Novel Organic Salts Based on Mefloquine: Synthesis, Solubility, Permeability, and In Vitro Activity against Mycobacterium tuberculosis.

The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).

Mefloquine synergism with anti-tuberculosis drugs and correlation to membrane effects: Biologic, spectroscopic and molecular dynamics simulations studies.

Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.

Synthesis and evaluation of copper(II) complexes with isoniazid-derived hydrazones as anticancer and antitubercular agents.

In this study, the N,N,O metal chelator 2-pyridinecarboxaldehydeisonicotinoyl hydrazone (HPCIH, 1) and its derivatives 2-acetylpyridine-(HAPIH 2), 2-pyridineformamide-(HPAmIH, 3) and pyrazineformamide-(HPzAmIH, 4) were employed in the synthesis of four copper(II) complexes, [Cu(HPCIH)Cl2]·0.4H2O (5), [Cu(HAPIH)Cl2]·1.25H2O (6), [Cu(HPAmIH)Cl2]·H2O (7) and [Cu(HPzAmIH)Cl2]·1.25H2O (8). The compounds were assayed for their action toward Mycobacterium tuberculosis H37Rv ATCC 27294 strain and the human tumor cell lines OVCAR-8 (ovarian cancer), SF-295 (glioblastoma multiforme) and HCT-116 (colon adenocarcinoma). All copper(II) complexes were more effective in reducing growth of HCT-116 and SF-295 cells than the respective free hydrazones at 5 µg/mL, whereas only complex 7 was more cytotoxic toward OVCAR-8 lines than its ligand HPAmIH. 6 proved to be cytotoxic at submicromolar doses, whose IC50 values (0.39-0.86 µM) are similar to those ones found for doxorubicin (0.23-0.43 µM). Complexes 5 and 6 displayed high activity against M. tuberculosis (MIC = 0.85 and 1.58 µM, respectively), as compared with isoniazid (MIC = 2.27 µM), which suggests the compounds are attractive candidates as antitubercular drugs.

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.

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.

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.

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.

(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].

4-[(E)-2-(2-Chloro-benzyl-idene)hydrazin-1-yl]quinolin-1-ium chloride dihydrate.

In the title hydrated salt, C(16)H(13)ClN(3) (+)·Cl(-)·2H(2)O, a small twist is evident in the cation so that the chloro-benzene ring is not coplanar with the central hydrazinyl group [the N-C-C-C torsion angle = -4.8 (12)°]. The conformation about the imine N=C bond [1.284 (10) Å] is E. The components of the structure are connected into a three-dimensional architecture via O-H⋯O, O-H⋯Cl and N-H⋯Cl hydrogen bonds. One water H atom is disposed over two sites of equal occupancy.

N'-[(E)-2-Meth-oxy-benzyl-idene]pyrazine-2-carbohydrazide.

In the title compound, C(13)H(12)N(4)O(2), all the non-H atoms lie on a crystallographic mirror plane and an intra-molecular N-H⋯N hydrogen bond generates an S(5) ring; the conformation about the imine bond [1.280 (3) Å] is E. In the crystal, mol-ecules assemble into a two-dimensional array via C-H⋯O(carbon-yl) and C-H⋯N(pyrazine) contacts. Layers stack along the b-axis direction via weak π-π inter-actions between pyrazine rings [ring centroid distance = 3.8028 (8) Å].

tert-Butyl N-((1S)-2-hy-droxy-1-{N'-[(1E)-4-meth-oxy-benzyl-idene]hydrazinecarbon-yl}eth-yl)carbamate.

The mol-ecule of the title compound, C(16)H(23)N(3)O(5), is twisted about the chiral C atom, the dihedral angle formed between the amide residues being 79.6 (3)°. The conformation about the imine bond [1.278 (5) Å] is E. In the crystal, O-H⋯O and N-H⋯O hydrogen bonding between the hy-droxy, amine and carbonyl groups leads to the formation of supra-molecular layers, which stack along the c-axis direction.

Benzyl N-(2-hy-droxy-1-{N'-[(1E)-2-hy-droxy-benzyl-idene]hydrazinecarbon-yl}eth-yl)carbamate.

The mol-ecule of the title compound, C(18)H(19)N(3)O(5), adopts a curved arrangement with the terminal benzene rings lying to the same side. The hydroxyl-benzene ring is close to coplanar with the adjacent hydrazine residue [dihedral angle = 11.14 (12)°], an observation which correlates with the presence of an intra-molecular O-H⋯N hydrogen bond. The benzyl ring forms a dihedral angle of 50.84 (13)° with the adjacent carbamate group. A twist in the mol-ecule, at the chiral C atom, is reflected in the dihedral angle of 80.21 (12)° formed between the amide residues. In the crystal, two-dimensional arrays in the ac plane are mediated by O-H⋯O and N-H⋯O hydrogen bonds.