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.

Crystal structures and Hirshfeld surface analyses of the di- and tri-hydrates of (5α,17E)-17-hydrazonoandrostan-3-ol: Significant differences in the hydrogen bonding patterns and supramolecular arrangements.

The crystal structures, Hirshfeld surface analyses and electrostatic potential surfaces of the di- and tri-hydrates of (5α,17E)-17-hydrazonoandrostan-3-ol, 3, namely [3·(H2O)2] and [3·(H2O)3], are reported. The trihydrate, isolated from a solution of 3 in moist methanol, recrystallizes in the orthorhombic space group, P212121, while that of the dihydrate, isolated from a 1:1 aqueous methanol solution, recrystallizes in the monoclinic space group, P21. The asymmetric unit of the trihydrate involves one steroid and three water molecules, while that of the dihydrate has two similar but independent steroid molecules and four hydrate molecules. Very similar conformations are found for the steroid molecules in both hydrates. As expected, the different mole ratios of water: steroid have major influences on the structures. In both cases, complex crystal structures are constructed from various classical hydrogen bonds, involving the hydrate molecules and the hydroxy and hydrazonyl moieties of the steroid. In the trihydrate, there are no direct connections between the steroid molecules, instead the water molecules link the steroid molecules, with only weak van der Waals forces between the steroid molecules. There are some direct links between the steroid molecules in the dihydrate, involving OH(steroid hydroxyl)⋯O(steroid oxo) hydrogen bonds, in a head to head fashion, and OH⋯N(hydrazonyl) hydrogen bonds, in a head to tail fashion. However, the major occurrence throughout the structure is of steroid molecules linked by water molecules.

Crystal structures and Hirshfeld surface analyses of the hemi-hydrate and hemi-methanolate of 3α-hydroxy-16α-bromoandrostan-17-one, 3: Differences in supramolecular arrangements.

The crystal structures and Hirshfeld surface analyses of two hemi-solvates of 3α-hydroxy-16α-bromoandrostan-17-one, 3, namely [(3)2.(H2O)] and [(3)2.(MeOH)], are reported. Both solvates crystallize in the monoclinic space group, P21, with Z = 4.. The asymmetric unit of the hemi-hydrate [(3)2.(H2O)] contains two independent but similar steroid molecules and a water molecule, while that of the hemi-methanoate [(3)2.(MeOH)] has four similar but independent steroid molecules and two methanol molecules. Very similar conformations are found for the steroid molecules in both solvates. In both solvates, the strongest intermolecular interactions are OH···O hydrogen bonds, involving hydroxyl groups of the steroid and the solvate molecule, which result in head-to-head directly linked steroid molecules and solvate separated steroid molecules. In both cases, the oxygen atoms of the carbonyl groups of the steroids are involved in weaker CH···O hydrogen bonds which directly link steroid molecules in tail-to-tail fashions. Combinations of the hydrogen bonds, both OH···O and CH···O, result in two-molecule wide sheets in the hemi-hydrate, which are further weakly linked in the hemi--methanoate into a 3-dimensional array. Very different hydrogen bonded chains are found in the two solvates. There is a higher proportion of CH···O to OH···O hydrogen bonds in the hemi-methanoate, [8-6], compared to that in the hemi-hydrate [1-4]: this is an indication of the weaker solvating influence of methanol compared to water.

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.

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.

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.

Phenylnaphthalenes: sublimation equilibrium, conjugation, and aromatic interactions.

In this work, the interplay between structure and energetics in some representative phenylnaphthalenes is discussed from an experimental and theoretical perspective. For the compounds studied, the standard molar enthalpies, entropies and Gibbs energies of sublimation, at T = 298.15 K, were determined by the measurement of the vapor pressures as a function of T, using a Knudsen/quartz crystal effusion apparatus. The standard molar enthalpies of formation in the crystalline state were determined by static bomb combustion calorimetry. From these results, the standard molar enthalpies of formation in the gaseous phase were derived and, altogether with computational chemistry at the B3LYP/6-311++G(d,p) and MP2/cc-pVDZ levels of theory, used to deduce the relative molecular stabilities in various phenylnaphthalenes. X-ray crystallographic structures were obtained for some selected compounds in order to provide structural insights, and relate them to energetics. The thermodynamic quantities for sublimation suggest that molecular symmetry and torsional freedom are major factors affecting entropic differentiation in these molecules, and that cohesive forces are significantly influenced by molecular surface area. The global results obtained support the lack of significant conjugation between aromatic moieties in the α position of naphthalene but indicate the existence of significant electron delocalization when the aromatic groups are in the ß position. Evidence for the existence of a quasi T-shaped intramolecular aromatic interaction between the two outer phenyl rings in 1,8-di([1,1'-biphenyl]-4-yl)naphthalene was found, and the enthalpy of this interaction quantified on pure experimental grounds as -(11.9 ± 4.8) kJ·mol(-1), in excellent agreement with the literature CCSD(T) theoretical results for the benzene dimer.

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.

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.

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.

9-Benzoyl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8-octahydroxanthene-1,8-dione: molecular conformation and supramolecular aggregation in xanthenediones.

In the title compound, C(24)H(26)O(4), (I), the central ring of the fused tricyclic ring system adopts a shallow boat conformation, while the two outer rings adopt envelope conformations. The molecules are linked into C(9) chains by a single C-H...O hydrogen bond. The significance of this study lies in its comparison of the conformation and supramolecular aggregation of (I) with those of related compounds in the published literature.

(1RS,2SR,3RS,5SR)-2-benzoyl-4,4-dicyano-1,3,5-triphenylcyclohexanol at 120 K: complex sheets built from C-H...O and C-H...N hydrogen bonds.

At 120 K, the title compound [systematic name: (2RS,3SR,4RS,6SR)-3-benzoyl-4-hydroxy-2,4,6-triphenylcyclohexane-1,1-dicarbonitrile], C(33)H(26)N(2)O(2), has unit-cell dimensions apparently different from those reported at 294 K [Rong, Li, Yang, Wang & Shi (2006). Acta Cryst. E62, o1766-o1767]. The molecules are linked by two C-H...O hydrogen bonds and three C-H...N hydrogen bonds into complex sheets, and the hydrogen-bonded structures at the two temperatures are the same, although incorrectly described in the earlier report. The significance of the present study lies in its correct description of the hydrogen bonding and in its analysis of the unit-cell dimensions; the differences between the cell angles at 120 and 294 K arise from the fact that one such angle in the triclinic cell is extremely close to 90 degrees so that a very small change in this angle can induce significant changes in the reduced cell.

Hexamethylenediammonium bis(chloroacetate): a three-dimensional hydrogen-bonded framework structure.

In the title compound, C(6)H(18)N(2)(2+).2C(2)H(2)ClO(2)(-), the cation lies across an inversion centre in the P\overline{1} space group. The ions are linked by two two-centre N-H...O hydrogen bonds and by one three-centre N-H...(O)(2) hydrogen bond to form a three-dimensional framework structure. The significance of this study lies in the analysis of the complex hydrogen-bonded structure and in the comparison of this structure with those of other simple hexamethylenediammonium salts.

Three styryl-substituted tetrahydro-1,4-epoxy-1-benzazepines: configurations, conformations and hydrogen-bonded chains.

(2SR,4RS)-7-Chloro-2-exo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(16)ClNO, (I), crystallizes as a racemic twin in the space group P2(1) and the molecules are linked into a chain of edge-fused R(3)(3)(9) rings by a combination of C-H...O and C-H...N hydrogen bonds. The diastereoisomer (2RS,4RS)-7-chloro-2-endo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (II), also crystallizes as a racemic twin, but in the space group P2(1)2(1)2(1), and a two-centre C-H...N hydrogen bond and a three-centre C-H...(O,N) hydrogen bond combine to link the molecules into a complex chain of rings. In (2R,4R)-7-fluoro-2-endo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(16)FNO, (III), which is not isomorphous with (II), the molecules are linked by a single C-H...O hydrogen bond into simple chains, but the molecular arrangements in (II) and (III) are nonetheless very similar. The significance of this study lies in its observation of the variations in molecular configuration and conformation, and in the variation in the supramolecular aggregation, consequent upon modest changes in the peripheral substituents.