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.

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.

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.

2-{(E)-1-[2-(4-Nitro-phen-yl)hydrazin-1-yl-idene]eth-yl}benzene-1,3-diol.

The title compound, C(14)H(13)N(3)O(4), is close to planar, the dihedral angle between the terminal benzene rings being 5.80 (16)°; the nitro group is coplanar with the benzene ring to which it is bonded [O-N-C-C torsion angle = -177.3 (3)°]. The hy-droxy group forms an intra-molecular hydrogen bond with the imine N atom, and the conformation about the imine bond is E. In the crystal, layers in the (101) plane with an undulating topology are formed by O-H⋯O and N-H⋯O hydrogen bonds along with C-H⋯O inter-actions. Centrosymmetrically related layers are connected via π-π inter-actions [ring centroid-centroid distance = 3.5739 (19) Å] into double layers.

2-{(E)-1-[2-(2-Nitro-phen-yl)hydrazin-1-yl-idene]eth-yl}benzene-1,3-diol mono-hydrate.

The hydrazone mol-ecule in title monohydrate, C(14)H(13)N(3)O(4)·H(2)O, is almost coplanar, the dihedral angle between the terminal benzene rings being 3.22 (15)°; the nitro group is coplanar with the benzene ring to which it is bonded [O-N-C-C = -2.8 (4)°]. The hy-droxy group forms an intra-molecular hydrogen bond with the imine N atom, and the conformation about the imine bond [1.305 (3) Å] is E. In the crystal, supra-molecular layers in the (203) plane are connected into a double layer via water-nitro O-H⋯O hydrogen bonds, along with π-π inter-actions [ring centroid-centroid distance = 3.7859 (19) Å].

2-[(E)-Phen-yl(2-phenyl-hydrazin-1-yl-idene)meth-yl]phenol.

In the title hydrazone derivative, C(19)H(16)N(2)O, a twist is found between the hy-droxy-phenyl and N-bound phenyl rings [dihedral angle = 24.37 (7)°]. The C-bound phenyl ring is almost perpendicular to each of these planes [dihedral angles = 75.30 (7) and 86.00 (7)°, respectively]. The conformation about the imine bond [1.2935 (17) Å] is E. The hy-droxy group forms an intra-molecular hydrogen bond with the imine N atom. Zigzag chains along [001] mediated by N-H⋯O hydrogen bonds feature in the crystal packing.

1,3-Diphenyl-4,5-dihydro-1H-pyrazol-5-one.

In the title pyrazolone derivative, C(15)H(12)N(2)O, the five-membered ring is approximately planar (r.m.s. deviation = 0.018 Å), and the N- and C-bound benzene rings are inclined to this plane [dihedral angles = 21.45 (10) and 6.96 (10)°, respectively] and form a dihedral angle of 20.42 (10)° with each other. Supra-molecular layers are formed in the crystal structure via C-H⋯O and C-H⋯N inter-actions, and these are assembled into double layers by C-H⋯π and π-π inter-actions between the pyrazole and C-bound benzene rings [ring centroid-centroid distance = 3.6476 (12) Å]. The double layers stack along the a axis being connected by π-π inter-actions between the N- and C-bound benzene rings [ring centroid-centroid distance = 3.7718 (12) Å].

3,5-Dimethyl-1-(4-nitro-phen-yl)-1H-pyrazole.

In the title pyrazole derivative, C(11)H(11)N(3)O(2), the benzene ring is twisted [dihedral angle = 31.38 (12)°] with respect to the pyrazole ring (r.m.s. deviation = 0.009 Å). The nitro group is effectively coplanar with the benzene ring to which it is attached [O-N-C-C torsion angle = -6.5 (3)°]. Supra-molecular chains along the b axis are formed owing to π-π inter-actions [3.8653 (2) Å] between translationally related mol-ecules involving both the five- and six-membered rings.

1-(4-Methyl-phen-yl)-3-phenyl-1H-pyrazol-5-yl 4-nitro-benzene-sulfonate.

In the title mol-ecule, C(22)H(17)N(3)O(5)S, the pyrazole ring is planar (r.m.s. deviation = 0.018 Å) and forms dihedral angles of 21.45 (10) and 6.96 (10)° with the N- and C-bound benzene rings, respectively. Supra-molecular layers in the bc plane are formed in the crystal via C-H⋯O and π-π inter-actions involving the sulfonamide benzene ring inter-acting with the N- and C-bound benzene rings [centroid-centroid distances = 3.790 (2) and 3.730 (2) Å, respectively]. The crystal studied was found to be a merohedral twin (twin law 1 0 0.678, 0 -1 0, 0 0 -1), the fractional contribution of the minor component being approximately 36%.

4-[3,4-Dimethyl-1-(4-methyl-phen-yl)-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-3,4-dimethyl-1-(4-methyl-phen-yl)-4,5-dihydro-1H-pyrazol-5-one.

In the title compound, C(24)H(26)N(4)O(2), the complete mol-ecule is generated by the application of twofold symmetry. The pyrazole ring is approximately planar [r.m.s. deviation = 0.026 Å] and the benzene ring is twisted out of this plane [dihedral angle = 21.94 (7)°]. A twist in the mol-ecule about the central C-C bond [1.566 (3) Å] is also evident [C-C-C-C torsion angle = 44.30 (14)°]. Supra-molecular layers in the bc plane are formed in the crystal packing via C-H⋯O and C-H⋯π inter-actions.

(2S,3R)-tert-Butyl N-[4-(N-benzyl-4-fluoro-benzene-sulfonamido)-3-hy-droxy-1-phenyl-butan-2-yl]carbamate.

In the title mol-ecule, C(28)H(33)FN(2)O(5)S, the mean plane about the tertiary amine group (sum of the angles subtended at the sp(2)-hybridized N atom = 359.7°) forms a dihedral angle of 16.66 (6)° with the phenyl ring adjacent to the carbamate group. The sulfonamide benzene ring and the hy-droxy group lie to either side of the C(2)NS plane, whereas the benzyl-phenyl (connected to the N atom) and carbamate substituents lie to the other side. Supra-molecular layers propagating in the ac plane are found in the crystal, linked by hy-droxy-sulfonamide O-H⋯O and carbamate-carbamate N-H⋯O hydrogen bonds along with C-H⋯O and C-H⋯π inter-actions.

7-Chloro-4-[(E)-2-(3,4,5-trimeth-oxy-benzyl-idene)hydrazin-1-yl]quinoline.

In the title compound, C(19)H(18)ClN(3)O(3), the r.m.s. deviation through the 23 non-H and non-meth-oxy atoms is 0.088 Å, indicating a planar mol-ecule with the exception of the meth-oxy groups. One meth-oxy group, surrounded on either side by the other meth-oxy groups, is almost normal to the benzene ring to which it is connected [C-O-C(ar)-C(ar) torsion angle = 81.64 (15)°]. In the crystal, N-H⋯O, C-H⋯O and π-π inter-actions [between quinoline residues; centroid-centroid distance = 3.4375 (8) Å] link mol-ecules into a three-dimensional architecture.

4-[(E)-2-(2,4-Dichloro-benzyl-idene)hydrazin-1-yl]quinolin-1-ium chloride monohydrate.

In the title hydrated salt, C(16)H(12)Cl(2)N(3) (+)·Cl(-)·H(2)O, there is a small twist in the cation as seen in the torsion angle linking the benzene ring to the rest of the mol-ecule [171.96 (17)°]. In the crystal, the quinolinium H atom forms a hydrogen bond to the lattice water mol-ecule, which also forms hydrogen bonds to two Cl(-) anions. Each Cl(-) ion also accepts a hydrogen bond from the hydrazine H atom. The three-dimensional architecture is also stabilized by π-π inter-actions between centrosymmetrically related quinoline residues [centroid-centroid distance = 3.5574 (11) Å].

7-Chloro-4-[(E)-2-(2,5-dimeth-oxy-benzyl-idene)hydrazin-1-yl]quinoline.

In the nearly planar title compound (r.m.s. deviation for the 24 non-H atoms = 0.064 Å), C(18)H(16)ClN(3)O(2), the conformation about the N=C bond is E. Supra-molecular chains propagated by glide symmetry along [001] are found in the crystal packing. These are sustained by N-H⋯N hydrogen bonds with the quinoline N atom being the acceptor. The chains are connected into a three-dimensional architecture by π-π inter-actions involving all three aromatic rings [centroid-centroid distances = 3.5650 (9)-3.6264 (9) Å].

N-(4-Chloro-phen-yl)-5-(4,5-dihydro-1H-imidazol-2-yl)thieno[2,3-b]pyridin-4-amine.

In the title compound, C(16)H(13)ClN(4)S, the thienopyridine fused-ring system is nearly planar (r.m.s. deviation = 0.0333 Å) and forms a dihedral angle of 4.4 (3)° with the attached dihydro-imidazole ring (r.m.s. deviation = 0.0429 Å) allowing for the formation of an intra-molecular (exocyclic amine)N-H⋯N(imine) hydrogen bond. The benzene rings of the disordered (50:50) -N(H)-C(6)H(4)Cl residue form dihedral angles of 59.1 (3) and 50.59 (15)° with the fused ring system. In the crystal, (imidazole amine)N-H⋯N(pyridine) hydrogen bonds lead to a supra-molecular helical chain along the b axis. The chains assemble into layers (ab plane) with inter-digitation of the chloro-benzene rings which results in weak C-H⋯Cl inter-actions in the c-axis direction.