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The pyrido[2,3‐d]pyrimidine moieties are one of the most biologically widespread heterocyclic compounds as antimicrobial, antioxidant, antitubercular, antiviral and anti‐inflammatory. Hence, we synthesized an efficient new series of 2‐thioxo‐pyrido[2,3‐d]pyrimidinone, 2‐hydrazinyl‐(quinolin‐2‐yl)pyrido[2,3‐d]pyrimidinone,N′‐(quinolin‐2‐yl)‐pyrido[2,3‐d]pyrimidine‐(formo/aceto)‐hydrazide and substituted‐(quinolin‐2‐yl)pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinone derivatives. The characterization of new compounds was corresponded by using spectroscopic techniques, IR, NMR and Mass spectra. In vitro, all compounds were evaluated as antimicrobial activity compared with cefotaxime sodium and nystatin as the standard drug. This work deals with the exploration of the new heterocyclic compounds and medicinal diversity of quinoline‐pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidine derivatives that might pave the way for long in the discovery of therapeutic medicine for future drug design. [ABSTRACT FROM AUTHOR]

A lead aryl pyrrolidinone anilide identified using high-throughput in vivo screening was optimized for efficacy, crop safety, and weed spectrum, resulting in tetflupyrolimet. Known modes of action were ruled out through in vitro enzyme and in vivo plant-based assays. Genomic sequencing of aryl pyrrolidinone anilide-resistant Arabidopsis thaliana progeny combined with nutrient reversal experiments and metabolomic analyses confirmed that the molecular target of the chemistry was dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the fourth step in the de novo pyrimidine biosynthesis pathway. In vitro enzymatic and biophysical assays and a cocrystal structure with purified recombinant plant DHODH further confirmed this enzyme as the target site of this class of chemistry. Like known inhibitors of other DHODH orthologs, these molecules occupy the membrane-adjacent binding site of the electron acceptor ubiquinone. Identification of a new herbicidal chemical scaffold paired with a novel mode of action, the first such finding in over three decades, represents an important leap in combatting weed resistance and feeding a growing worldwide population. [ABSTRACT FROM AUTHOR]

We present a study on a new class of Schiff bases with pyrimidine linked hydrazinyl azole backbone. These compounds were synthesized using conventional and ultrasonication methods. Our design strategy incorporated three heteroaromatic azoles and various substituents on the pyrimidine scaffold to enhance antimicrobial properties. Antibacterial and antifungal screenings were conducted against specific pathogens, and molecular docking studies supported the results. The compounds exhibited significant antimicrobial activities, particularly against K. pneumoniae, surpassing the standard drug. These Schiff bases hold promise as potential antimicrobial agents. [ABSTRACT FROM AUTHOR]

The pyrido[1,2‐a]pyrimidine scaffold has great potential for the creation of bioactive substances. Here we propose a simple, cost‐effective, efficient approach to forming this core based on a one‐pot three‐component reaction of commercially available 3‐oxo esters, α,β‐unsaturated aldehydes and 1,3‐diaminopropane. The developed strategy makes it possible to obtain diverse pyrido[1,2‐a]pyrimidines thanks to alternative intramolecular cyclization pathways that depend on the substituent in the 3‐oxo ester. Their diastereomeric structure was determined using NMR spectroscopy and XRD. A mechanism for the formation of new pyrido[1,2‐a]pyridines has been proposed. [ABSTRACT FROM AUTHOR]

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 μM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 μM, 2.3 ± 5.91 μM and 5.65 ± 2.33 μM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted. [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]

HRMS-ESI: I m i / I z i [M + H] SP + sp calcd for C SB 11 sb H SB 7 sb Cl SB 2 sb N SB 2 sb O SB 3 sb : 284.9834; found: 284.9835. I Due to long relaxation time of the hydroxypyrimidine ring (when R SP 1 sp /R SP 3 sp = Me or R SP 1 sp /R SP 3 sp = H), some quaternary carbon signals may be broadened or even may not be responsive in SP 13 sp C NMR analysis. Keywords: isoxazoles; N-O bond cleavage; hydroxypyrimidines; molybdenum; one-pot; -amino enones; 1,3-diketones EN isoxazoles N-O bond cleavage hydroxypyrimidines molybdenum one-pot -amino enones 1,3-diketones 3841 3850 10 11/01/23 20231116 NES 231116 Graph Nitrogen-based heterocycles are one of the privileged core structural motifs in organic chemistry. HRMS-ESI: I m i / I z i [M + H] SP + sp calcd for C SB 10 sb H SB 6 sb ClF SB 3 sb N SB 3 sb O: 276.0151; found: 276.0157. [Extracted from the article]

We report herein an unprecedented synthesis of difluoromethoxylated nitrogen‐containing heterocycles from the corresponding α‐(difluoromethoxy)ketones as versatile building blocks. Pyrazoles, isoxazoles and pyrimidines could be obtained via an enaminone intermediate, whereas in the direct reaction of α‐(difluoromethoxy)ketones with arylhydrazines, a Fischer indole synthesis was achieved. All these scaffolds, which are uncommon, or even sometimes novel, due to the directly attached emerging fluorinated group (EFG) −OCF2H, might be of high potential in life sciences and appear as an interesting alternative to more and more controversial classical fluorinated groups, such as the ubiquitous trifluoromethyl group. [ABSTRACT FROM AUTHOR]

The 3 : 1 reaction of [Cu(C2H4)n]ClO4 with 2,4-bis(2-pyridyl)pyrimidine (bpprd) in Me2CO under C2H4 afforded yellow prism crystals of the dinuclear Cu(I)–C2H4 complex [Cu2(bpprd)(η2-C2H4)2(ClO4)2] (1). The 3 : 1 reaction of [Cu(C2H4)n]NO3 with bpprd in Me2CO under C2H4 afforded yellow plate crystals of the tetranuclear Cu(I)–C2H4 complex [Cu4(bpprd)2(η2-C2H4)4(μ-NO3)2](NO3)2 (2). The 10 : 1 reaction of [Cu(C2H4)n]BF4 with bpprd in Me2CO under C2H4 afforded yellow plate crystals of the dinuclear Cu(I)–C2H4 complex [Cu2(bpprd)(η2-C2H4)2(BF4)]BF4 (3). The 3 : 1 reaction of [Cu(C2H4)n]BF4 with bpprd in Me2CO under C2H4 afforded red prism crystals of the polymeric Cu(I)–C2H4 complex {[Cu6(bpprd)4(η2-C2H4)2(μ–η2:η2-C2H4)(μ-BF4)2](BF4)4}n (4). The X-ray crystal structures of complexes 1–4 have been determined. The structural diversity of Cu(I)–C2H4 complexes bridged by bpprd with different anions was demonstrated. The 1D Cu(I)–bpprd/C2H4 coordination polymer 4 bridged by unusual μ–η2:η2-C2H4 and the μ-BF4− anion is of particular significance. Complex 1 exhibited relatively well-resolved 1H NMR signals of bpprd and C2H4 (δ = 4.97 ppm) in (CD3)2CO at 23 °C. [ABSTRACT FROM AUTHOR]

Brønsted acid‐mediated intramolecular cyclization of 2‐amidoazulene derivatives, prepared by the reaction of 1‐cyano‐2‐aminoazulene derivatives with perfluoroalkyl acid anhydrides, resulted in the formation of 2‐perfluoroalkylazuleno[2,1‐d]pyrimidin‐4(3H)‐ones. Heating of these products in phosphoryl chloride led to 4‐chloro‐2‐perfluoroalkylazuleno[2,1‐d]pyrimidines. We also evaluated the reactivity of these pyrimidin‐4(3H)‐ones and pyrimidine derivatives toward the electrophilic and nucleophilic substitution reactions, revealing that a variety of functional groups can be incorporated into these derivatives. The NMR studies, NICS calculations, and single‐crystal X‐ray structure analyses revealed structural features including the bond‐length alternation of the azuleno[2,1‐d]pyrimidin‐4(3H)‐ones and pyrimidine derivatives. [ABSTRACT FROM AUTHOR]

This study provides straightforward synthesis of 4H-pyran-annulated heterocycles that serve as drug-like candidates for biological purposes. It was found that these multicomponent reactions performed under green conditions in the presence of sodium benzoate as an efficient, environmentally benign, and commercially available organo-salt catalyst. The target 2-amino-4-aryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles, 7-amino-5-aryl-2,4-dioxo/(4-oxo-2-thioxo)-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitriles, and 2-amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitriles, which are estimated to be important in organic synthetic and medicinal chemistry, were obtained in high yields and relatively shorter reaction times through a simple filtration. The method is versatile and amenable to many substrates, as it requires no specialized devices such as microwave, ultrasound and ball-milling. The aim of the work is the synthesis of pyran-annulated compounds in the presence of sodium benzoate as the organo-catalyst. This procedure has several further advantages, such as isolation of heterocyclic products without column chromatography or other chromatographic methods, atom-economy, step-economy, and clean reaction profiles. [ABSTRACT FROM AUTHOR]

The chemical reactivity of 2-methylchromone-3-carbonitrile (1) was investigated toward a diversity of active methylene nucleophiles. Ring-opening followed by recyclization reactions of compound 1 with some active methylene nitriles afforded 2-amino-3-substituted-4-methylchromeno[2,3-b]pyridin-5-ones. Also, reactions of carbonitrile 1 with some active methylene ketones produced 2,4-dimethylchromeno [2,3-b]pyridin-5-ones. Annulated chromeno[2,3-b]pyrazolo[4,3-e]pyridine, chromeno[2,3-b][1,3]thiazolo[5,4-e]pyridine and chromeno[2,3-b]quinoline were efficiently synthesized from reaction of carbonitrile 1 with some cyclic methylene compounds. Heteroannulated chromeno[3′,2′:5,6]pyrido[2,3-d]pyrimidines and chromeno[2,3-b][1,8]naphthyridines were synthesized from reaction of compound 2 with formic acid, formamide, and malononitrile, cyanoacetamide, respectively. Chromeno[2′,3′:6,5]pyrido[2,3-b][1,8]naphthyridine 17 was synthesized from reaction of compound 2 with malononitrile dimer. Structures of the newly synthesized products were deduced based on their analytical and spectral data. [ABSTRACT FROM AUTHOR]

A series of fifteen 2-substituted-3-(4-(pyridin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-2-yl)thiazolidin-4-one, was prepared and characterized using analytical techniques like FT-IR, NMR (1H and 13C), and mass spectrophotometry. On screening, the compounds for antibacterial and antifungal potential, the findings portrayed to be the potent inhibitor of bacterial and fungal strains. The cytotoxicity of the prepared molecules was checked against HepG2 cells to calculate the percent viable cells, which was observed to be in the range of 70–81% up to 100 µM. The molecular docking assay was performed to assess the binding modes, the extent of the H-bond, and binding affinities against the receptor glucosamine-6-phosphatase (GlcN-6P) and lanosterol 14-α-demethylase. The findings portrayed that TYR312, SER316, GLU396, LEU 448, SER303, GLY398, and SER401 were the only amino acids of GlcN-6P that formed the H-bond with the prepared molecules. Similarly, the residues GLC5, GLC6, GLC7, SER60, TYR63, THR104, ASP229, LEU230, SER249, SER251, THR485 were the only amino acids of lanosterol 14-α-demethylase) that formed H-bond with the prepared molecules. The binding affinities for both receptors were found to be in the range of –8.5 to –6.3 kcal/mole (GlcN-6P), and –8.4 to –6.8 kcal/mole (lanosterol 14-α-demethylase). [ABSTRACT FROM AUTHOR]

A novel heterocyclic compounds containing pyrimido[4,5-d]pyrimidine (IIIa–IIIb) and (IVa–IVb), pyrazolo[3,4-d]pyrimidine (Va'–Ve') and (VIa'–VIe'), and pyrimido[4,5-b]quinoline (VIIa'–VIIe') and (VIIIa'–VIIIe') were designed and synthesized from the starting materials, 5-(bis(methylthio)methylene)-1,3-diphenylpyrimidine-2,4,6(1H,3H,5H)-trione (IIa) and 5-(bis(methylthio)methylene)-1,3-diphenyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (IIb) as efficient α,α-ketene dithioacetals is reported. The synthetic approaches of these types of compounds will provide an innovative molecular framework to the designing of new active heterocyclic compounds. In our study, we also present optimization of the method for synthesis along with antimicrobial evaluation of these newly synthesized compounds as antibacterial agents against the bacterial strains, like E. coli, B. subtilis, S. aureus, and P. aeruginosa also as antifungal agents against B. cinerea, C. arachidicola, A. solani, G. zeae, S. sclerotiorum, and R. cerealis. Preliminary bioassay showed that most of them exhibited certain-to-excellent antibacterial and antifungal activity. Among all the evaluated compounds, it was found that the synthesized compounds (IVb) and (VIIIc') showed the outstanding antibacterial activity (100%) against the strains E coli and S. aureus respectively comparable to the standard drug Ciprofloxacin at the same concenteration while the others exhibited better antifungal activity at 100 µg/mL. The outstanding antifungal activity (>90%) comparable to the positive controls trifloxystrobin and azoxystrobin exhibited by (VIIIc') against B. cinerea, (IVb) and (Vc') against A. solani, (IVb) against S. sclerotiorum alongwith compounds (VIb'–VIc') against R. cerealis. The structures of all the new synthesized compounds were elucidated by elemental analysis, IR, 1H NMR, and 13C NMR. [ABSTRACT FROM AUTHOR]

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction. [ABSTRACT FROM AUTHOR]

Pyrimidine annulated five‐membered heterocyclic scaffolds containing oxygen as furopyrimidine, particularly furo[2,3‐d]pyrimidine derivatives are an important class of heterocyclic compounds in pharmaceutical discovery research. Furo[2,3‐d]pyrimidines are generally synthesized either from a pyrimidine derivative by constructing a furan ring on the parent pyrimidine ring or from a suitably functionalized furan ring by generating the pyrimidine ring on the parent furan ring. Moreover, there is a wide range of multicomponent reactions that include barbituric acids as starting material for the synthesis of these compounds. Also, the reaction of barbituric acids with alkenes, alkynes, aldehydes, ketones, ninhydrin, and chloroacetylchloride, and Cloke–Wilson rearrangement of spirocyclopropyl barbiturates afforded furo[2,3‐d]pyrimidine derivatives. This review is an attempt to compile the literature of various synthetic procedures toward barbituric acids‐based furo[2,3‐d]pyrimidine and spirofuro[2,3‐d]pyrimidines. [ABSTRACT FROM AUTHOR]

Estradiol methyl ether (EDME) has recently been described by us as a very potent and subtype-specific inhibitor of the lysosomal cation channel TRPML1. Following the principle of bioisosteres, we worked out efficient synthetic approaches to ring-A aza-analogs of EDME, namely a methoxypyridine and a methoxypyrimidine analog. Both target compounds were obtained in good overall yields in six and eight steps starting from 19-nortestosterone via the oxidative cleavage of ring A followed over several intermediates and with the use of well-selected protective groups by re-cyclization to provide the desired hetero-analogs. The methoxypyridine analog largely retained its TRPML1-inhibitory activity, whereas the methoxypyrimidine analog significantly lost activity. [ABSTRACT FROM AUTHOR]

Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a series of new pyrido[2,3-d] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with 1H NMR, 13C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (Lactuca sativa), field mustard (Brassica campestris), monocotyledonous bentgrass (Agrostis stolonifera) and wheat (Triticum aestivum) were determined. The results indicated that most of the pyrido[2,3-d] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-d] pyrimidine derivatives possessed good activity against bentgrass at 1 mM. Among them, the most active compound, 3-methyl-1-(2,3,4-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2o), was as active as the positive controls, the commercial herbicides clomazone and flumioxazin. Molecular simulation was performed with molecular docking and DFT calculations. The docking studies provided strong evidence that 2o acts as an herbicide by inhibition of protoporphyrinogen oxidase. However, the physiological results indicate that it does not act on this target in vivo, implying that it could be metabolically converted to a compound with a different molecular target. [ABSTRACT FROM AUTHOR]

A novel family of 3-chloro-4-benzylidene-1-(pyrimidin-2-yl) azetidin-2-one 5a-o has been developed because antimicrobial resistance (AMR) poses a significant concern to global public health and has made it exceedingly difficult to effectively manage infectious diseases that have been connected to it. The structures of the relevant compounds have been determined and verified using spectral methods. As substances are tested against gram-positive and gram-negative strains of bacteria and fungi, results must be compared to those of conventional drugs. Products with chloro substituents in both the pposition and the m-position demonstrate good activity against the fungi Aspergillus niger and Fusarium javanicum, while those with nitro, methyl, and bromo substituents in the benzene ring's p-position, as well as those with the nitro group at the ring's m-position, demonstrate excellent activitiy against bacterial strains. [ABSTRACT FROM AUTHOR]

Keywords: photocatalyst-free; C-H selenylation; pyrazolo[1,5- a ]pyrimidine; persulfate; visible light EN photocatalyst-free C-H selenylation pyrazolo[1,5- a ]pyrimidine persulfate visible light 3693 3699 7 10/19/23 20231102 NES 231102 Graph Pyrazolo[1,5- I a i ]pyrimidine derivatives, an important class of fused heterocycles exhibit various biological activities like antiviral, antifungal, anti-inflammatory, antibacterial, antiobesity, etc. [1] A number of commercially available agrochemicals and pharmaceuticals such as indiplon, lorediplon and zaleplon (hypnotic), ocinaplon (anxiolytic), reversan (anticancer), pyrazophos (fungicide), etc. contain pyrazolo[1,5- I a i ]pyrimidine as the core structure (Figure 1). The screening of other persulfates like Na SB 2 sb S SB 2 sb O SB 8 sb and K SB 2 sb S SB 2 sb O SB 8 sb as well as oxidants like PIDA, TBHP, and oxygen revealed that K SB 2 sb S SB 2 sb O SB 8 sb was the most efficient for this transformation (entries 2-6). Under the optimized reaction conditions, 2-methyl-5,7-diphenylpyrazolo[1,5- I a i ]pyrimidine, 2,5,7-tri-methylpyrazolo[1,5- I a i ]pyrimidine, and 2,7-diphenyl pyrazolo[1,5- I a i ]pyrimidine afforded the C3-selenylated product B 3l b , B 3m b , and B 3n b in 77, 70 and 79% yield, respectively. Selenylation of Pyrazolo[1,5- a ]pyrimidines; General Procedure In an oven-dried reaction vial containing B 1 b (0.2 mmol) and B 2 b (0.12 mmol) DMSO (1 mL) was added followed by K SB 2 sb S SB 2 sb O SB 8 sb (0.065 g, 1.2 equiv.). [Extracted from the article]

The quantum chemical simulation of complexes of the glycyl-L-glutamic acid anion and the - alanyl-L-tyrosine Ala-L-Tyr zwitterion with nucleic bases (uracyl and cytosine) is performed using the DFT/B97D method. The most energetically favorable configurations of the complexes are found. Changes in the peptide structure during the formation of the complexes are analyzed. It is shown that the complexes are stabilized by intermolecular hydrogen bonds. The stacking effect competing with the hydrogen bonding in the orientation of peptide ions in the complex is described. The topological analysis is carried out within which bond critical points and their parameters are studied and hydrogen bond energies are found in the complexes. [ABSTRACT FROM AUTHOR]

The effective methods for obtaining Fe3O4/CeO2, Fe3O4(TEOS)CeO2 nanocomposites with cerium dioxide content from 38 to 82% and from 32 to 70%, respectively were developed, their morphological, structural and magnetic studies were carried out. Cerium dioxide and magnetite composites have a crystalline structure and ferromagnetic properties characteristic for magnetite with non-magnetic impurities. Thereby it can be easily separated from the reaction medium by means of a permanent magnet. The nanocomposites exhibit catalytic activity in cyclocondensation reactions: the interaction of chalcones with acetoacetic ester in an alkaline medium in the presence of the 1.6 wt % resulting nanocomposite leads to the formation of m-terphenyl derivatives in one-stage reaction, and in the condensation reaction with the formation of the 4,6-dimethyl-N-(4-methyl-3-nitrophenyl)pyrimidine-2-amine and 4,6-dimethyl-N-(2-methyl-5-nitrophenyl)pyrimidine-2-amine, the yield of the target product was increased to 52 and 96.8%, respectively. The resulting composites can be used repeatedly, providing sufficiently high yields of the target product. [ABSTRACT FROM AUTHOR]

We have designed and synthesized a new series of amide derivatives of thiazolo[5,4-d]pyrimidines (10a-j) and their structures were characterized by 1H NMR, 13C NMR and mass spectral data. Furthermore, all compounds were evaluated for in vitro cytotoxicity effects against four human cancer cell lines such as PC3 (prostate cancer), A549 (lung cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer) by employing MTT assay. The cytotoxicity effects of the amide derivatives (10a-j) were compared with etoposide utilized as the positive control. Among them, five compounds 10a, 10b, 10c, 10h and 10j possessed significant cytotoxicity properties as compared with etoposide. [ABSTRACT FROM AUTHOR]

CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N5-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development. [ABSTRACT FROM AUTHOR]

Triazolopyrimidines are emerging as potential anticancer agents. Herein, we report a novel one‐pot four component synthesis of 2‐((2‐oxo‐2‐phenylethyl/benzyl)thio)‐10‐phenyl‐4,10‐dihydro‐9H‐indeno[1,2‐d][1,2,4]‐Triazolo[1,5‐a]pyrimidin‐9‐ones by the reaction of 1,3‐indanedione, aromatic aldehyde, 5‐amino‐4H‐1,2,4‐Triazol‐3‐thiol and phenacyl bromide in acetic acid with piperidine as catalyst at 90 °C for 13 hours. All the final compounds were identified on the basis of their FT‐IR, 1H NMR, 13C NMR and HRMS. The synthesized compounds were evaluated for their cell growth inhibition potential using MTT and wound healing assay, 13 compounds induced concentration dependent inhibition with IC50 below 10 μM against breast cancer cell lines (MCF‐7). Further, the molecular docking simulation were carried out for all the derivatives, amongst these thio phenacyl, 2,4‐dichlorophenyl 9H‐indeno [1,2,4]‐Triazolo[1,5‐a]pyrimidin‐9‐one (5 g) shows good binding interaction with amino acid residues. This is further confirmed by wound healing assay which shows that 5 g inhibits cell migration at increasing concentrations. [ABSTRACT FROM AUTHOR]

Abstract In June 2023, the Purine and Pyrimidine Society (PPS) organized the 20th biennial symposium on Purine and Pyrimidine metabolism (PP23). The symposium was organized in Los Angeles, California, USA, by Pr Caius Radu affiliated to UCLA. The scientific program covered various topics such as inborn errors, cancer, immunity, enzymatic reactions, drug development etc and was presented at 9 sessions over three days. The current issue of Nucleosides, Nucleotides & Nucleic Acids is a special issue covering proceedings from PP23-presentations and other PPS-related manuscripts, and in this editorial, we will give an overview of the scientific program of the meeting. [ABSTRACT FROM AUTHOR]

The starting substrate 5-chloro-4,9-dimethoxy-7-oxo-7H-furo[3,2-g]chromene-6-carbonitrile (2) was efficiently synthesized from chlorination of the corresponding hydroxy derivative. The presence of adjacent cyano and chloro functions was employed for construction a variety of five, six and seven membered rings annulated furo[3,2-g]chromenes. Treating precursor 2 with hydrazine, phenylhydrazine and hydroxylamine yielded furo[3,2:6,7]chromeno[4,3-c]pyrazoles 3, 4 and furo[3,2:6,7] chromeno[3,4-d]isoxazole 5, respectively. Also, reaction of compound 2 with a diversity of 1,3-N,N-binucleophiles such as guanidine, cyanoguanidine, thiourea, acetamidine and benzamidine produced annulated furo[3,2:6,7]chromeno[4,3-d]pyrimidines 6–10, respectively. Further, treatment of compound 2 with a variety of 1,4-binucleophiles namely ethylenediamine, o-phenylenediamine and 2-aminophenol yielded furo[3,2:6,7]chromeno[4,3-e][1,4]diazepine 11, furo[3,2:6,7]chromeno[4,3-b][1,5]benzodiazepine 12 and furo[3,2:6,7]chromeno[4,3-b][1,5]benzoxazepine 13, respectively. Some of the synthesized compounds seemed good antimicrobial activity especially compounds 3, 6 and 8. Using analytical and spectral results, the structures of the prepared compounds were established. [ABSTRACT FROM AUTHOR]

Novel five-membered ring (pyrrole, pyrazole and imidazole)-based pyrimidine and quinazoline derivatives were synthesized by one-pot domino approach. This approach has the advantages of high yield, mild reaction conditions and a simple work-up procedure. The structure of the synthesized compound was elucidated by spectroscopy technique and elemental analysis. The synthesized compound were examined for antimicrobial activity against four bacteria (E. coli, S. pyogenes, S. aureus, and P. aeruginosa) and two fungi (C. albicans and A. clavatus) and most of the synthesized compound exhibited moderate to good activity against reference drug ampicillin, ciprofloxacin, norfloxacin, gentamycin, nystatin and griseofulvin, respectively. [ABSTRACT FROM AUTHOR]

Opportunistic infections like tuberculosis (TB) are prevalent in HIV‐infected individuals. In an approach to introducing an industrial‐scale microwave‐assisted production of agents having both antiviral and antibacterial properties, a set of hydrophilic 2,3‐substituted quinazolinones, 4‐oxo‐2‐phenylquinazoline‐3(4H)‐carboximidamide (Qg) and 4‐oxo‐2‐phenylquinazoline‐3(4H)‐carboxamide (Qu), were afforded in encouraging yields. They were obtained by treating 2‐benzamidobenzoyl chloride with guanidine hydrochloride or urea in the presence of potassium carbonate in DMF. DFT calculations were employed for geometrical optimization and vibrational frequency analysis of the compounds. Free energies of solvation (ΔGsol) of Qg, and Qu calculated using DFT lend evidence in support of their hydrophilicity The anti‐HIV‐1 activities of the small‐molecule quinazolinone derivatives Qg and Qu were investigated. The synthons under in vitro conditions inhibit the entry of HIV in receptor cells with low cytotoxicity (EC50=50.53 nM for Qu and EC50=97.92 nM for Qg). The study identifies the antiviral properties of the two benzo‐fused pyrimidine derivatives, which were earlier reported to have antitubercular activity. Our findings indicate the scope for further synthetic explorations of these quinazolinone scaffolds that can lead to developing promising alternatives in drug design, pharmaceutics, and clinical research. [ABSTRACT FROM AUTHOR]

In this study a new and procedure was reported for the synthesis of Ag/TiO2/Fe3O4@MWCNTs MNCs as a new heterogeneous organometallic catalyst. XRD, FESEM, EDX and TEM analysis were used for confirming the structure of synthesized nanocatalyst. The Ag/TiO2/Fe3O4@MWCNTs MNCs as a high performance catalyst was employed for the preparation of a new family of functionalized spiro pyrrolo[3,4-d]pyrimidine via the one-pot condensation reactions of ethyl 2,4-dioxo-4-arylbutanoate, ammonium acetate, isatin, primary amines and tert-butyl isocyanide in water at room temperature. Also, antioxidant property of some prepared compounds was investigated using diphenyl-picrylhydrazine (DPPH) radical trapping experiment. Presently, bacteria that is not destroied with drug have generated many problems in the performance of many transferable disease. For this reason, discovering appropriate and new procedures for the dealing with these pathogens are important and recent study have focused on the investigation of the antibacterial effects on the prepared compounds. The pyrimidine ring is an azaaromatic scaffold that can be found in many molecules of biological or pharmaceutical interest. multicomponent reactions (MCRs) are more interesting type of reaction due to mixing three or more reactants in one-pot and generating one product and economically useful and environmentally secure than to multi-step methods. Carrying out synthesis of organic compounds in water media is very interesting because of water is cheap solvent, more available with high amounts. [ABSTRACT FROM AUTHOR]

A series of halogenated systems for pyrazolo[1,5-a]pyrimidines have been developed. Selective transformations of pyrazolo[1,5-a]pyrimidines by mono- and di-iodination were achieved by varying the ratio of pyrazolo[1,5-a]pyrimidines to NIS. In addition, the reaction of pyrazolo[1,5-a]pyrimidines with NBS or NCS uniquely gave dibrominated or dichlorinated products. The wide range of substrates, good functional group tolerance and gram-scale synthesis further demonstrate the application potential of this reaction. This work provides an efficient method for the construction of structurally diverse halogenated pyrazolo[1,5-a]pyrimidine derivatives. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q2 = 0.828, r2 = 0.988, r2pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r2 = 0.968, r2pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs. [ABSTRACT FROM AUTHOR]

A new set of pyrazolo[1,5-a]pyrimidines 5–8 and imidazo[1,2-b]pyrazoles 9–11 incorporating isoxazole as pharmacologically attractive cores were synthesized starting with aminopyrazole derivative 4. Moreover, the treatment of arylidine derivative 3 with hydroxylamine hydrochloride as nucleophilic reagent afforded the isoxazole derivative 12. All the new target derivatives were assessed in vitro antimicrobial candidates against six strains (three Gram + ve Bacteria and three Gram -ve Bacteria) and two fungi. Target compounds 4, 5, 6, 9 and 10 illustrated potent activity against some of the pathogens compared to the reference drug Ampicillin with minimum inhibitory concentration (MIC) values in some cases less than the reference the other derivatives represented moderate to week and in some cases inactive as a compound 8. Compounds 4, 5, 6 and 10 showed moderate activity against fungi. Finally, antioxidant activities were performed for the most promising targets (except 3a,b and 8) which displayed moderate to very strong antioxidant activities. [ABSTRACT FROM AUTHOR]

A new bunch of substituted aryl amino derivatives structurally modified pyrido[3,2-d]pyrimidines (10a–j) have been synthesized and evaluated for anticancer effects against PC3 (human prostate), A549 (human lung), MCF-7 (human breast) and Colo-205 (human colon) cancer cell lines by utilizing of MTT procedure. Most of the synthesized compounds were showed anticancer activity good to moderate activities with IC50 values range from 0.013 ± 0.0058 µM to 8.22 ± 5.87 µM, whereas, standard 9 etoposide used as standard drug) showed IC50 values from 0.14 ± 0.017 µM to 3.08 ± 0.135 µM, respectively. Among the synthesized compounds, five compounds 10a, 10b, 10c, 10d and 10e demonstrated more potent activity on all cell lines. Mainly, compound 10e displayed higher anticancer activity. [ABSTRACT FROM AUTHOR]

Fluorescently labeled nucleotides that contain a zwitterionic indodicarbocyanine dye have been synthesized. The dye has been attached at the C5 position of the pyrimidine base through a trans-alkene spacer. The substrate efficiency of the labeled nucleotides has been tested in recombinase polymerase amplification (RPA). As a result of RPA, full-sized target products of the ebpS gene fragment of the causative agent of bacterial pneumonia (Staphylococcus aureus) have been formed with a high density of fluorescent label. [ABSTRACT FROM AUTHOR]

A novel series of heterocyclic compounds containing thiazolo[3,2-a]pyrimidine and pyrimido[5,4-d]thiazolo[3,2-a]pyrimidine analogues were designed and synthesized starting from α,α-ketene dithioacetals (I), and their structures were confirmed by elemental analysis, IR, 1H NMR, and 13C NMR. In our study, we also present optimization of the synthetic method along with a biological evaluation of these newly synthesized compounds as antioxidants and antifungal. Preliminary bioassay showed that most of them exhibited certain-to-excellent antioxidant and antifungal activity. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 µg/mL while the others exhibited better antifungalal activity at 100 µg/mL. Thiazolo[3,2-a]pyrimidines (IVa–IVb) and (IVc–IVd) showed higher than 80% inhibition activity against C. arachidicola and P. infestans respectively whereas the thiazolo[3,2-a]pyrimidines (VIc–VId) showed maximum activity against B. cinerea and C. arachidicola, as for the tested pyrimido[5,4-d]thiazolo[3,2-a]pyrimidines (IXc–IXd) against G. zeae, P. piricola, and P. sasakii. In particular, thiazolo[3,2-a]pyrimidines (IVc–IVd) exhibited outstanding activity (> 90%) against G. zeae. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 µg/mL and the maximum DPPH radical scavenging activity was observed with synthetic thiazolo[3,2-a]pyrimidines (VIIc–VIId) and pyrimido[5,4-d]thiazolo[3,2-a]pyrimidine (IXc–IXd), especially pyrimido[5,4-d]thiazolo[3,2-a]pyrimidine (IXc) which possessed the highest antioxidant activity in comparable to that of standard vitamin C at similar concentration. [ABSTRACT FROM AUTHOR]

Metastasis, the dissemination of tumor cells, stands as the second most prominent contributor to mortality arising from breast cancer. To counteract this phenomenon, the molecular markers associated with angiogenesis, particularly vascular endothelial growth factor (VEGF) and its receptor (VEGFR), have emerged as promising strategies for impeding the progression of tumor cells. Compounds like pyrimidines, coumarins, oxadiazoles, and triazoles have undergone comprehensive investigations due to their notable anticancer potential, highlighting their encouraging capacities in inhibiting VEGFR-2, an essential mediator of angiogenesis signaling. Herein, we have synthesized pyrimidine–triazoles and oxadiazole–triazoles using electrochemical and conventional methods. The newly synthesized compounds were evaluated for anticancer activity against MCF-7 breast cancer cells, and it was found that the compounds 8a and 8b showed IC50 values of 5.29 and 15.54 μM, respectively. Our in silico mode of action revealed that these compounds could target VEGFR-2, which was further evidenced by our in silico structure-based bioinformatic analysis. In conclusion, we reported an electrochemical method to prepare novel drug-like compounds, based on triazole and other heterocyclic hybrids, that could be used to design VGFR-targeting drugs. [ABSTRACT FROM AUTHOR]

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3–24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase (SDH), a pivotal enzyme linking the respiratory electron transport chain and tricarboxylic acid (TCA) cycle, has been identified as an ideal target for developing effective fungicides. In this study, 20 novel trifluoromethyl pyrimidine derivatives containing 1,3,4-oxadiazole and thioether moieties were prepared and characterized their structures by ¹H NMR, 13C NMR, and HRMS. Bioassay results showed that some of the target com- pounds revealed moderate to good in vitro antifungal activities toward Rhizoctonia solani (R. solani), Botryosphaeria dothidea (B. dothidea), Phomopsis sp., Botrytis cinerea (B. cinerea), Fusarium oxysporum (F. oxysporum), Sclerotinia sclerotiorum (S. sclerotiorum), Phytophthora infestans (P. infestans), and Magnaporthe oryzae (M. oryzae). In particular, compounds 6g and 6i had better in vitro antifungal activity against B. cinerea, with the EC50 values of 19.43 and 28.22 μg/mL, respectively, than that of Pyrimethanil (57.30 μg/mL). As well, compound 6r exhibited good in vitro antifungal activity against F. oxysporum, with the EC50 value of 3.61 μg/mL, which were lower than that of Boscalid (0.40 μg/mL). In addition, the molecular docking simulation revealed that compound 6r interacted with GLN-150, ASP-153, LYS-151, GLY-154, and GLY-228 of SDH through hydrogen bond, which could explain the probable mechanism of action between the target compounds and SDH. This is the first report on the antifungal activity of novel trifluoromethyl pyrimidine derivatives containing 1,3,4-oxadiazole and thioether moieties as potential SDH inhibitors. [ABSTRACT FROM AUTHOR]

In this study, we aimed to establish an efficient method for synthesizing two new series of arene-linked pyrazolo[1,5-a]pyrimidines. This was achieved by reacting 1H-pyrazole-3,5-diamines with the respective acetophenones and benzaldehydes in a 1:1:1 ratio. To optimize this three-component reaction, various bases, and solvents were investigated. Use of two equivalents of KOH in ethanol at reflux for 4--6 h resulted in 89%--96% yields of the desired products. Structure of new products was elucidated by considering their elemental and spectral data. [ABSTRACT FROM AUTHOR]

A novel series of 6-acetyl-[1,2,4]triazolo[1,5-a]pyrimidines, hexahydro-[1,2,4] triazolo[5,1-b]quinazolines, tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1-ones, and 3-acetyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidines linked to phenoxy-N-arylacetamide moieties were prepared via Biginelli-like cyclocondensation reaction of the 2-(4-formylphenoxy)-N-arylacetamides, with the appropriate active methylene containing reagents and nitrogen binucleophiles. Elements and spectroscopic data were used to confirm the compositions of the novel compounds. We proposed a reasonable mechanism for the creation of target products. [ABSTRACT FROM AUTHOR]

Chagas' disease affects approximately eight million people throughout the world, especially the poorest individuals. The protozoan that causes this disease–Trypanosoma cruzi–has the enzyme cruzipain, which is the main therapeutic target. As no available medications have satisfactory effectiveness and safety, it is of fundamental importance to design and synthesize novel analogues that are more active and selective. In the present study, molecular docking and the in silico prediction of ADMET properties were used as strategies to optimize the trypanocidal activity of the pyrimidine compound ZN3F based on interactions with the target site in cruzipain. From the computational results, eight 4‐amino‐5‐carbonitrile‐pyrimidine analogues were proposed, synthesized (5a‐f and 7g‐h) and, tested in vitro on the trypomastigote form of the Tulahuen strain of T. cruzi. The in silico study showed that the designed analogues bond favorably to important amino acid residues of the active site in cruzipain. An in vitro evaluation of cytotoxicity was performed on L929 mammal cell lines. All derivatives inhibited the Tulahuen strain of T. cruzi and also exhibited lower toxicity to L929 cells. The 5e product, in particular, proved to be a potent, selective (IC50 = 2.79 ± 0.00 μM, selectivity index = 31.3) inhibitor of T. cruzi. The present results indicated the effectiveness of drugs based on the structure of the receptor, revealing the potential trypanocidal of pyrimidines. This study also provides information on molecular aspects for the inhibition of cruzipain. [ABSTRACT FROM AUTHOR]

Orotic acid (OA) is an intermediate metabolite of pyrimidine nucleotide biosynthesis and represents a minor diet constituent. The measurement of urinary orotic acid is useful in confirming the diagnosis of hereditary metabolic diseases. Moreover, it could be of interest to know how the physiological concentration of this metabolite changes in relation to different conditions of clinical normality. The purpose of this study was to determine the orotic acid concentration in the urine of healthy patients, to observe normal oroticuria and to evaluate if the expression of pyrimidine intermediate biosynthesis differs between healthy males and females. The orotic acid concentration in urine was performed via the ICH M10-validated analytical method. Unexpectedly, females showed a greater oroticuria than males in pediatric age (0–10); conversely, we did not find significant differences until 70 years of age. The LC-MS/MS method was suitable for use in the differential diagnosis of hereditary metabolic disease and metabolic monitoring of anticancer drug-induced toxicity. The analytical protocol was found to be rapid and ideal, and was used in the routine analysis of a clinical chemistry laboratory. The biochemical aspects related to the expression of pyrimidine biosynthesis should be further investigated in light of the obtained results. [ABSTRACT FROM AUTHOR]

A cyclo condensation reaction is an effective method for a two-component reaction of 2-amino-1,5-diphenyl-1H-pyrrole-3-carbonitrile 3a-c and active methylene compounds in acetic acid and catalytic hydrochloric acid to produce new substituted 1H-pyrrolo[2,3-b]pyridine 4a-c, 5a-c, and 6a-c have been established. Additionally, a new series of substituted 1H-pyrrolo[2,3-d]pyrimidines 7a-c and 8a-c could be synthesized utilizing a feasible and efficient approach, including urea and thiourea substrates. Spectroscopic data IR, MS, ¹H, and 13C NMR, as well as elemental analyses, elucidated these compounds' structures. [ABSTRACT FROM AUTHOR]

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC50 down to 1–4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (N-(4-methoxyphenyl)-N,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca2+ or Mg2+ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation. [ABSTRACT FROM AUTHOR]

Leishmaniasis and Chagas disease are still considered neglected illnesses due to the lack of investment in research, despite the fact that almost one million new cases are reported every year. Four 7-oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (HftpO) first-row transition complexes (Cu, Co, Ni, Zn) have been studied for the first time in vitro against five different species of Leishmania spp. (L. infantum, L. braziliensis, L. donovani, L. peruviana and L. mexicana) as well as Trypanosoma cruzi, showing higher efficacy than the reference commercial drugs. UV and luminescence properties were also evaluated. As a proof of concept, anchoring of a model high-effective-metal complex as an antiparasitic agent on silica nanoparticles was carried out for the first time, and drug-release behaviour was evaluated, assessing this new approach for drug vehiculation. [ABSTRACT FROM AUTHOR]

[Display omitted] A series of new bis(pyrimidines) with p- hydroquinone linker was prepared and evaluated as AMPA receptor modulators. Both positive and negative modulators were found among the investigated compounds. [ABSTRACT FROM AUTHOR]

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

Two new polyoxometalate (POM)-based metal–organic supramolecular architectures, [Cu(Hpypa)2(PMo12O40)(μ2-Cl)] 3H2O (1) and [Co(H2bpap)(γ-Mo8O28)0.5(H2O)2] H2O (2), were successfully synthesized by using two self-designed pyrimidine-amide organic ligands [N-(pyridin-3-ylmethyl)pyrimidine-4-carboxamide (pypa) and N,N′-bis(4-pyrimidinecarboxamido)-1,5-pentane (bpap)], as well as Keggin-type POM anions and octamolybdate anions under hydrothermal conditions. Complex 1 is a 1D supramolecular structure containing dinuclear [Cu2(Hpypa)4(PMo12O40)2(μ2-Cl)2] units. Complex 2 exhibits a 3D supramolecular framework consisting of 1D [Co(H2bpap)(H2O)2]n4n+ metal–organic chains and free [Mo8O28]8− anions. The supercapacitor performances of complexes 1 and 2 in a three-electrode system were investigated. When the current density is 1 A g−1, 1 and 2 exhibit specific capacitances of 555 and 675 F g−1, respectively. The symmetrical supercapacitor assembled with complex 2 as the electrode modifier exhibits an energy density of 13.4 W h kg−1 with a power density of 450 W kg−1. Capacitance retention remains at 96% after 6500 cycles. At the same time, the electrochemical sensors prepared with complexes 1 and 2 can be used for the determination of Cr(VI)/Fe(III) ions in aqueous solution with high sensitivity and low detection limit. [ABSTRACT FROM AUTHOR]

Tetrahydropyrazolo[1,5-a]pyrimidine (THPP) is an attractive scaffold for designing biologically active compounds. The most obvious way to obtain such compounds is to reduce pyrazolopyrimidines with complex hydrides, because the pyrimidine ring is reduced in the preference over the pyrazole ring. The presence of substituents at positions five and seven of pyrazolo[1,5-a]pyrimidines complicates the set of reaction products but makes it more attractive for medicinal chemistry because four possible stereoisomers can be formed during reduction. However, the formation of only syn-isomers has been described in the literature. This article is the first report on the formation of anti-configured isomers along with syn-isomers in the reduction of model 5,7-dimethylpyrazolo[1,5-a]pyrimidine, which was confirmed by NMR. The bicyclic core in the syn-configuration was shown to be conformationally stable, which was used to estimate the long-range interproton distances using NOESY data. At the same time, long-range dipole–dipole interactions corresponding to a distance between protons of more than 6 Å were first registered and quantified. In turn, the bicyclic core in the trans-configuration represents a conformationally labile system. For these structures, an analysis of conformations observed in solutions was carried out. Our results indicate the significant potential of trans-configured tetrahydropyrazolo[1,5-a]pyrimidines for the development of active small molecules. While possessing structural lability due to the low energy of the conformational transition, they have the ability to adjust to the active site of the desired target. [ABSTRACT FROM AUTHOR]