Design, synthesis and biological evaluation of (E)-2-(2-arylhydrazinyl)quinoxalines, a promising and potent new class of anticancer agents.

A series of forty-seven quinoxaline derivatives, 2-(XYZC6H2CHN-NH)-quinoxalines, 1, have been synthesized and evaluated for their activity against four cancer cell lines: potent cytotoxicities were found (IC50 ranging from 0.316 to 15.749 µM). The structure-activity relationship (SAR) analysis indicated that the number, the positions and the type of substituents attached to the aromatic ring are critical for biological activity. The activities do not depend on the electronic effects of the substituents nor on the lypophilicities of the molecules. A common feature of active compounds is an ortho-hydroxy group in the phenyl ring. A potential role of these ortho-hydroxy derivatives is as N,N,O-tridentate ligands complexing with a vital metal, such as iron, and thereby preventing proliferation of cells. The most active compound was (1: X,Y=2,3-(OH)2, Z=H), which displayed a potent cytotoxicity comparable to that of the reference drug doxorubicin.

Experimental support for the role of dispersion forces in aromatic interactions.

Herein a core scaffold of 1-phenylnaphthalenes and 1,8-diphenylnaphthalenes with different substituents on the phenyl rings was used to study substituent effects on parallel-displaced aromatic π⋅⋅⋅π interactions. The energetics of the interaction was evaluated in gas phase based on the standard molar enthalpies of formation, at T=298.15 K, for the compounds studied; these values were derived from the combination of the results obtained by combustion calorimetry and Knudsen/Quartz crystal effusion. A homodesmotic gas-phase reaction scheme was used to quantify and compare the intramolecular interaction enthalpies in various substituted 1,8-diphenylnaphthalenes. The application of this methodology allowed a direct evaluation of aromatic interactions, and showed that substituent effects on the interaction enthalpy cannot be rationalized solely on classical electrostatic grounds, because no correlation with the σ(meta) or σ(para) Hammett constants was observed. Moreover, the results obtained indicate that aromatic π⋅⋅⋅π interactions are significantly enhanced by substitution, in a way that correlates with the ability of the interacting aryl rings to establish dispersive interactions. A combined experimental and computational approach for calculation of the true aromatic π⋅⋅⋅π interaction energies in these systems, free of secondary effects, was employed, and corroborates the rationale derived from the experimental results. These findings clearly emphasize the role of dispersion and dilute the importance of electrostatic forces on this type of interactions.

Elucidating the role of aromatic interactions in rotational barriers involving aromatic systems.

The measurement of aryl-naphthyl rotational barriers, ΔG(⧧), in various solvents for two substituted 1,8-diarylnaphthalenes by dynamic (1)H NMR showed that ΔG(‡) trends in aromatic systems can be fully rationalized only when considering the different types of aromatic interactions that can be established in the ground and transition states, namely, intramolecular interactions involving the aromatic rings and specific solvation interactions.

Structural and thermodynamic characterization of polyphenylbenzenes.

The thermodynamic and structural study of a series of polyphenylbenzenes, from benzene, n(Ph) = 0, to hexaphenylbenzene, n(Ph) = 6, is presented. The available literature data for this group of compounds was extended by the determination of the relevant thermodynamic properties for 1,2,4-triphenylbenzene, 1,2,4,5-tetraphenylbenzene, and hexaphenylbenzene, as well as structural determination by X-ray crystallography for some of the studied compounds. Gas phase energetics in this class of compounds was analyzed from the derived standard molar enthalpies of formation in the gaseous phase. The torsional profiles relative to the phenyl-phenyl hindered rotations in some selected polyphenylbenzenes, as well as the gas phase structures and energetics, were derived from quantum chemical calculations. In the ideal gas phase, a significant enthalpic destabilization was observed in hexaphenylbenzene relative to the other polyphenylbenzenes, due to steric crowding between the six phenyl substituents. A relatively low enthalpy of sublimation was observed for hexaphenylbenzene, in agreement with the decreased surface area able to establish intermolecular interactions. The apparently anomalous low entropy of sublimation observed for hexaphenylbenzene is explained by its high molecular symmetry and the six highly hindered phenyl internal rotations. For the series of polyphenylbenzenes considered, it was shown that the differentiation in the entropy of sublimation can be chiefly ascribed to the torsional freedom of the phenyl substituents in the gas phase and the entropy terms related with molecular symmetry.

Synthesis, Antitrypanosomal and Antimycobacterial Activities of Coumarin N-acylhydrazonic Derivatives.

BACKGROUND: Near to 5-7 million people are infected with T. cruzi in the world, and about 10,000 people per year die of problems associated with this disease. METHODS: Herein, the synthesis, antitrypanosomal and antimycobacterial activities of seventeen coumarinic N-acylhydrazonic derivatives have been reported. RESULTS: These compounds were synthesized using methodology with reactions global yields ranging from 46%-70%. T. cruzi in vitro effects were evaluated against trypomastigote and amastigote, forming M. tuberculosis activity towards H37Rv sensitive strain and resistant strains. DISCUSSION: Against T. cruzi, the more active compounds revealed only moderate activity IC50/96h~20 µM for both trypomastigotes and amastigotes intracellular forms. (E)-2-oxo-N'- (3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide showed meaningful activity in INH resistant/RIP resistant strain. CONCLUSION: These compound acting as multitarget could be good leads for the development of new trypanocidal and bactericidal agents.

The role of aromatic interactions in the structure and energetics of benzyl ketones.

A qualitative and quantitative energetic and structural study of dibenzyl ketone (DBK) and benzyl ethyl ketone (BEK) was carried out in order to obtain insights into the type and magnitude of aromatic interactions that these systems present in their different phases. The crystal structure of DBK was obtained by X-ray crystallography, and it shows that the conformation adopted in the crystalline state is governed by the intermolecular interactions. The standard (p(0) = 10(5) Pa) molar enthalpy of formation in the gaseous state at T = 298.15 K was derived by Calvet and combustion calorimetry. Using a homodesmic reaction scheme, the first calorimetric evaluation of the interaction enthalpy between two stacked phenyl rings is presented. A stabilizing enthalpic effect of (12.9 ± 4.9) kJ mol(-1) associated with the intramolecular π-π interaction in DBK was found. The gas phase intramolecular ππ interaction in DBK is in agreement with quantum chemical calculations at B3LYP/6-311++G(d,p) and MP2 with various basis-sets. An intramolecular ππ interaction in DBK and a weak C-Hπ interaction in BEK were found by variable-temperature (1)H-NMR spectroscopy in MeOD. These observations are consistent with a hindered rotor interpretation, supported by ab initio calculations for the gas phase at the MP2/cc-pVDZ level. The global results indicate a distinct molecular structure on going from crystalline DBK to liquid, gas, and solution phases, ruled by the overall contribution of the intra- and intermolecular interactions.

Energetic and structural study of diphenylpyridine isomers.

The energetic and structural study of three diphenylpyridine isomers is presented in detail. The three isomers, 2,6-, 2,5-, and 3,5-diphenylpyridines, were synthesized via Suzuki-Miyaura methodology based on palladium catalysis, and the crystal structures of the isomers were obtained by X-ray diffraction. The relative energetic stabilities in the condensed and gaseous phases as well as volatilities and structures of the three studied isomers were evaluated, regarding the position of the phenyl groups relative to the nitrogen atom of the pyridine ring. The temperature, standard molar enthalpies, and entropies of fusion were measured and derived by differential scanning calorimetry. The vapor pressures of the considered isomers were determined by a static apparatus based on a MKS capacitance diaphragm manometer. The standard molar enthalpies, entropies, and Gibbs energies of sublimation, at T = 298.15 K, were derived, and the phase diagram near the triple point coordinates were determined for all isomers. The standard (p(o) = 0.1 MPa) molar enthalpies of combustion of all crystalline isomers were determined, at T = 298.15 K, by static bomb combustion calorimetry. The standard molar enthalpies of formation, in the crystalline and gaseous phases, at T = 298.15 K, were derived. The experimental results for the energetics in the gaseous phase of the three compounds were compared and assessed with the values obtained by ab initio calculations at different levels of theory (DFT and MP2) showing that, at this level of theory, the computational methods underestimate the energetic stability, in the gaseous phase, for these molecules. In order to understand the aromaticity in the central ring of each isomer, calculations of NICS (B3LYP/6-311G++(d,p) level of theory) values on the pyridine ring were also performed.

N6-substituted 2-amino-4-chloro-5-formylpyrimidines: puckered versus planar pyrimidine rings, and hydrogen-bonded aggregation in zero, one, two and three dimensions.

The structures of 12 new N(6)-substituted 2-amino-4-chloro-5-formylpyrimidines, where the N(6) substituent is of the type NHR or NR(1)R(2), have been determined. The intramolecular dimensions provide strong evidence for the development of polarized, charge-separated molecular-electronic structures, with the positive charge delocalized over the two exocyclic amino N atoms and with negative charge on the formyl O atom. This polarization appears to be independent of the significant puckering, in seven of the compounds, of the pyrimidine rings from planarity towards boat, twist-boat or screw-boat conformations. In 11 of the compounds studied here, N-H...N hydrogen bonds link pairs of molecules into centrosymmetric R2(2)(8) dimer units, and their overall crystal structures are determined by the patterns of hydrogen bonds by which these units are further linked. Examples are reported in which no further hydrogen bonding occurs; in which the R2(2)(8) dimers are linked into chains of rings, or into sheets; and in which sheets are formed by the pi-stacking of hydrogen-bonded chains of rings. In the sole structure lacking the R2(2)(8) dimer motif, N-H...O and N-H...N hydrogen bonds cooperate to generate a three-dimensional framework structure.

Anhydrous versus hydrated N4-substituted 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamines: hydrogen bonding in two and three dimensions.

Ten new N(4)-substituted 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamines have been synthesized and the structures of nine of them are reported here, falling into two clear groups, those which are stoichiometric hydrates and those which crystallize in solvent-free forms. In each of N(4)-methyl-N(4)-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, C(12)H(12)N(6) (I), N(4)-cyclohexyl-N(4)-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, C(12)H(18)N(6) (II), and N(4)-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, C(11)H(9)ClN(6) (III), the molecules are linked into hydrogen-bonded sheets. The molecules of 2-{4-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl}ethanol, C(11)H(17)N(7)O (IV), are linked into a three-dimensional framework, while the structure of N(4)-methyl-N(4)-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine monohydrate, C(13)H(14)N(6) x H(2)O (V), is only two-dimensional despite the presence of five independent hydrogen bonds. The stoichiometric hemihydrates N(4)-ethyl-N(4)-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine hemihydrate, C(13)H(14)N(6) x 0.5 H(2)O (VI) and N(4)-(4-methoxyphenyl)-N(4)-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine hemihydrate, C(13)H(14)N(6)O x 0.5 H(2)O (VII), exhibit remarkably similar sheet structures, despite different space groups and Z' values, Z' = 0.5 in C2/c for (VI) and Z' = 1 in P1 for (VII). N(4)-4-Benzyl-N(4)-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine monohydrate, C(18)H(16)N(6) x H(2)O (VIII), crystallizes with Z' = 2 in P2(1)/n, and the four independent molecular components are linked into sheets by a total of 11 intermolecular hydrogen bonds. The sheet structure in {4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine} ethanol hemisolvate hemihydrate, C(9)H(12)N(6).0.5C(2)H(6)O x 0.5 H(2)O (IX), is built from the pyrimidine and water components only; it contains eight independent hydrogen bonds, and it very closely mimics the sheets in (VI) and (VII); the ethanol molecules are pendent from these sheets. The N(4)-alkyl-N(4)-aryl-4-aminopyrazolopyrimidine molecules in (I), (V)-(VIII) all adopt very similar conformations, dominated in each case by an intramolecular C-H...pi(arene) hydrogen bond: this interaction is absent from (III) where the molecular conformation is entirely different and probably dominated by the intermolecular hydrogen bonds.

Ethyl 2-methoxy-6-[(triphenylphosphoranylidene)amino]nicotinate and ethyl 2-methylsulfanyl-6-[(triphenylphosphoranylidene)amino]nicotinate.

The molecules of ethyl 2-methoxy-6-[(triphenylphosphoranylidene)amino]nicotinate, C(27)H(25)N(2)O(3)P, (I), and ethyl 2-methylsulfanyl-6-[(triphenylphosphoranylidene)amino]nicotinate, C(27)H(25)N(2)O(2)PS, (II), have almost identical bond lengths and molecular conformations, and both show evidence for polarized electronic structures. However, the crystal structures, as illustrated by the weak hydrogen bonds linking the molecules, are significantly different. The significance of this study lies in the observation that two compounds which are almost identical in constitution, configuration and conformation nonetheless adopt different crystal structures.

Dimethyl 6-[1,2-bis(methoxycarbonyl)-2-(triphenyl-lambda5-phosphanylidene)ethylideneamino]-2-methylsulfanyl-3,4-pyridinedicarboxylate forms a chain of hydrogen-bonded rings.

In the title compound, C(34)H(31)N(2)O(8)PS, the intramolecular distances provide evidence for polarization of the molecular-electronic structure. The molecules are linked into complex chains of rings by three independent C-H...O hydrogen bonds. The significance of this study lies in its finding that two of the four carbonyl O atoms play no role in the hydrogen bonding, despite the large excess of potential hydrogen-bond donors present.

A hydrogen-bonded chain of rings in 5-amino-1-(4-methoxybenzoyl)-3-methylpyrazole and a three-dimensional hydrogen-bonded framework in 5-amino-3-methyl-1-(2-nitrobenzoyl)pyrazole.

The molecules of 5-amino-1-(4-methoxybenzoyl)-3-methylpyrazole, C(12)H(13)N(3)O(2), (I), and 5-amino-3-methyl-1-(2-nitrobenzoyl)pyrazole, C(11)H(10)N(4)O(3), (II), both contain intramolecular N-H...O hydrogen bonds. The molecules of (I) are linked into a chain of rings by a combination of N-H...N and N-H...pi(arene) hydrogen bonds, while those of (II) are linked into a three-dimensional framework structure by N-H...N and C-H...O hydrogen bonds.

Three 4,7-diaryl-2-ethylsulfanylpyrazolo[1,5-a][1,3,5]triazines.

The molecular dimensions of 2-ethylsulfanyl-7-(4-methylphenyl)-4-phenylpyrazolo[1,5-a][1,3,5]triazine, C20H18N4S, (I), 7-(4-chlorophenyl)-2-ethylsulfanyl-4-phenylpyrazolo[1,5-a][1,3,5]triazine, C19H15ClN4S, (II), and 4,7-bis(4-chlorophenyl)-2-(ethylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine, C19H14Cl2N4S, (III), show evidence for some aromatic delocalization in the pyrazole rings. The conformations adopted by the ethylsulfanyl substituents are different in all three compounds. There are no hydrogen bonds in any of the crystal structures, but pairs of molecules in (II) and (III) are linked into centrosymmetric dimers by pi-stacking interactions.

Four N(7)-benzyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-diones as ethanol hemisolvates: similar molecular constitutions but different crystal structures.

3-tert-Butyl-7-(4-chlorobenzyl)-4',4'-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione ethanol hemisolvate, C(30)H(34)ClN(3)O(2) x 0.5C(2)H(6)O, (I), its 7-(4-bromobenzyl)- analogue, C(30)H(34)BrN(3)O(2) x 0.5C(2)H(6)O, (II), and its 7-(4-methylbenzyl)- analogue, C(31)H(37)N(3)O(2) x 0.5C(2)H(6)O, (III), are isomorphous, with the ethanol component disordered across a twofold rotation axis in the space group C2/c. In the corresponding 7-[4-(trifluoromethyl)benzyl]- compound, C(31)H(34)F(3)N(3)O(2) x 0.5C(2)H(6)O, (IV), the ethanol component is disordered across a centre of inversion in the space group P\overline{1}. In each of (I)-(IV), the reduced pyridine ring adopts a half-chair conformation. The heterocyclic components in (I)-(III) are linked into centrosymmetric dimers by a single C-H...pi interaction, with the half-occupancy ethanol component linked to the dimer by a combination of C-H...O and O-H...pi(arene) hydrogen bonds. The heterocyclic molecules in (IV) are linked into chains of centrosymmetric rings by C-H...O and C-H...pi hydrogen bonds, again with the half-occupancy ethanol component pendent from the chain. The significance of this study lies in the isomorphism of the related derivatives (I)-(III), in the stoichiometric hemisolvation by ethanol, where the disordered solvent molecule is linked to the heterocyclic component by a two-point linkage, and in the differences between the crystal structures of (I)-(III) and that of (IV).

Four 2-amino-6-aryl-4-methoxy-11H-pyrimido[4,5-b][1,4]benzodiazepines: similar molecular structures but different crystal structures.

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.

Four N(7)-alkoxybenzyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-diones: hydrogen-bonded supramolecular structures in zero, one, two or three dimensions.

3-tert-Butyl-7-(4-methoxybenzyl)-4',4'-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione, C(31)H(37)N(3)O(3), (I), 3-tert-butyl-7-(2,3-dimethoxybenzyl)-4',4'-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione, C(32)H(39)N(3)O(4), (II), 3-tert-butyl-4',4'-dimethyl-7-(3,4-methylenedioxybenzyl)-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione, C(31)H(35)N(3)O(4), (III), and 3-tert-butyl-4',4'-dimethyl-1-phenyl-7-(3,4,5-trimethoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione ethanol 0.67-solvate, C(33)H(41)N(3)O(5) x 0.67C(2)H(6)O, (IV), all contain reduced pyridine rings having half-chair conformations. The molecules of (I) and (II) are linked into centrosymmetric dimers and simple chains, respectively, by C-H...O hydrogen bonds, augmented only in (I) by a C-H...pi hydrogen bond. The molecules of (III) are linked by a combination of C-H...O and C-H...pi hydrogen bonds into a chain of edge-fused centrosymmetric rings, further linked by weak hydrogen bonds into supramolecular arrays in two or three dimensions. The heterocyclic molecules in (IV) are linked by two independent C-H...O hydrogen bonds into sheets, from which the partial-occupancy ethanol molecules are pendent. The significance of this study lies in its finding of a very wide range of supramolecular aggregation modes dependent on rather modest changes in the peripheral substituents remote from the main hydrogen-bond acceptor sites.

Hydrogen-bonded chains of rings in 3-tert-butyl-1-phenyl-7-(4-trifluoromethylbenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione and 3-tert-butyl-7-(4-methoxybenzyl)-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione.

In each of 3-tert-butyl-1-phenyl-7-(4-trifluoromethylbenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione, C(29)H(30)F(3)N(3)O(2), (I), and 3-tert-butyl-7-(4-methoxybenzyl)-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione, C(29)H(33)N(3)O(3), (II), the reduced pyridine ring adopts a half-chair conformation. The molecules of compound (I) are linked by two C-H...O hydrogen bonds to form a C(5)C(5)[R(1)(2)(8)] chain of rings, while in compound (II), two C-H...O hydrogen bonds link the molecules into a C(6)C(7)[R(2)(2)(11)] chain of rings, which is further reinforced by a C-H...pi hydrogen bond. The significance of this study lies in its observation of significant differences in hydrogen-bonded structures consequent upon very minor changes in remote substituents.

2-tert-Butylamino-4-chloro-6-ethylamino-1,3,5-triazine: a structure with Z' = 4 containing two different molecular conformations and two independent chains of hydrogen-bonded R(2)2(8) rings.

The title compound (trivial name terbutylazine), C(9)H(16)ClN(5), (I), crystallizes with Z' = 4 in the space group Pca2(1), and equal numbers of molecules adopt two different conformations for the ethylamine groups. The four independent molecules form two approximately enantiomorphic pairs. Eight independent N-H...N hydrogen bonds link the molecules into two independent chains of R(2)(2)(8) rings, in which the arrangement of the alkylamine substituents in the independent molecules precludes any further crystallographic symmetry. The significance of this study lies in its finding of two distinct molecular conformations within the structure and two distinct ways in which the molecules are organized into hydrogen-bonded chains, and in its comparison of the hydrogen-bonded structure of (I) with those of analogous 1,3,5-triazines and pyrimidines.