between active molecules with receptor. Results: The structures of synthesized bis-pyrimidine Schiff bases were confirmed by spectral studies. The synthesized bis-pyrimidine derivatives were evaluated for their antimicrobial activity (MIC = µmol/mL) against selected Gram positive; Gram negative bacterial and fungal strains by tube dilution method. The anticancer activity (IC = µmol/mL) of the synthesized compounds was determined against human colorectal carcinoma (HCT116) cancer cell line by Sulforhodamine B (SRB) assay. Molecular docking studies provided information regarding the binding mode of active bis-pyrimidine Schiff bases with the cyclin-dependent kinase 8 (CDK8) receptor. Conclusions: The antimicrobial screening results indicated that compounds, q1 (MIC = 0.83 µmol/mL), q16 (MIC = 1.54 µmol/mL and MIC = 0.77 µmol/mL), q1 and q19 (MIC = 0.41 µmol/mL) and q20 (MIC = 0.36 µmol/mL) are the most active ones. Compounds q1 (IC = 0.18 µmol/mL) have emerged as potent anticancer molecule against human colorectal carcinoma cancer cell line than the reference drug, 5-fluorouracil. Molecular docking studies indicated that compound q1 (the most active molecule) has the maximum hydrogen bond interaction (four) and π-π stacking (three) network among the bis-pyrimidine Schiff bases. [ABSTRACT FROM AUTHOR]

In this work, an efficient isocyanide-based three component method is developed for the synthesis of the novel substituted pyrano[2,3- d][1,3,4]thiadiazolo[3,2- a]pyrimidine system, having both the biologically active pyranopyrimidine and thiadiazolopyrimidine scaffolds, from the readily attainable reaction of 7-hydroxy-2-phenyl-5 H-[1,3,4]thiadiazolo[3,2- a]pyrimidine-5-one, isocyanides, and dialkylacetylenedicarboxylates. This procedure has the chief advantages of fairly high reaction yields, mild reaction conditions, high atom-economy, and catalyst-free reaction. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Background: Pyridopyrimidines are of current interest because of their extensive variety of biological and pharmacological activities. Results: A series of pyrido[2′,3′:4,5]pyrimido[2,1- b][1,3,5]thiadiazinones was obtained by aminomethylation of pyridopyrimidinethione with formaldehyde solution (37%) and different primary aromatic amines. Another series of pyrido[2′,3:4,5]pyrimido[2,1- b][1,3]thiazinones was prepared by Michael addition reaction of pyridopyrimidinethione to the activated double bond of a number of arylidene malononitrile and 2-(benzo[ d][1,3]dioxol-5-ylmethylene)malononitrile. The mechanisms of formation of the synthesized compounds were discussed and the assigned structure was established via microanalysis and spectral data (IR, H NMR, and Ms.). A comparative study of the biological activity of the synthesized compounds with chloramphenicol and trimethoprim/sulphamethoxazole is shown in Table 1. Generally, all synthesized compounds showed adequate inhibitory effects on the growth of Gram-positive and Gram-negative bacteria. Conclusions: In this study, we use a simple (synthetic) strategy for the synthesis of pyrimidothiadiazines, based on their aminomethylation through the Mannich reaction; they have also been synthesized by the application of the Michael addition to activated nitriles. Mechanisms and structures of the newly synthesized compounds were examined: the antimicrobial activity of some selected compounds was evaluated, which demonstrated adequate inhibitory effects. [ABSTRACT FROM AUTHOR]

Derivatives of a new heterocyclic system, pyrimido[5,4- e]thiazolo[3,2- a]pyrimidine 3, were prepared by sequential treatment of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 1 with 4,5-dihydrothiazol-2-amine 2 and various secondary amines. Single crystal X-ray analysis confirmed the structure of the regioisomer 3. The photophysical characterization of these new compounds was performed by UV/VIS absorption and fluorescence emission spectroscopy. Out of six derivatives studied, only four products 4a-d showed relatively strong fluorescence intensity. The relevant photophysical parameters for all derivatives in this series, including quantum yields and Stokes shifts for the best fluorophores are given. [ABSTRACT FROM AUTHOR]

New thermally stable 2,4,6-trisubstituted pyrimidines containing aromatic (ferrocene and para-substituted benzene) fragments at the C and C positions and an amino group or pyrrole ring at the C positions of the pyrimidine ring have been synthesized, and their optical and electrochemical properties have been studied. The redox potentials of the ferrocene fragments therein have been determined by cyclic voltammetry. [ABSTRACT FROM AUTHOR]

The known methods for synthesis of thioxopyrimidines and their condensed analogs with exocyclic sulfur atom are summarized and discussed. The most popular approaches are based on [3+3], [4+2], [5+1] cyclization processes or domino reactions. The literature data analysis shows that the title compounds possess diverse biological activities, such as antioxidant, radioprotective, analgesic, antiinflammatory, antihypertensive, anxiolytic, anamnestic, anticonvulsant, antimicrobial, fungicidal, herbicidal, antiviral, and anticancer. [ABSTRACT FROM AUTHOR]

Background: A novel series of 5-(substituted aldehyde)-7-methyl-3-oxo- N-phenyl-2-((3,4,5,6-tetrahydroxytetrahydro-2 H-pyran-2-yl)methylene)-1,2,3,5-tetrahydroimidazo[1,2- a]pyrimidine-6-carboxamide analogues ( 1- 24) was synthesized using the Biginelli condensation. Results and discussion: The synthesized compounds were screened for their in vitro antimicrobial potential against Gram (positive and negative) bacterial and fungal strains by tube dilution technique. In the series, compound 15 exhibited significant antimicrobial activity against Candida albicans and Aspergillus niger with MIC value = 1.04 × 10 µM/ml and compound 2 was found to be most active antioxidant agent with IC value = 46.31 using DPPH assay. Anticancer activity results indicated that compound 23 displayed better anticancer activity against human breast cancer cell line (MCF-7) with GI value = 34.78 using SRB assay. Conclusions: All synthesized derivatives exhibited good antimicrobial, antioxidant and anticancer activity using specific method and compared with standard drugs, especially compounds 2, 15 and 23 displayed more activity than reference drugs. Structure activity relationship demonstrated that presence of electron releasing groups of the synthesized compounds enhanced the antibacterial activity against Escherichia coli as well as antioxidant activity and electron withdrawing groups improved the antimicrobial as well as anticancer activity against human breast (MCF-7) cancer cell line. [ABSTRACT FROM AUTHOR]

Electrogenerated chemiluminescence (ECL) reactions between tris(2,2′-bipyridine)ruthenium(II) and PAMAM dendrimers of the full (G1.0) and half (G1.5) generations were carried out in an aqueous medium at pH 6.1 and 10.0. In the absence of 5-fluoro-1 H,3 H-pyrimidine-2,4-dione (5-fluorouracil, 5-Fu) (coreactant effect study), the ECL efficiency trends as a function of [G1.0] and [G1.5] at pH 6.1 and 10.0 revealed that PAMAM dendrimers are about 100 (G1.5, pH 6.1), 60 (G1.5, pH 10.0), 26 (G1.0, pH 10.0) and 13 (G1.0, pH 6.1) times more efficient as ECL coreactants than oxalate anion is. Moreover, ECL reactions were done in the presence of several solutions of 5-Fu at a fixed concentration of the G1.0 and G1.5 dendrimers at pH 6.1 and 10.0 (binding study). The ECL efficiency trends as a function of [5-Fu] highlighted a dendrimer/5-Fu binding. Therefore, one of the most remarkable and novel findings of this work is the potential of PAMAM dendrimers to be used as both sensors and biosensors in an aqueous medium in the presence of a suitable sensitizer. Redox potentials of the [Ru(bpy)] couple were also determined in the absence and presence of 5-Fu at both pHs. In the absence of 5-Fu the positive or negative shift of redox potentials showed the influence of the repulsive or attractive electrostatic long-range and short-range interactions between the charged dendrimer surface and the oxidized and reduced forms of the couple. In the presence of 5-Fu the trends of redox potentials highlighted the existence of a charged dendrimer/5-Fu species. [ABSTRACT FROM AUTHOR]

A series of new pyrazolo[1,5- a]pyrimidine derivatives has been synthesized by using 7-hydrazinyl- 5-methylpyrazolo[1,5- a]pyrimidine-3-carbonitrile 1 and 7-amino-5-methylpyrazolo[1,5- a]pyrimidine-3-carbonitrile 2 as precursors. The pyrazolo[3,4- d] pyrimidines 3a-b have been synthesized by a three-step reaction starting with 1. Compound 1 was utilized for the synthesis of dioxopyrrolidindolinylamio-pyrazolo-pyrimidines 4a-b, and dioxoisoindolin-pyrazolo-pyrimidines 4c-d. Also, compounds 4a-dwere synthesized using deep eutectic solvents (DES). This method using DES provides several advantages such as benign environment, high yield, scalable and simple work-up procedure. Similarly, the cyclocondensation of 2 with α-acetyl- γ-butyrolactone afforded pyrazolo-pyrido-pyrimidine 5 and dihydrofuro-pyrido-pyrazolo-pyrimidine 6. All synthesized compounds were screened for antimicrobial activity. [ABSTRACT FROM AUTHOR]

The reaction of N-substituted isatins with 5-amino-1-phenyl-1 H-pyrazole-4-carboxamide in refluxing methanol in the presence of excess sodium methoxide led to cyclocondensation with the formation of 1- R-1'-phenyl-1',7'-dihydrospiro[indole-3,6'-pyrazolo[3,4- d]pyrimidine]-2,4'(1 H,5' H)-diones. Analogous reaction with 5-amino-1-phenyl-1 H-pyrazole-4-carbonitrile was a cascade process that involved the formation of 1-R-4'-(methoxy)-1'-phenyl-1',7'-dihydrospiro[indole-3,6'-pyrazolo[3,4- d]pyrimidine]-2(1 H)-ones as intermediates and led to N-R-2-[4-(methoxy)-1-phenyl-1 H-pyrazolo[3,4- d]pyrimidin-6-yl]anilines. [ABSTRACT FROM AUTHOR]

A method for preparing the amino, alkoxy, and alkylsulfanyl derivatives of pyrano[4″,3″:4′,5′]pyrido-[3′,2′:4,5]thieno[3,2- d]pyrimidines based on 8-chloro-2,2-dimethyl-5-pyrrolidin-1-yl-1,4-dihydro-2H-pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidine was developed. The anticonvulsant activity of the compounds synthesized here was investigated. [ABSTRACT FROM AUTHOR]

The reaction of 6-methyl-2-(2-oxo-2-phenylethylidene)-2,3-dihydropyrimidine-4(1 H)-one with arylhydrazines leads in high yields to the corresponding hydrazones, in which the ethylidene fragment of the starting compound is transformed to the ethylene fragment. By oxidation of the hydrazones with hydrogen peroxide or selenium dioxide the corresponding 6-methyl-2-[2-phenyl-2-(arylhydrazono)acetyl]-3 H-pyrimidine-4-ones were synthesized. [ABSTRACT FROM AUTHOR]

The reactions of benzene-1,2-diamine with 5-substituted 2-(alkylsulfanyl)-4-methylpyrimidin-6(1 H)-ones and 2-(propylsulfanyl)- and 5-iodo-2-(propylsulfanyl)-3,4-dihydroquinazolines at 175-185°C under solvent-free conditions unexpectedly afforded benzo[4,5]imidazo[1,2- a]pyrimidine, benzo[4,5]imidazo[2,1- b]-quinazoline, and 2,2′-(benzene-1,2-diyldiimino)bis[pyrimidin-4(3 H)-ones]. The described reaction is the first example of synthesis of these heterocyclic systems by fusion of benzimidazole to pyrimidine or quinazoline and is likely to follow ANRORC mechanism. [ABSTRACT FROM AUTHOR]

The review is focused on the synthesis of fluoroalkyl-containing heteroannulated pyrimidines via the reactions of alkyl 3-oxo-3-polyfluoroalkylpropionates and their ethoxymethylidene and 2-arylmethylidene derivatives with hetarylamines. Heteroannulation of polyfluoroalkyl-containing pyrimidines is also discussed. [ABSTRACT FROM AUTHOR]

2-Amino-4-[(2-aryloxyethyl)sulfanyl]-6-methylpyrimidines were obtained by S-alkylation of 2-amino-6-methylpyrimidin-4(3 H)-thione with 2-aryloxyethyl chlorides. Since 2-amino-4-[(2-chloroethyl)sulfanyl]-6-methylpyrimidine is prone to in situ intramolecular cyclization it cannot be used in Claisen reaction. The bromination of the target compounds provided 5-bromo derivatives; some of their hydrochlorides exhibited fungicidal activity. [ABSTRACT FROM AUTHOR]

A series of novel pyrimidines ( 6a-6i) has been synthesized from corresponding chalcones and isonicotinimidamide.HCl in the presence of potassium carbonate involving Michael addition followed by cycloaddition. All newly synthesised chalcones and pyrimidines were screened for in vitro antimicrobial activity against various Gram positive, Gram negative bacterial and fungal strains. Most of compounds displayed high antimicrobial activity compared to standard drugs Penicillin, Streptomycin and Ampothericin-B. [ABSTRACT FROM AUTHOR]