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.

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.

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 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.

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.

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.

Three aryl-substituted tetrahydro-1,4-epoxy-1-benzazepines: hydrogen-bonded structures in two or three dimensions.

In (2SR,4RS)-7-chloro-2-exo-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(16)H(13)Cl(2)NO, (I), the molecules are linked by a combination of C-H...O and C-H...N hydrogen bonds into a chain of edge-fused R(3)(3)(12) rings. The isomeric compound (2S,4R)-7-chloro-2-exo-(2-chlorophenyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (II), crystallizes as a single 2S,4R enantiomer and the molecules are linked into a three-dimensional framework structure by two C-H...O hydrogen bonds and one C-H...pi(arene) hydrogen bond. The molecules of (2S,4R)-7-chloro-2-exo-(1-naphthyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(20)H(16)ClNO, (III), are also linked into a three-dimensional framework structure, here by one C-H...O hydrogen bond and two C-H...pi(arene) hydrogen bonds. The significance of this study lies in its observation of the variations in molecular configuration and conformation, and in the variation in the patterns of supramolecular aggregation, consequent upon modest changes in the peripheral substituents.

Three tetrahydro-1,4-epoxy-1-benzazepines carrying pendent heterocyclic substituents: supramolecular structures in zero, one or two dimensions.

(2SR,4RS)-7-Fluoro-2-exo-(2-furyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(14)H(12)FNO(2), (I), crystallizes with Z' = 2 in the space group P2(1)/c. A combination of three C-H...O hydrogen bonds and one C-H...N hydrogen bond links the molecules into a complex chain of rings, and pairs of such chains are linked into a tube-like structure by two C-H...pi(arene) hydrogen bonds. There are no hydrogen bonds in the structure of racemic (2SR,4RS)-2-exo-(5-bromo-2-thienyl)-7-fluoro-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(14)H(11)BrFNOS, (II), while the molecules of (2S,4R)-2-exo-(5-bromo-2-thienyl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(15)H(14)BrF(3)NO(2)S, (III), are linked into sheets by a combination of two C-H...O hydrogen bonds and one C-H...pi(arene) hydrogen bond. The significance of this study lies in its observation of the wide variation in the patterns of supramolecular aggregation, consequent upon modest changes in the peripheral substituents.

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.

10-Ethyl-4-oxo-2,3,4,10-tetrahydropyrimido[4,5-b]quinolin-2-iminium 4-toluenesulfonate: a polarized electronic structure in the cation and a hydrogen-bonded sheet structure.

In the title compound, C(13)H(13)N(4)O(+).C(7)H(7)O(3)S(-), the bond distances within the cation provide evidence for the delocalization of the positive charge in a manner reminiscent of guanidinium cations. Three independent N-H...O hydrogen bonds link the ions into centrosymmetric four-ion aggregates, and these are further linked into sheets by a single C-H...O hydrogen bond. This study shows how a single hydrogen bond can link centrosymmetric entities into a continuous sheet structure.

(E)-3-Dimethylamino-2-(1H-indol-3-ylcarbonyl)acrylonitrile: a chain of edge-fused rings built from a three-centre N-H...(N,O) hydrogen bond.

In the title compound, C(14)H(13)N(3)O, the intramolecular distances provide evidence for polarization of the molecular-electronic structure. A single three-centre N-H...(N,O) hydrogen bond links the molecules into chains of edge-fused R(2)(2)(16) and R(2)(4)(12) rings. Comparison with a number of related structures identifies factors of significance controlling the pattern of supramolecular aggregation.

2-(4-chlorophenyl)-5-(4-nitrophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehyde: a chain of rings built from N-H...O and C-H...O hydrogen bonds.

In the title compound, C20H13ClN4O4, the six-membered heterocyclic ring is planar and the molecular dimensions provide evidence for polarization of the molecular-electronic structure. Molecules are linked into a chain of rings by a combination of N-H...O and C-H...O hydrogen bonds, but the nitro group does not participate in the supramolecular aggregation. This study illustrates the marked influence of peripheral substituents on the pattern of hydrogen-bonded aggregation in compounds of this type.

Hydrogen-bonded sheet structures in neutral, anionic and hydrated 6-amino-2-(morpholin-4-yl)-5-nitrosopyrimidines.

In each of 6-amino-3-methyl-2-(morpholin-4-yl)-5-nitrosopyrimidin-4(3H)-one, C(9)H(13)N(5)O(3), (I), morpholin-4-ium 4-amino-2-(morpholin-4-yl)-5-nitroso-6-oxo-1,6-dihydropyrimidin-1-ide, C(4)H(10)NO(+) x C(8)H(10)N(5)O(3)(-), (II), and 6-amino-2-(morpholin-4-yl)-5-nitrosopyrimidin-4(3H)-one hemihydrate, C(8)H(11)N(5)O(3) x 0.5 H(2)O, (III), the bond distances within the pyrimidine components are consistent with significant electronic polarization, which is most marked in (II) and least marked in (I). Despite the high level of substitution, the pyrimidine rings are all effectively planar, and in each of the pyrimidine components, there are intramolecular N-H...O hydrogen bonds. In each compound, the organic components are linked by multiple N-H...O hydrogen bonds to form sheets of widely differing construction, and in compound (III) adjacent sheets are linked by the water molecules, so forming a three-dimensional hydrogen-bonded framework. This study also contains the first direct geometric comparison between the electronic polarization in a neutral aminonitrosopyrimidine and that in its ring-deprotonated conjugate anion in a metal-free environment.

Hydrogen-bonded ribbons in ethyl (E)-3-[2-amino-4,6-bis(dimethylamino)pyrimidin-5-yl]-2-cyanoacrylate and 2-[(2-amino-4,6-di-1-piperidylpyrimidin-5-yl)methylene]malononitrile.

The pyrimidine rings in ethyl (E)-3-[2-amino-4,6-bis(dimethylamino)pyrimidin-5-yl]-2-cyanoacrylate, C(14)H(20)N(6)O(2), (I), and 2-[(2-amino-4,6-di-1-piperidylpyrimidin-5-yl)methylene]malononitrile, C(18)H(23)N(7), (II), which crystallizes with Z' = 2 in the P1 space group, are both nonplanar with boat conformations. The molecules of (I) are linked by a combination of N-H...N and N-H...O hydrogen bonds into chains of edge-fused R(2)(2)(8) and R(4)(4)(20) rings, while the two independent molecules in (II) are linked by four N-H...N hydrogen bonds into chains of edge-fused R(2)(2)(8) and R(2)(2)(20) rings. This study illustrates both the readiness with which highly-substituted pyrimidine rings can be distorted from planarity and the significant differences between the supramolecular aggregation in two rather similar compounds.

Four products from the cyanoacetylation of pyrimidines: hydrogen-bonded dimers, pi-stacked hydrogen-bonded chains and hydrogen-bonded chains of edge-fused rings.

The molecules of 2-[6-amino-3-methyl-2-(methylsulfanyl)-4-oxo-3,4-dihydropyrimidin-5-ylcarbonyl]acetonitrile, C(9)H(10)N(4)O(2)S, (I), are linked in pairs by N-H...O hydrogen bonds to form cyclic centrosymmetric R(2)(2)(4) dimers. Similar dimers formed by 2-(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylcarbonyl)acetonitrile, C(9)H(10)N(4)O(3), (II), are reinforced by paired N-H...N hydrogen bonds and linked into chains of rings by C-H...O hydrogen bonds. The molecules of 2-cyano-N-[6-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]acetamide, C(9)H(10)N(4)O(2)S, (III), are linked into simple C(6) chains by an N-H...N hydrogen bond, and the chains are weakly linked into sheets by a pi-pi stacking interaction. A combination of one two-centre N-H...N hydrogen bond and one three-centre C-H...(N,O) hydrogen bond links the molecules of 2-cyano-N-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]acetamide, C(8)H(7)ClN(4)OS, (IV), into a chain of alternating edge-fused R(2)(1)(6) and R(1)(2)(6) rings. The crystal structures reported in this study, and those of some related examples from the recent literature, show a wide variation in hydrogen-bonded aggregation consequent upon rather small changes in molecular constitution.

Dispiro[indene-2,5'-indeno[2,1-a]fluorene-6',2''-indene]-1,1'',3,3'',11',12'-hexaone: a three-dimensional hydrogen-bonded framework.

The title compound, C(36)H(16)O(6), (I), was obtained as a new and unexpected oxidation product of 1,2'-biindene-1',3,3'(2H)-trione. The molecules of (I) exhibit approximate, but noncrystallographic, twofold rotation symmetry and the central ring of the fused pentacyclic portion is distinctly puckered, with a conformation intermediate between half-chair and screw-boat. Six independent C-H...O hydrogen bonds link the molecules into a three-dimensional framework structure of considerable complexity. Comparisons are drawn between the crystal structure of (I) and those of several simpler analogues, which show wide variation in their patterns of supramolecular aggregation.

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.