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A method based on the use of difluoroboron complexes was developed for the introduction of aminopyrimidinyl substituents into the side chain of ring A in (13α)-estrones. [ABSTRACT FROM AUTHOR]

(benzylthio)acetic acid (HBTA) and some aminopyrimidines, namely 2-aminopyrimidine (2-AP), 5-aminopyrimidine (5-AP), 2-amino-4,6-dimethylpyrimidine (2-A-4,6-DMP), and 2,4,6-triaminopyrimidine (2,4,6-TAP), were successfully embodied as structural units into the construction of a total of four novel supramolecular organic frameworks. The received crystalline solids were inspected by single-crystal X-ray diffraction (SC XRD) in order to obtain insight into the structural and supramolecular facets. The SOFs deriving from 2-AP, 5-AP, and 2-A-4,6-DMP crystallize in the form of co-crystals (1–3), while the one originating from 2,4,6-TAP crystallizes as a salt solvate (4). The SC XRD results indicated the different contents of structural residues present in the asymmetric units of the crystals 1–4 despite using the same molar ratio of molecular co-former components in each case. The molecular structures of co-crystals 1–3 consist of either one neutral residue of each starting component (1 and 3) or one nonionized residue of the aminopyrimidine ingredient and two neutral residues of the acidic component (2). The asymmetric unit of salt solvate 4 is composed of two ionized residues of each co-former (two 2,4,6-TAP+ cations and two BTA− anions) and one MeOH solvent molecule. The most extensive H-bonding network is observed in the crystal structure of salt solvate 4. The relevant molecular ingredients in co-crystals 1–3 are mainly held together by the neutral Ocarboxylic–H···Npyrimidine and Namine–H···Ocarboxylic H-bonds. In the case of aggregate 4, the corresponding ionic residues are predominantly sustained by the charged-assisted Npyrimidinium–H···Ocarboxylate and Namine–H···Ocarboxylate hydrogen interactions. The MeOH solvent, incorporated into the crystal lattice of adduct 4, is also involved in H-bonding by simultaneously serving as the single donor in OMeOH–H···S and the single acceptor in Namine–H···OMeOH H-bonds, which afforded the structural diversity within the 2,4,6-TAP+ cations and BTA− anions. Other weaker sets of additional non-covalent contacts existing in the crystal structures of analyzed conglomerates are involved in the self-assembly, stabilization, and expansion of total supramolecular organic frameworks. The fact of the formation of non-covalent bonded supramolecular organic frameworks in question is also reflected in corresponding results obtained through elemental analysis (EA), Fourier transform infrared spectroscopy (FT–IR), and thermal analysis (TG/DSC). [ABSTRACT FROM AUTHOR]

(benzylthio)acetic acid (HBTA) and some aminopyrimidines, namely 2-aminopyrimidine (2-AP), 5-aminopyrimidine (5-AP), 2-amino-4,6-dimethylpyrimidine (2-A-4,6-DMP), and 2,4,6-triaminopyrimidine (2,4,6-TAP), were successfully embodied as structural units into the construction of a total of four novel supramolecular organic frameworks. The received crystalline solids were inspected by single-crystal X-ray diffraction (SC XRD) in order to obtain insight into the structural and supramolecular facets. The SOFs deriving from 2-AP, 5-AP, and 2-A-4,6-DMP crystallize in the form of co-crystals (1–3), while the one originating from 2,4,6-TAP crystallizes as a salt solvate (4). The SC XRD results indicated the different contents of structural residues present in the asymmetric units of the crystals 1–4 despite using the same molar ratio of molecular co-former components in each case. The molecular structures of co-crystals 1–3 consist of either one neutral residue of each starting component (1 and 3) or one nonionized residue of the aminopyrimidine ingredient and two neutral residues of the acidic component (2). The asymmetric unit of salt solvate 4 is composed of two ionized residues of each co-former (two 2,4,6-TAP+ cations and two BTA− anions) and one MeOH solvent molecule. The most extensive H-bonding network is observed in the crystal structure of salt solvate 4. The relevant molecular ingredients in co-crystals 1–3 are mainly held together by the neutral Ocarboxylic–H···Npyrimidine and Namine–H···Ocarboxylic H-bonds. In the case of aggregate 4, the corresponding ionic residues are predominantly sustained by the charged-assisted Npyrimidinium–H···Ocarboxylate and Namine–H···Ocarboxylate hydrogen interactions. The MeOH solvent, incorporated into the crystal lattice of adduct 4, is also involved in H-bonding by simultaneously serving as the single donor in OMeOH–H···S and the single acceptor in Namine–H···OMeOH H-bonds, which afforded the structural diversity within the 2,4,6-TAP+ cations and BTA− anions. Other weaker sets of additional non-covalent contacts existing in the crystal structures of analyzed conglomerates are involved in the self-assembly, stabilization, and expansion of total supramolecular organic frameworks. The fact of the formation of non-covalent bonded supramolecular organic frameworks in question is also reflected in corresponding results obtained through elemental analysis (EA), Fourier transform infrared spectroscopy (FT–IR), and thermal analysis (TG/DSC).

Abstract Robenidine (E)‐N′‐((E)‐1‐(4‐chlorophenyl)ethylidene)‐2‐(1‐(4‐chlorophenyl)ethylidene)hydrazine‐1‐carboximidhydrazide displays methicillin‐resistant Staphyoccoccus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE) MICs of 2 μg mL−1. Herein we describe the structure‐activity relationship development of a novel series of guanidine to 2‐aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2‐NH2 pyrimidine moiety renders these analogues inactive. Introduction of a central 2‐NH2 triazine moiety saw a 10‐fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4‐BrPh and 4‐CH3Ph with MIC values of 2 and 4 μg mL−1, against MRSA and VRE respectively, are promising candidates for future development.

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

Robenidine (E)‐N′‐((E)‐1‐(4‐chlorophenyl)ethylidene)‐2‐(1‐(4‐chlorophenyl)ethylidene)hydrazine‐1‐carboximidhydrazide displays methicillin‐resistant Staphyoccoccus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE) MICs of 2 μg mL−1. Herein we describe the structure‐activity relationship development of a novel series of guanidine to 2‐aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2‐NH2 pyrimidine moiety renders these analogues inactive. Introduction of a central 2‐NH2 triazine moiety saw a 10‐fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4‐BrPh and 4‐CH3Ph with MIC values of 2 and 4 μg mL−1, against MRSA and VRE respectively, are promising candidates for future development. [ABSTRACT FROM AUTHOR]

Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small-molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy-induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34. [ABSTRACT FROM AUTHOR]

A new series of 2-amino-4-alkylamino-6-methylamino-5-nitrosopyrimidine derivatives 10- 14 have been synthesized from 5-nitrosopyrimidine analog 9 by nucleophilic aromatic substitution reaction with various amines using dimethylformamide as a solvent at 70-90 °C. Similarly, various 4-alkylamino-5-nitrosopyrimidine analogs 16- 24 were obtained from 9 and primary and secondary amines using dichloromethane at room temperature. Analogously, treatment of 9 with 2-thioglycolic acid afforded 4-thioalkyl derivative 15. Treatment of 9 with chloroacetyl chloride ( 26) gave the corresponding chloroacetamido analog 27, which afforded the desired 2-(benzothiazol-2-ylthio)- N-(4-isopropoxy-6-(methylamino)-5-nitrosopyrimidine-2-yl)acetamide ( 29) on treatment with 2-mercaptobenzothiazole ( 28) in the presence of triethylamine and dichloromethane. Condensation of 9 with butyraldehyde in acidic ethanol gave the corresponding 2-butylideneamino analog 30. Selected examples of the synthesized compounds were evaluated for their 17β-hydroxysteroid dehydrogenase type 1 and 2 (17β-HSD1 and 2) inhibitory activity. Futhermore, same compounds were evaluated for their antiproliferative activity against two solid tumour-derived cell lines consisting Hep-G2 (human hepatocarcinoma) and MCF-7 (breast cancer). [ABSTRACT FROM AUTHOR]

Anilinopyrimidines are the main chemical agents for management of Botrytis cinerea. However, the drug resistance in fungi against this kind of compounds is very serious. To explore new potential fungicides against B. cinerea, a series of 4-phenyl-6-trifluoromethyl-2-amino-pyrimidine compounds (compounds III-1 to III-22) were synthesized, and their structures were confirmed by 1H-NMR, IR and MS. Most of these compounds possessed excellent fungicidal activity. The compounds III-3 and III-13 showed higher fungicidal activity than the positive control pyrimethanil on fructose gelatin agar (FGA), and compound III-3 on potato dextrose agar (PDA) indicated high activity compared to the positive control cyprodinil. In vivo greenhouse results indicated that the activity of compounds III-3, III-8, and III-11 was significantly higher than that of the fungicide pyrimethanil. Scanning electron micrography (SEM) and transmission electron micrography (TEM) were applied to illustrate the mechanism of title compounds against B. cinerea. The title compounds, especially those containing a fluorine atom at the ortho-position on the benzene ring, could maintain the antifungal activity against B. cinerea, but their mechanism of action is different from that of cyprodinil. The present study lays a good foundation for us to find more efficient reagents against B. cinerea. [ABSTRACT FROM AUTHOR]

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM. [Display omitted] • Fifteen KHS101 analogs were designed and synthesized. • Compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101. • TACC3 was identified as a biologically relevant target of compound 7g. • 7g reduced tumor weight by 72.7% in U87 xenograft model without obvious toxicity. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) T790M mutant is found in approximately 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). Here, a series of novel aminopyrimidines bearing a hydrazone moiety were identified as potent and selective EGFR inhibitors. Compounds 14a , 15g , and 15i potently inhibited all EGFR mutants including EGFR T790M/L858R, EGFR T790M/delE746_A750, and EGFR T790M while they showed weak effects on the wild type (WT) EGFR. In addition, these compounds effectively suppressed proliferation of gefitinib-resistant H1975 (EGFR T790M/L858R) cells but were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. Therefore, 14a , 15g , and 15i might be promising candidates to overcome drug resistance mediated by the EGFR T790M mutant. [ABSTRACT FROM AUTHOR]

Therapeutics of metastatic or triple-negative breast cancer are still challenging in clinical. Herein we demonstrated the design and optimization of a series of hybrid of 2,4-diaminopyrimidine and arylthiazole derivatives for their anti-proliferative properties against two breast cancer cell lines (MCF-7 as human breast cancer and MDA-MB-231 as triple-negative breast cancer). More importantly, some of those compounds with potent antiproliferative activities also indicated excellent inhibitory activities against MDA-MB-231 cell migration. These results suggested that the new series of hybridation of aryl-thiazoles and aminopyrimidines could be identified and developed as novel highly potential anticancer agents against the triple-negative breast cancer as well as metastatic one in the future. [ABSTRACT FROM AUTHOR]

We report combined study of k- nearest neighbor, pharmacophore and 2D QSAR was performed on a series of 2,4-diaminopyrimidines dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum as antimalarial agents to gain insights into the structural determinants and their structure-activity relationship. The QSAR models for the prediction of activity of antiplasmodial activities against P. falciparum clones with wild-type TM/8.2 and KCB strains have been developed by the SA-PLS and SW-PLS methods, and the proposed models gain satisfactory results. The statistically significant best 2D QSAR model having correlation coefficient r = 0.8569, 0.7853 and cross-validated squared correlation coefficient q = 0.7104, 0.7216 with external predictive ability of pred_ r = 0.7995, 0.7064 was developed by wild-type TM/8.2 and KCB strains with SA-PLS. 3D QSAR studies using k-nearest neighbor molecular field analysis (kNN-MFA) method, identifies two models obtained by SA-PLS and SW-PLS methods leading to antimalarial activity prediction. The obtained pharmacophore model with lowest RMSD value (0.1548 Å), consisting of one hydrogen donor, two hydrogen acceptors and one aromatic region was developed. These models were found to yield reliable clues for further optimization of 2,4-diaminopyrimidines derivatives in the data set. We hope that these results will give new insights into chemical modifications that can be realized with the aim of designing new inhibitors with improved pharmacological properties. [ABSTRACT FROM AUTHOR]

A novel series of carbazole substituted aminopyrimidines ( 5a-p) were synthesized and screened for their in vitro urease inhibition and antimicrobial activity. Among the compounds, 4-(2,4-dichlorophenyl)-6-(9-methyl-9H-carbazol-3-yl)-pyrimidin-2-amine (5i) was found to be the most potent showing urease inhibitory activity with an IC50 value 19.4 ± 0.43 µM. Compounds 5c, 5g, 5j and 5o showed good activity against all selected bacterial strains and compounds 5b, 5c, 5m and 5o showed good activity against selected fungal strains. All the compounds were subjected for ADME predictions by computational method. [ABSTRACT FROM AUTHOR]

The 5,6,7,8,9,10-hexahydro-2-methylthiopyrimido[4,5- b]quinolines 4a 4b 4c 4d, 5a 5b 5c 5d and their oxidized forms 6a 6b 6c 6d, 7a 7b 7c 7d were obtained from the reaction of 6-amino-2-(methylthio)pyrimidin-4(3 H)-one 2 or 6-amino-3-methyl-2-(methylthio)pyrimidin-4(3 H)-one 3 and α, β-unsaturated ketones 1a 1b 1c 1d using BF3.OEt2 as catalyst and p-chloranil as oxidizing agent. Some of the new compounds were evaluated in the US National Cancer Institute (NCI), where compound 5a presented remarkable activity against 46 cancer cell lines, with the most important GI50 values ranging from 0.72 to 18.4 μM from in vitro assays. [ABSTRACT FROM AUTHOR]

Abstract: The relation between molecular energetics and aromaticity was investigated for the interaction between the amino functional group and the nitrogen atoms of the pyridine and pyrimidine rings, using experimental thermodynamic techniques and computational geometries, enthalpies, chemical shifts, atomic charges and the Quantum Theory of Atoms in Molecules. 2,4-diaminopyrimidine and 2,4,6-triaminopyrimidine were studied by static bomb combustion calorimetry and Knudsen effusion technique. The derived gaseous-phase enthalpies of formation together with the enthalpies of formation of the three isomers of aminopyridine reported in the literature, were compared with the calculated computationally ones and extended to other diamino- and triaminopyrimidine isomers using the MP2/6-311++G(d,p) level of theory. The results were analyzed in terms of enthalpy of interaction between substituents and, due to the absence of meaningful stereochemical hindrance, strong inductive effects, or intramolecular hydrogen bonds according to QTAIM results, the resonance electron delocalization plays an almost exclusive role in the very exothermic enthalpies obtained. Therefore, this enthalpy of interaction was used as an experimental energetic measure of resonance effects and analyzed in terms of aromaticity. It was found that more conjugation between substituents means less aromaticity according to the magnetic (NICS) and electronic (Shannon) criteria, but more aromaticity according to the geometric (HOMA) criterion. [Copyright &y& Elsevier]

The luminescent patterns of several members of the aminopyrimidine family are very different, showing not fluorescence at all, only a fluorescence band, normal or anomalous, or dual fluorescence, depending on the substituents and on the environment (gas phase vs. polar solvents). In this work, we study the lowest excited states of several members of this family that exhibit different fluorescence patterns to try to explain their photochemistry and to understand the effect of the substituents and the environment. We have found that several excited states (local excited (LE), charge transfer (CT) and n-π* states) have minima on the lowest excited potential energy surface (S), being their relative energy the determinant factor of the luminescent behavior. If the more stable S minima are of n-π* character, a non-radiative deexcitation channel is the most efficient and the system shows no fluorescence. If the CT and/or LE states are the most stable, the non-radiative deactivation channel is not accessible and the system fluoresces. The relative energies of the CT and LE minima (affected by substituents and by the presence of a polar solvent) and the different magnitude of the oscillator strength for the radiative transition to the ground state determine which emission is more efficient, giving place to normal, anomalous or dual fluorescence. The study has been carried out by CASSCF/CASPT2 computations, including the solvent effect by means of the PCM model. [ABSTRACT FROM AUTHOR]

Abstract: A series of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d]pyrimidines 9a–q were obtained by the three-component reaction between 6-aminopyrimidines 6, 7, 8, dimedone 2, and arylglyoxal 5a,b. The unexpected cyclization process was established by NMR and X-ray diffraction measurements. [Copyright &y& Elsevier]

Abstract: A new series of 6,6a,7,8-tetrahydro-5H-naphtho[1,2-e]pyrimido[4,5-b][1,4]diazepines 4a-f and 5a-f were efficiently synthesized in good yields from the reaction of E-2-arylidene-1-tetralones 1 and the respective tri- or tetraaminopyrimidines 2 or 3 under microwave irradiation using DMF as solvent and catalytic amounts of BF3·OEt2. Six of the obtained compounds were selected and tested by the National Cancer Institute (NCI-USA) against 60 different tumor cell lines. In particular, compounds 5a, 5c and 5e presented remarkable anti-tumor activity against melanoma cancer in SK-MEL-5 cell line. [Copyright &y& Elsevier]

2-Amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d]pyrimidin-4-ols were synthesized from various ethyl 2,6-diaryl-4-oxopiperidin-3-carboxylates with guanidine hydrochloride in presence of sodium ethoxide. [ABSTRACT FROM AUTHOR]

Abstract: Amino- and imino- forms of pyrimidine are widely presented as part of antibiotics, corrective medications for heart failures and metabolic stimulators. Hydrogen bonding is one of the fundamental interactions between biologically active molecules. This type of interactions provides flexibility, speed and variety of the biochemical processes. Proton donation properties of aminopyrimidines significantly depend on the position, number and kind of the substituent in its aromatic ring. In present work we studied the influence of the methoxy- and nitro-substitutions in the phenyl radical of pyridine and pyrimidine cycles on the proton donation ability of the amino group in hydrogen bonds as well as on its geometrical, force, electro-optical and thermodynamical characteristics in free and H-bonded (1:1 and 1:2, with various proton acceptors) molecules of primary aromatic amines. Acetonitrile, dioxane, tetrahydrofourane, dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide (whose proton accepting properties vary within a wide range) were used as proton acceptors in our research. In the region of the amino group stretching and deformation vibrations the IR spectra of free and H-bonded (1:1) molecules of 2-amino-4,6-dimethoxy- and 2-amino-5-nitropyrimidine were studied in complexes with proton acceptors in CCl4 within the temperature range 288–328K. The spectra of 1:2 complexes were studied in undiluted aprotic solvents. The following spectral characteristics of absorption bands in amino group stretching vibrations were determined: M (0) (zero spectral moment, integrated intensity B); M (1) (first spectral moment, band “centre of gravity”); effective half width, related to the second central moment (Δν 1/2)eff =2(M (2))1/2, frequencies of the deformation vibrations δ(HNH) of free and H-bonded molecules. It was shown that changes of the absorption band spectral characteristics of the amino group stretching and deformation vibrations in the analyzed temperature interval are actually linear. Linear regression parameters Y = aT + b (where Y = M (0), M (1), 2(M (2))1/2) of free and H-bonded (1:1, with proton acceptors) molecules of 2-aminopyrimidines were determined. Vibrational and electro-optic tasks were solved for free and H-bonded molecules. Valence angles γ(HNH), force constants K(NH), electrooptic parameters ∂μ/∂q NH and were determined. Comparative analysis of the influence of methoxy- and nitro-substitution on the amino group spectral characteristics of aniline, 2-aminopyridine and 2-aminopyrimidine in CCl4 was performed. It was shown that effect of hetero substitution and external substituents in the aromatic ring on spectral characteristics is not additive. Linear correlations were established between spectral, geometrical, force and electro-optical characteristics of the amino group in free and H-bonded (1:1 and 1:2) molecules of substituted 2-aminopyrimidines. Some of these correlations are universal, while most of them are sensitive to the kind, position and number of the substituents in the aromatic ring. During association of 2-aminopyrimidines with dioxane and tetrahydrofourane (1:1 complexes) the charge transfer through the hydrogen bond reveals quite considerable influence on complex formation. The temperature dependence of monomer–complex (1:1) equilibrium constants was studied and following thermodynamical characteristics were determined (using Vant-Hoff equation): enthalpy −ΔH 1 and entropy ΔS 1. Enthalpy −ΔH 2 of 1:2 complexes was determined using the empirical “Intensity rule”. It was shown that H-bond strength in 1:1 complexes is higher than in 1:2 complexes. This is also confirmed by the independent calculations of force constants K(NH) in complexes of different composition. The qualitative agreement was stated between experimental results and quantum-mechanical calculations (DFT-B3LYP/6-31G(d,p)) of the amino group spectral characteristics, valence angles γ(HNH) and force constants K(NH). The tendency in changes of values mentioned above is correctly reflected by quantum-mechanical calculations, depending on kind, position and number of substituents in pyrimidine cycle, so the results of these calculations can be used in research of free molecules and systems with hydrogen bonds. [Copyright &y& Elsevier]

A facile synthetic approach to 2-amino-5-halogen-pyrimidine-4-carboxylic acids from 5-halogen-2-methylsulfonylpyrimidine-4-carboxylic acid by nucleophilic displacement of the methylsulfonyl group with primary and secondary aliphatic amines has been developed. The titled amino acids underwent decarboxylation, yielding 2-amino-5-halogenpyrimidines. Starting from 2-amino-5-chloropyrimidine-4-carboxylic acid chlorides, 2-[5-chloro-2-(amino)-4-pyrimidinyl]-2-oxo-1-(2-pyridyl)-ethyl cyanides were obtained in excellent yields. [ABSTRACT FROM AUTHOR]

Abstract: The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. [Copyright &y& Elsevier]

An unusual direction has been found for the interaction of alkyl 5, 6-dialkyl-2-amino-3-cyanopyridine-4-carboxylates with primary amines leading to the formation of 2,6, 7-trialkyl-4-amino-2, 3-dihydro-1H- pyrrolo[3, 4-c]pyridine- 1, 3-diones. [ABSTRACT FROM AUTHOR]

Condensation of 4-bromobenzaldehyde, urea, and 4-alkyl-substituted acetophenones gave substituted hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-diones or 1H-pyrimidin-2-ones, depending on the substituent on the acetophenone ring and the nature of the solvent (i-PrOH, BuOH, AcOH). The corresponding 5-bromopyrimidin-2-ones were formed on bromination of these compounds. The structures of these compounds were confirmed by IR, UV, and 1H NMR spectroscopy. [ABSTRACT FROM AUTHOR]

The spectra of free and H-bonded (1:1 and 1:2) molecules of aminopyrimidines with CH3CN, THF, dioxane, DMF, DMSO, and HMPA were studied in the area of stretching and bending vibrations of amino group. The spectral moments of absorption bands M(0), M(1), M(2) and ‘effective’ half-width (Δν1/2)eff=2(M(2))1/2 were determined.The temperature dependence of spectral moments was studied in the range of 290–330 K. Equilibrium constants K298 and enthalpy–ΔH1 of 1:1 complexes of 2- and 4-aminopyrimidines with DMF, DMSO and HMPA were determined.Valence angles γ(HNH), force constants K(NH), electro optical parameters ∂μ/∂qNH and ∂μ/∂q′NH were calculated within R-NH2 model of valence force field for free and H-bonded molecules of aminopyrimidines. The distribution of electron density on C–NH2 moiety and dipole moments μe of aminopyridines were estimated using semi-empirical AM1, PM3 and DFT-B3LYP/6-31G**, ab initio MP2/6-31G** quantum mechanical methods.The comparative analysis stated the influence of heteroatom position and number in the aromatic ring on spectral, geometric, force and energetic characteristics of free and H-bonded molecules in the row of compounds: Aniline, aminopyridines, aminopyrimidines.Correlations between spectral and structural, electrooptic and force characteristics of amino group in aminopyrimidines were established. It was stated that position and number of hetero atoms in the aromatic ring profoundly influence parameters and proton donor ability of amino group in intermolecular H-bonded complexes. However, the parameters of the correlation function change slightly upon the second nitrogen introduction into aromatic ring.Temperature sensitivity of spectral moments M(0) (integrated intensity) and M(1) (center gravity position) of aminopyrimidines compared to aminopyridines shows a great increase. [Copyright &y& Elsevier]

Nitrogen-containing derivatives of 5-nitro-4,6-diphenylpyrimidine have been synthesized by the reaction of 2-chloro-5-nitro-4,6-diphenylpyrimidine with amines or of 2-hydrazino-5-nitro-4,6-diphenylpyrimidine with carbonyl or β-dicarbonyl compounds. Their structures were confirmed by data of IR spectroscopy and mass spectrometry. [ABSTRACT FROM AUTHOR]

We have synthesized imidazo[1,2- a]pyrimidine derivatives by reaction of 2-aminopyrimidines with methyl aryl ketones and halogens (bromine, iodine). Using bromine leads to formation of 6-bromo- and 3,6-dibromo-substituted 2-arylimidazo[1,2- a]pyrimidines. [ABSTRACT FROM AUTHOR]

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically. [ABSTRACT FROM AUTHOR]

The pyrimidine scaffold represents one of the privileged structures in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. The review compiles the strategies and methods of development of aminopyrimidine derivatives. The advances in organic and heterocyclic chemistry are considered in the targeted synthesis of aminopyrimidine derivatives whose series contains the most demanded and efficient antitumor pharmaceuticals. Optimization of synthetic protocols of cyclocondensation reaction and implement multicomponent reactions have been performed to obtain desired aminopyrimidines. In addition, this review aims to be a comprehensive and general summary of numerous aminopyrimidines, their use as medicinal agents and their main anticancer activities. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: A new, safe, and efficient methodology for the thiocyanation of some aminopyrimidine derivatives has been implemented. The thiocyanation reactions proceeded at room temperature with high yields and selectivity. This route is a less toxic alternative to other common thiocyanation techniques because it uses molecular iodine as a halogen source, which is less reactive and easier to handle than chlorine or bromine. [Copyright &y& Elsevier]

Abstract: Synthesis and biological evaluation of some 5-ethoxycarbonyl-6-isopropylamino-4-(substitutedphenyl)aminopyrimidines have been achieved by cyclization of N-[2-ethoxycarbonyl-2-cyano-1-(isopropylamino)vinyl] formamidine in presence of dry HCl in dioxane followed by nucleophilic substitution of 4-chloro group with substituted aromatic amine or phenoxide. Target compounds were evaluated for their analgesic and anti-inflammatory potential by known experimental models. Some of the compounds emerged out as more potent than standard drugs. Very low ulcer index was observed for the potent compounds. [Copyright &y& Elsevier]

Anilinopyrimidines are the main chemical agents for management of Botrytis cinerea. However, the drug resistance in fungi against this kind of compounds is very serious. To explore new potential fungicides against B. cinerea, a series of 4-phenyl-6-trifluoromethyl-2-amino-pyrimidine compounds (compounds III-1 to III-22) were synthesized, and their structures were confirmed by ¹H-NMR, IR and MS. Most of these compounds possessed excellent fungicidal activity. The compounds III-3 and III-13 showed higher fungicidal activity than the positive control pyrimethanil on fructose gelatin agar (FGA), and compound III-3 on potato dextrose agar (PDA) indicated high activity compared to the positive control cyprodinil. In vivo greenhouse results indicated that the activity of compounds III-3, III-8, and III-11 was significantly higher than that of the fungicide pyrimethanil. Scanning electron micrography (SEM) and transmission electron micrography (TEM) were applied to illustrate the mechanism of title compounds against B. cinerea. The title compounds, especially those containing a fluorine atom at the ortho-position on the benzene ring, could maintain the antifungal activity against B. cinerea, but their mechanism of action is different from that of cyprodinil. The present study lays a good foundation for us to find more efficient reagents against B. cinerea.