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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]

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]

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]

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]

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]

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]

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]

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]