ABSTRACT
A concise and versatile synthesis of 5-(arylmethylideneamino)-4-(1H-benzo[d]imidazol-1-yl)pyrimidines has been developed, starting from 4-(1H-benzo[d]imidazol-1-yl)pyrimidines, and we report here the synthesis and spectroscopic and structural characterization of three such products, along with those of two intermediates in the reaction pathway. The intermediates 4-[2-(4-chlorophenyl)-1H-benzo[d]imidazol-1-yl]-6-methoxypyrimidine-2,5-diamine, (II), and 4-[2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl]-6-methoxypyrimidine-2,5-diamine, (III), crystallize as the isostructural monohydrates C18H15ClN5O·H2O and C18H15BrN5O·H2O, respectively, in which the components are linked into complex sheets by O-H...N and N-H...O hydrogen bonds. In the product (E)-4-methoxy-5-[(4-nitrobenzylidene)amino]-6-[2-(4-nitrophenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-amine, which crystallizes as a 1:1 solvate with dimethyl sulfoxide, C25H18N8O5·C2H6OS, (IV), inversion-related pairs of the pyrimidine component are linked by N-H...N hydrogen bonds to form cyclic centrosymmetric R22(8) dimers to which pairs of solvent molecules are linked by N-H...O hydrogen bonds. (E)-4-Methoxy-5-[(4-methylbenzylidene)amino]-6-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-amine, C27H24N6O, (V), crystallizes with Z' = 2 and the molecules are linked into a three-dimensional framework structure by a combination of N-H...N, C-H...N and C-H...π(arene) hydrogen bonds. The analogous product (E)-4-methoxy-5-[(4-chlorobenzylidene)amino]-6-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-amine, C26H21ClN6O, (VI), crystallizes from dimethyl sulfoxide in two forms: one, denoted (VIa), is isostructural with (V), and the other, denoted (VIb), crystallizes with Z' = 1, but as an unknown solvate in which the pyrimidine molecules are linked by N-H...N hydrogen bonds to form a ribbon containing two types of centrosymmetric ring.
ABSTRACT
A concise and efficient synthesis of a series of amino-substituted benzimidazole-pyrimidine hybrids has been developed, starting from the readily available N4-(2-aminophenyl)-6-methoxy-5-nitrosopyrimidine-2,4-diamine. In each of N5-benzyl-6-methoxy-4-(2-phenyl-1H-benzo[d]imidazol-1-yl)pyrimidine-2,5-diamine, C25H22N6O, (I), 6-methoxy-N5-(4-methoxybenzyl)-4-[2-(4-methoxyphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidine-2,5-diamine, C27H26N6O3, (III), 6-methoxy-N5-(4-nitrobenzyl)-4-[2-(4-nitrophenyl)-1H-benzo[d]imidazol-1-yl]pyrimidine-2,5-diamine, C25H20N8O5, (IV), the molecules are linked into three-dimensional framework structures, using different combinations of N-H...N, N-H...O, C-H...O, C-H...N and C-H...π hydrogen bonds in each case. Oxidative cleavage of 6-methoxy-N5-(4-methylbenzyl)-4-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidine-2,5-diamine, (II), with diiodine gave 6-methoxy-4-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidine-2,5-diamine, which crystallized as a monohydrate, C19H18N6O·H2O, (V), and reaction of (V) with trifluoroacetic acid gave two isomeric products, namely N-{5-amino-6-methoxy-6-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-yl}-2,2,2-trifluoroacetamide, which crystallized as an ethyl acetate monosolvate, C21H17F3N6O2·C4H8O2, (VI), and N-{2-amino-6-methoxy-4-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-5-yl}-2,2,2-trifluoroacetamide, which crystallized as a methanol monosolvate, C21H17F3N6O2·CH4O, (VIIa). For each of (V), (VI) and (VIIa), the supramolecular assembly is two-dimensional, based on different combinations of O-H...N, N-H...O, N-H...N, C-H...O and C-H...π hydrogen bonds in each case. Comparisons are made with some related structures.
ABSTRACT
We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modeling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1. The QTAIM study has allowed us to obtain an excellent correlation between the electronic densities and the experimental data of IC50. Also, using combined techniques (MD simulations and QTAIM calculations) enabled us to describe in detail the molecular interactions that stabilize the different L-R complexes. In addition, our results allowed us to determine what portion of these compounds should be changed in order to increase their affinity with the BACE1. Another interesting result is that a sort of synergism was observed when the effects of these new catalytic site inhibitors were combined with Ac-Tyr5-Pro6-Tyr7-Asp8-Ile9-Pro10-Leu11-NH2, which we have recently reported as a modulator of BACE1 acting on its exosite.
Subject(s)
Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/chemistry , Pyrimidines/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Binding Sites , Biological Assay , Catalytic Domain , Drug Design , Humans , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Quantitative Structure-Activity RelationshipABSTRACT
A concise and efficient synthesis of 6-benzimidazolyl-5-nitrosopyrimidines has been developed using Schiff base-type intermediates derived from N4-(2-aminophenyl)-6-methoxy-5-nitrosopyrimidine-2,4-diamine. 6-Methoxy-N4-{2-[(4-methylbenzylidene)amino]phenyl}-5-nitrosopyrimidine-2,4-diamine, (I), and N4-{2-[(ethoxymethylidene)amino]phenyl}-6-methoxy-5-nitrosopyrimidine-2,4-diamine, (III), both crystallize from dimethyl sulfoxide solution as the 1:1 solvates C19H18N6O2·C2H6OS, (Ia), and C14H16N6O3·C2H6OS, (IIIa), respectively. The interatomic distances in these intermediates indicate significant electronic polarization within the substituted pyrimidine system. In each of (Ia) and (IIIa), intermolecular N-H...O hydrogen bonds generate centrosymmetric four-molecule aggregates. Oxidative ring closure of intermediate (I), effected using ammonium hexanitratocerate(IV), produced 4-methoxy-6-[2-(4-methylphenyl-1H-benzimidazol-1-yl]-5-nitrosopyrimidin-2-amine, C19H16N6O2, (II) [Cobo et al. (2018). Private communication (CCDC 1830889). CCDC, Cambridge, England], where the extent of electronic polarization is much less than in (Ia) and (IIIa). A combination of N-H...N and C-H...O hydrogen bonds links the molecules of (II) into complex sheets.
ABSTRACT
A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.
Subject(s)
Folic Acid Antagonists/pharmacology , Molecular Dynamics Simulation , Quantum Theory , Tetrahydrofolate Dehydrogenase/metabolism , Electrons , Humans , Protein Conformation , Reproducibility of Results , Tetrahydrofolate Dehydrogenase/chemistry , ThermodynamicsABSTRACT
The molecules of 3-amino-4-anilino-1H-isochromen-1-one, C15H12N2O2, (I), and 3-amino-4-[methyl(phenyl)amino]-1H-isochromen-1-one, C16H14N2O2, (II), adopt very similar conformations, with the substituted amino group PhNR, where R = H in (I) and R = Me in (II), almost orthogonal to the adjacent heterocyclic ring. The molecules of (I) are linked into cyclic centrosymmetric dimers by pairs of N-H···O hydrogen bonds, while those of (II) are linked into complex sheets by a combination of one three-centre N-H···(O)2 hydrogen bond, one two-centre C-H···O hydrogen bond and two C-H···π(arene) hydrogen bonds.
Subject(s)
Acetic Acid/chemistry , Aniline Compounds/chemistry , Benzoic Acid/chemistry , Isocoumarins/chemistry , Crystallography, X-Ray , Dimerization , Hydrogen Bonding , Methanol/chemistry , Molecular StructureABSTRACT
En este trabajo se describen tanto la síntesis como la caracterización de E,E-1,4-dimetoxi-2,5-bis[2-(4-nitrofenil)etenil] benceno, mediante la reacción de acoplamiento cruzado de Heck usando trifenil-fosfito como ligante, lo cual -y teniendo en cuenta la literatura científica consultada- es el primer reporte de un doble acoplamiento de Heck empleando fosfitos como ligante en la formación del complejo catalítico con paladio. La caracterización del sistema fenilvinilideno obtenido muestra que el mecanismo es altamente estereoselectivo hacia la formación de enlaces trans, y su altísimo rendimiento (98%) indica que el sistema catalítico es bastante promisorio para realizar multiacoplamientos cruzados necesarios para obtener polímeros fenilvinilideno con altos pesos moleculares y altas eficiencias en las propiedades optoelectrónicas, necesarios para la tecnología de la electrónica de polímeros.
The synthesis and characterization of E,E-1,4-dimethoxy-2,5-bis[2-(4-nitrop-henyl)ethenyl]benzene by cross coupling Heck reaction using phosphites as ligands is described. This, to the best of our knowledge, is the first report involving a double Heck coupling using phosphites as ligand in the palladium catalyst formation. The characterization for the phenylenevinylene system obtained showed that the mechanism is highly stereoselective towards trans bond formation and its quantitative yield showed that this catalytic system is very promising for the multicoupling needed to obtain phenylenevinylene polymers with high molecular weights and high efficiency optoelectronic properties, in order to be used in polymer electronic technologies.
Neste trabalho descreve-se a síntese e caracterização de E,E-1,4-dimetoxi-2,5-bis [2-(4-nitrofenil)etenil]benceno, mediante a reação de acoplamentos cruzado ao Heck com trifenilfosfito como ligante. O qual, e tendo em conta a literatura científica pesquisada, é o primeiro reporte de um duplo acoplamento de Heck empregando fosfitos como ligante na formação do complexo catalítico com paladio. A caracterização do sistema fenilvinilideno obtido mostra que o mecanismo é altamente estereoselectivo para a formação de enlaces trans e que o sistema catalítico é bastante promisorio para fazer os acoplamentos cruzados necessários para obter polímeros de fenilvinilideno com alta massa molecular e altas eficiências nas propriedades optoelectronicas, necessários para a tecnologia da eletrônica de polímeros.
ABSTRACT
Molecules of the title compound, C(16)H(13)N(5)O(2), have no internal symmetry despite the symmetric pattern of substitution in the pyrimidine ring. The intramolecular distances indicate polarization of the electronic structure. There are two intramolecular N-H...O hydrogen bonds and molecules are linked into centrosymmetric dimers by pairs of three-centre C-H...(O)(2) hydrogen bonds. These dimers are linked into chains by means of a pi-pi stacking interaction.
Subject(s)
Diamines/chemistry , Pyrimidines/chemistry , Crystallography, X-Ray , Dimerization , Hydrogen Bonding , Microscopy, Polarization , Models, MolecularABSTRACT
The pyrimidinone ring in the title compound, C(12)H(13)N(5)O(3), is effectively planar, despite the presence of five substituents. The bond distances provide evidence for significant polarization of the electronic structure, with charge separation, and the molecules are linked into sheets by a combination of N-H...O and N-H...pi(arene) hydrogen bonds. Comparisons are made with the molecular and supramolecular structures of the precursor compound 2-amino-6-[methyl(phenyl)amino]-5-nitropyrimidin-4(3H)-one.
Subject(s)
Crystallography, X-Ray , Pyrimidinones/chemistry , Dimerization , Hydrogen Bonding , Models, Molecular , StereoisomerismABSTRACT
The title solvates, (I) and (II), both C(18)H(16)N(6)O(3).C(2)H(6)OS, are isomeric. The conformations adopted by the 6-substituent are significantly different, with the 6-aminophenyl unit remote from the nitrophenyl ring in methoxypyrimidine (I) but adjacent to it in pyrimidinone (II). Pairs of pyrimidine molecules in (I) are linked by N-H...N hydrogen bonds to form cyclic centrosymmetric dimers from which the dimethyl sulfoxide molecules are pendent, while in (II) a combination of three independent N-H...O hydrogen bonds links the components into a chain containing both R(2)(2)(8) and R(4)(2)(8) rings, in which the dimethyl sulfoxide component acts as a double acceptor of hydrogen bonds. The significance of this study lies in its observation of different conformations for the pyrimidine components in (I) and (II), and different hydrogen-bonded structures, apparently dominated by the different roles adopted by the dimethyl sulfoxide components.
Subject(s)
Dimethyl Sulfoxide/chemistry , Pyrimidines/chemistry , Hydrogen Bonding , Molecular StructureABSTRACT
2-Amino-4-methoxy-6-phenyl-11H-pyrimido[4,5-b][1,4]benzodiazepine, C(18)H(15)N(5)O, (I), and its 6-(2-fluorophenyl)-, 6-(3-nitrophenyl)- and 6-(4-methoxyphenyl)- analogues, viz. C(18)H(14)FN(5)O, (II), C(18)H(14)N(6)O(3), (III), and C(19)H(17)N(5)O(2), (IV), respectively, all adopt molecular conformations which are almost identical, containing boat-shaped seven-membered rings. In each structure, paired N-H...N hydrogen bonds link the molecules into centrosymmetric dimers. In each of (I)-(III), the dimers are further linked, forming a different three-dimensional framework in each case, while in compound (IV) the dimers are linked into sheets. The significance of this study lies in the observation of different crystal structures in four compounds whose molecular structures are very similar.
Subject(s)
Benzodiazepines/chemistry , Crystallography , Molecular StructureABSTRACT
Molecules of the title compound, C(12)H(13)ClN(4), are linked by two independent N-H...N hydrogen bonds into a chain of edge-fused R(2)(2)(8) rings. The significance of this study lies in its attempt to rationalize the patterns of supramolecular aggregation in the title compound and in a range of analogous 4,6-disubstituted 2-aminopyrimidines.
ABSTRACT
The molecules of the title compound, C(14)H(11)N(3)O(4), have approximate but noncrystallographic twofold rotational symmetry. The molecules are linked into chains by a C-H...O hydrogen bond, and these chains are linked into sheets by a pi-pi stacking interaction. The significance of this study lies in its comparison of the modes of supramolecular aggregation in the title compound and those in some close analogues.
ABSTRACT
The molecular dimensions of both 2-amino-6-(N-methylanilino)pyrimidin-4(3H)-one, C11H12N4O, (I), and 2-amino-6-(N-methylanilino)-5-nitropyrimidin-4(3H)-one, C11H11N5O3, (II), are consistent with considerable polarization of the molecular-electronic structures. The molecules of (I) are linked into a three-dimensional framework by a combination of one N-H...N hydrogen bond, two independent N-H...O hydrogen bonds and one C-H...pi(arene) hydrogen bond. The molecules of (II) are linked into ribbons containing three types of edge-fused ring by the combination of two independent three-centre N-H...(O)2 hydrogen bonds.
Subject(s)
Aniline Compounds/chemistry , Benzodiazepines/chemistry , Pyrimidinones/chemistry , Aniline Compounds/chemical synthesis , Anti-Anxiety Agents/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular Structure , Pyrimidinones/chemical synthesisABSTRACT
In the title compound, C(10)H(19)NO(6), both rings adopt almost perfect chair conformations and their mutual orientation is influenced by an intramolecular O-H...N hydrogen bond. The molecules are linked by three independent O-H...O hydrogen bonds into sheets containing equal numbers of R2(2)(10) and R4(4)(24) rings.
