Synthesis and activity of benzimidazole N-Acylhydrazones against Trypanosoma cruzi, Leishmania amazonensis and Leishmania infantum.

In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.

Correction: Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction.

Correction for 'Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction' by Ramon Borges da Silva, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02508k.

Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction.

In the present study a series of N-phenyl-1,10-phenanthroline-2-amine derivatives were obtained by heating 2-chlorophenanthroline with aniline derivatives under solvent free conditions in good to excellent yields. The N-phenyl-1,10-phenanthroline-2-amines were employed as substrates in a copper(ii)-catalyzed C-H amination reaction to give derivatives of the novel heterocyclic system benzo[4,5]imidazo[1,2-a][1,10]phenanthroline. The structure of these compounds was predicted to be helical by DFT calculations and single crystal X-ray diffraction of an example of this system confirmed the non-planar helical structure. The luminescence properties of the parent heterocyclic system were characterized.

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.

Anti-tuberculosis evaluation and conformational study of N-acylhydrazones containing the thiophene nucleus.

A series of N-acylhydrazonyl-thienyl derivatives (compounds 2 and 3), mainly of the type 2-(aryl-CH=N-NHCOCH2 )-thiene (2: aryl = substituted-phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5-nitrothien-2-yl or 5-nitrofuran-2-yl) with MIC values of 8.5 and 9.0 µM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin-2-yl) and compound 2 containing aryl = 2- or 4-hydroxyphenyl groups, with MIC values between 170 and 408 µM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan-2-yl, thien-2-yl, pyrrol-2-yl, imidazol-2-yl, pyridin-3-yl, and pyridin-4-yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro-heteroaryl groups, on the one hand, and the 2-hydroxyphenyl or pyridin-2-yl substituents, on the other hand. Compounds having 2- or 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, or 4-hydroxy-3-chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5-NO2 -furan-2-yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N /EC=N and ZC(O)N /EC=N conformers.

Crystal structures of potassium tri-fluorido-(4-meth-oxy-phen-yl)borate and potassium tri-fluorido(4-fluoro-phen-yl)borate.

The title compounds, K(+)·C7H7BF3O(-), (I), and K(+)·C6H4BF4 (-), (II), are mol-ecular salts containing para-substituted phenyl-tri-fluorido-borate anions. In each compound, the B atom adopts a distorted tetra-hedral BCF3 geometry. Despite their different compositions and space groups, the irregular KF8 coordination polyhedra of the potassium cations in the structures are almost identical. These polyhedra share faces and edges, generating infinite (010) layers in (I) and infinite (001) layers in (II). In (I), adjacent layers are stacked in an AAA… fashion, whereas in (II), they are stacked in an ABAB… sequence.

2-(2-Amino-4-nitro-phen-yl)-7-nitro-4H-3,1-benzoxazin-4-one.

In the title compound, C14H8N4O6, the benzoxazin-4-one fused-ring system (r.m.s. deviation = 0.018 Å) is coplanar with the attached benzene ring [dihedral angle = 0.81 (4)°], there being an intra-molecular N-H⋯N hydrogen bond between them. Each nitro group is twisted out of the plane of the attached benzene ring [O-N-C-C torsion angles = 167.94 (11) and 170.38 (11)°]. In the crystal, amine-nitro N-H⋯O hydrogen bonds lead to centrosymmetric dimeric aggregates that are connected into a three-dimensional architecture by oxazin-yl-nitro C-H⋯O and π-π inter-actions [inter-centroid distance between the oxazinyl and terminal benzene rings = 3.5069 (7) Å].

Crystal structure of (E)-4-hy-droxy-N'-(3-hy-droxy-benzyl-idene)benzohydrazide monohydrate.

In the title benzohydrazide hydrate, C14H12N2O3·H2O, the dihedral angle between the aromatic rings is 58.11 (6)° and the C=O and N-H groups adopt an anti orientation. The main twist in the mol-ecule occurs about the C(=O)-Car (ar = aromatic) bond, with an N-C(=O)-Car-Car torsion angle of -43.5 (2)°. In the crystal, the components are linked by N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds. These inter-actions generate [10-1] chains, with adjacent organic mol-ecules linked by inversion symmetry generating either pairs of N-H⋯O links [R 2 (2)(16) loops] or pairs of O-H⋯O links [R 2 (2)(20) loops]. Pairs of water mol-ecules are located in the R 2 (2)(20) loops and form their own O-H⋯O and O-H⋯N hydrogen bonds to adjacent organic mol-ecules in the chain. Finally, an inter-chain O-H⋯O hydrogen-bond link from the 4-hy-droxy group generates (010) sheets.

7-Chloro-4-(2-hy-droxy-ethyl-amino)-quinolin-1-ium chloride.

In the title salt, C11H12ClN2O(+)·Cl(-), the ten non-H atoms comprising the quinolinium residue are coplanar (r.m.s. deviation = 0.041 Å) and the hy-droxy-ethyl group is approximately perpendicular to this plane [Cring-N-Cmethyl-ene-C torsion angle = -74.61 (18)°]. A supra-molecular chain aligned along [101] mediated by charge-assisted O/N-H⋯Cl(-) hydrogen bonds features in the crystal packing. Chains are connected into a three-dimensional architecture by C-H⋯O(hy-droxy) inter-actions.

2-[(E)-2-(3,4-Di-chloro-benzyl-idene)hydrazin-1-yl]quinoxaline.

The 21 non-H atoms of the title compound, C15H10Cl2N4, are almost planar (r.m.s. deviation = 0.032 Å); the conformation about the N=C bond [1.277 (6) Å] is E. In the crystal, zigzag supra-molecular chains along the c axis (glide symmetry) are formed via N-H⋯N hydrogen bonds. These associate along the b axis by π-π inter-actions between the fused and terminal benzene rings [inter-centroid distance = 3.602 (3) Å] so that layers form in the bc plane.

Synthesis and trypanocidal activity of novel 2,4,5-triaryl-N-hydroxylimidazole derivatives.

Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC50 = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC50, being considered a good starting point for the development of new anti-Chagas drug candidates.

Contrasting the supramolecular structures in the isomeric pair 5-bromo-3-nitrosalicylaldehyde phenylhydrazone and 3-bromo-5-nitrosalicylaldehyde phenylhydrazone.

Isomeric 5-bromo-3-nitrosalicylaldehyde phenylhydrazone and 3-bromo-5-nitrosalicylaldehyde phenylhydrazone, C(13)H(10)BrN(3)O(3), both crystallize with two molecules in the asymmetric unit. In both isomers, an intramolecular O-H···N hydrogen bond links the hydroxy group and the imine N atom. In the 5-bromo-3-nitro isomer, there are two independent N-H···O hydrogen-bonded chains, each molecule in the asymmetric unit forming its own chain. These chains are then linked to form a three-dimensional framework by a combination of weak C-H···O, C-H···Br, C-H···π and π-π stacking interactions. In the 3-bromo-5-nitro isomer, N-H···O hydrogen bonds link the independent molecules alternately into a zigzag chain, which is reinforced by a weak C-H···O interaction. Individual chains are linked by a C-H···Br interaction and a three-dimensional framework is generated by π-π stacking interactions.

Three 2-(methysulfanyl)nicotinamides.

The molecular conformations of three N-alkyl-2-(methylsulfanyl)nicotinamide derivatives, namely N-cyclohexyl-2-(methylsulfanyl)nicotinamide, C13H18N2OS, (I), N-isopropyl-2-(methylsulfanyl)nicotinamide, C10H14N2OS, (II), in which there are two molecules in the asymmetric unit which were chosen to form a hydrogen-bonded pair, and N-(2-hydroxyethyl)-2-(methylsulfanyl)nicotinamide dihydrate, C9H12N2O2S·2H2O, (III), are compared with those of four unsubstituted N-alkylnicotinamide compounds. The substituted compounds show a higher degree of torsion of the pyridine ring with respect to the amide group than do the unsubstituted compounds, with dihedral angles in the range 40-60° for the former and 20-35° for the latter. In (I) and (II), the supramolecular structure is defined by amide-N to carbonyl-O chains. In (III), the nicotinamide molecules are linked by hydrogen bonds to two water molecules resulting in two linked chains of rings which form the three-dimensional network.

Substituted 4-alkoxy-7-Cl-quinolines exhibiting π-π stacking.

The molecules of 4-allyloxy-7-chloroquinoline, C(12)H(10)ClNO, (I), 7-chloro-4-methoxyquinoline, C(10)H(8)ClNO, (II), and 7-chloro-4-ethoxyquinoline, C(11)H(10)ClNO, (III), are all planar. In all three structures, π-π interactions between the quinoline ring systems are generated by unit-cell translations along the a axes, irrespective of space group. These structures are the first reported for 4-alkoxyquinolines.

Five N'-benzylidene-N-methylpyrazine-2-carbohydrazides.

The compounds N'-benzylidene-N-methylpyrazine-2-carbohydrazide, C13H12N4O, (IIa), N'-(2-methoxybenzylidene)-N-methylpyrazine-2-carbohydrazide, C14H14N4O2, (IIb), N'-(4-cyanobenzylidene)-N-methylpyrazine-2-carbohydrazide dihydrate, C14H11N5O·2H2O, (IIc), N-methyl-N'-(2-nitrobenzylidene)pyrazine-2-carbohydrazide, C13H11N5O3, (IId), and N-methyl-N'-(4-nitrobenzylidene)pyrazine-2-carbohydrazide, C13H11N5O3, (IIe), have dihedral angles between the pyrazine rings and the benzene rings in the range 55-78°. These methylated pyrazine-2-carbohydrazides have supramolecular structures which are formed by weak C-H···O/N hydrogen bonds, with the exception of (IIc) which is hydrated. There are π-π stacking interactions in all five compounds. Three of these structures are compared with their nonmethylated counterparts, which have dihedral angles between the pyrazine rings and the benzene rings in the range 0-6°.

Comparison of the structure of (E)-2-(2-benzylidenehydrazinylidene)quinoxaline with those of its chloro- and bromobenzylidene analogues.

(E)-2-(2-Benzylidenehydrazinylidene)quinoxaline, C15H12N4, crystallized with two molecules in the asymmetric unit. The structures of six halogen derivatives of this compound were also investigated: (E)-2-[2-(2-chlorobenzylidene)hydrazinylidene]quinoxaline, C15H11ClN4; (E)-2-[2-(3-chlorobenzylidene)hydrazinylidene]quinoxaline, C15H11ClN4; (E)-2-[2-(4-chlorobenzylidene)hydrazinylidene]quinoxaline, C15H11ClN4; (E)-2-[2-(2-bromobenzylidene)hydrazinylidene]quinoxaline, C15H11BrN4; (E)-2-[2-(3-bromobenzylidene)hydrazinylidene]quinoxaline, C15H11BrN4; (E)-2-[2-(4-bromobenzylidene)hydrazinylidene]quinoxaline, C15H11BrN4. The 3-Cl and 3-Br compounds are isomorphous, as are the 4-Cl and 4-Br compounds. In all of these compounds, it was found that the supramolecular structures are governed by similar predominant patterns, viz. strong intermolecular N-H...N(pyrazine) hydrogen bonds supplemented by weak C-H∙∙∙N(pyrazine) hydrogen-bond interactions in the 2- and 3-halo compounds and by C-H∙∙∙Cl/Br interactions in the 4-halo compounds. In all compounds, there are π-π stacking interactions.

3,3-Dimethyl-cis-9a,13a-diphenyl-2,3,9a,11,12,13a-hexa-hydro-1H-benzo[h][1,4]dioxino[2',3':5,6][1,4]dioxino[2,3-f]chromene.

In the title di-hydro-dioxin, C31H28O5, the dioxane ring has a chair conformation, whereas each of the pyran and dioxine rings has an envelope conformation with methyl-ene and quaternary C atoms, respectively, being the flap atoms. The phenyl rings are cis and form a dihedral angle of 82.11 (10)°. The molecular structure is stabilized by C-H⋯O contacts. In the crystal packing, supra-molecular layers parallel to (101) are sustained by C-H⋯π inter-actions.

Mefloquine-oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113.

Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33µM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1µM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.

1-Iodo-4-meth-oxy-2-nitro-benzene.

In the title compound, C(7)H(6)INO(3), the 12 non-H atoms are planar, with an r.m.s. deviation of 0.016 Å. A close intra-molecular I⋯O inter-action [3.0295 (13) Å] is present. Inter-molecular I⋯O inter-actions [3.3448 (13) Å] lead to the formation of zigzag chains along the b axis. These are assembled into layers by weak π-π inter-actions [centroid-centroid distance = 3.8416 (9) Å], and the layers stack along the a axis, being connected by C-H⋯O contacts.

6-Meth-oxy-2-phenyl-4,4a,6,7,8,8a-hexa-hydro-2H-pyrano[3,2-d][1,3]dioxine-7,8-diyl bis-(4-methyl-benzene-1-sulfonate).

In the title α-D-glucopyran-oside derivative, C(28)H(30)O(10)S(2), each heterocyclic ring adopts a chair conformation. In the tri-substituted ring, the meth-oxy and one sulfonate group occupy axial positions, whereas the second sulfonate group occupies an axial position. The phenyl group on the other ring is in an equatorial position. In the crystal, supra-molecular chains propagating along [100] are formed through C-H⋯O and C-H⋯π inter-actions.