Solange M. S. V. Wardell

Antiviral evaluation of N-amino-1,2,3-triazoles against Cantagalo virus replication in cell culture

This paper describes the antiviral evaluation of new N-amino-1,2,3-triazole derivatives, 1-(substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters, 3 and 1-(4-substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazides, 4, on Cantagalo virus replication. 1-(4-Fluoro-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazide, 4e, exhibited a significant antiviral effect. Characterization of all compounds was confirmed by IR, (1)H and (13)C spectroscopies and elemental analysis. In addition, molecular structure of 4e was also reported.

Antimony(III) complexes with 2-benzoylpyridine-derived thiosemicarbazones: Cytotoxicity against human leukemia cell lines

The antimony(III) complexes [Sb(2Bz4DH)Cl(2)] (1), [Sb(H2Bz4M)Cl(3)] x 2 H(2)O (2) and [Sb(2Bz4Ph)Cl(2)] (3) were obtained with 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N(4)-methyl (H2Bz4M) and N(4)-phenyl (H2Bz4Ph) derivatives. H2Bz4DH, H2Bz4Ph and complexes (1-3) exhibited high cytotoxic activity against HL-60 and Jurkat human leukemia cell lines. When these compounds were tested against HL-60 cells with ectopic expression of BcrAbl, Bcl-2 or Bcl-X(L), which confer resistance to apoptosis against a variety of death-inducing agents, the cytotoxicity was much lower, indicating apoptosis to be part of their mechanism of action. The cytotoxic activity of complexes 2 and 3 against HL-60 and Jurkat cells was significantly higher than that of the corresponding thiosemicarbazones, suggesting coordination to be an interesting strategy of cytotoxic dose reduction.

Assessing the persistence of the N–H⋯N hydrogen bonding leading to supramolecular chains in molecules related to the anti-malarial drug, chloroquine

Crystal packing patterns for a range of chloroquine derivatives have been investigated. For species where the amine-bound R substituent carries atoms not capable of forming significant hydrogen bonding interactions, i.e. R = methyl (1), n-propyl (2), n-butyl (3), 2-chloroethyl (4), 2-azidoethyl (5), N–H⋯N hydrogen bonding between the amine and pyridine groups predominate leading to supramolecular chains. In species carrying hydroxyl groups, i.e. R = 2-hydroxylethyl (6), 1-butanol (7), and (S)-1-butanol (8), the N–H⋯N interactions are subverted by O–H⋯N and N–H⋯O hydrogen bonding that results in the formation of 2-D arrays, establishing an hierarchy of hydrogen bonding interactions in these systems. Despite the differences in hydrogen bonding, globally, the crystal packing in all structures is similar in that the N–H⋯N mediated supramolecular chains of (1–5) aggregate into layers usually via C–H⋯π, C–Cl⋯π and π⋯π interactions. These layers, as with those formed in (6–8), stack into a 3-D arrangement being consolidated via C–H⋯Cl and π⋯π or C–Cl⋯π interactions.

The influence of cation upon the supramolecular aggregation patterns of dithiocarbamate anions functionalised with hydrogen bonding capacity—the prevalence of charge-assisted O–H⋯S interactions

A range of supramolecular architectures is found in the title dithiocarbamate salts, each with hydrogen bonding functionality in the form of aτ least one hydroxyl group. A common feature in the crystal packing is the prevalence of charge-assisted O–H⋯S hydrogen bonding. In [NH4][S2CN(CH2CH2OH)2] (1), a 3-D network is found mediated by cooperative O–H⋯S, N–H⋯O and N–H⋯S hydrogen bonding. Reducing the hydrogen bonding functionality by replacing the ammonium cation in (1) by the 4-aza-1-azoniabicyclo(2.2.2)octanium cation to give [DABCO-H][S2CN(CH2CH2OH)2] (2), results in a 2-D array. Further reduction of the hydrogen bonding functionality, this time by substituting a CH2CH2OH with an alkyl group to give [DABCO-H][S2CN(CH2CH2OH)CH3] (3) and [DABCO-H][S2CN(CH2CH2OH)CH2CH3] (4) allows for the formation of 1-D supramolecular chains. The introduction of alkali metal cations rather than protic cations removes the possibility of the hydroxyl-O participating in hydrogen bonding interactions as these now coordinate the alkali metal. In the sodium trihydrate, Na[S2CN(CH2CH2OH)2]·3H2O (5), O–H⋯O hydrogen bonds are found along with charge-assisted O–H⋯S contacts so that a 3-D network results. Substituting a CH2CH2OH group with a n-propyl group gives Na[S2CN(CH2CH2OH)CH2CH2CH3]·2H2O (6) and yields a 2-D array. For the anhydrous K[S2CN(CH2CH2OH)2] (7) and Cs[S2CN(CH2CH2OH)2] (8) salts, the crystal packing is dominated by charge-assisted O–H⋯S hydrogen bonding giving 3-D network structures. The systematic analysis of the crystal packing patterns of these salts reveals the importance of charge-assisted O–H⋯S hydrogen bonding in stabilising these crystal structures.

Crystallographic and computational study of 1-(arylamino)-1,2,3-triazole-4-carbohydrazides

The crystallography of mono-p-substituted derivatives of 1-(arylamino)-1,2,3-triazole-4-carbohydrazides, 1 (X = H), 2 (F), 3 (Cl) and 4 (Br), and a 2,5-dichloro (5) analogue, shows the molecular structures to be similar. Distinct hydrogen bonding patterns based on N–H⋯N and N–H⋯O are observed in their crystal structures with 1, having two independent molecules comprising the asymmetric unit, displaying one pattern, 2 and 5 another, and 3 and 4 yet another. Geometry optimisation calculations indicate that any conformational differences in the solid state do not persist in the gas-phase and that no influence of the substituents is seen on the geometric parameters. A natural population analysis, for both experimental and optimised structures, shows that the charge on the triazole-N3 atom is at a maximum for 1, as opposed to 2–5, an observation correlated with its distinctive packing based around a supramolecular synthon not seen in the other structures. For the molecules having electronegative substituents, molecular electrostatic potentials show that the energies of the amine-H4n atoms are reduced for 2 and 5, compared to 3 and 4. A further distinction in 2–5 is indicated by the Hirshfeld surface analysis which highlights the importance of π⋯π interactions in 2 and 5, i.e. with the more electronegative substituents. Clearly, there is interplay between various factors but all correlated with the influence of the electronegativity of the substituent(s).

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.

Supramolecular structures in N-isonicotinoyl arylaldehydehydrazones: multiple hydrogen-bonding modes in series of geometric isomers

Sixteen N-isonicotinoyl arylaldehydehydrazones, NC(5)H(4)CONHN=CHC(6)H(4)R, have been studied and the structures of 14 of them have been determined, including the unsubstituted parent compound with R = H, and the complete sets of 2-, 3- and 4-substituted geometric isomers for R = F, Br and OMe, and two of the three isomers for R = Cl and OEt. The 2-chloro and 3-chloro derivatives are isostructural with the corresponding bromo isomers, and all compounds contain trans amide groups apart from the isostructural pair where R = 2-Cl and 2-Br, which contain cis amide groups. The structures exhibit a wide range of direction-specific intermolecular interactions, including eight types of hydrogen bonds, N-H...N, N-H...O, O-H...O, O-H...N, C-H...N, C-H...O, C-H...pi(arene) and C-H...pi(pyridyl), as well as pi...pi stacking interactions. The structures exhibit a very broad range of combinations of these interactions: the resulting hydrogen-bonded supramolecular structures range from one-dimensional when R = 2-F, 2-OMe or 2-OEt, via two-dimensional when R = 4-F, 3-Cl, 3-Br, 4-OMe or 3-OEt, to three-dimensional when R = H, 3-F, 2-Cl, 2-Br, 4-Br or 3-OMe. Minor changes in either the identity of the substituent or its location can lead to substantial changes in the pattern of supramolecular aggregation, posing significant problems of predictability. The new structures are compared with the recently published structures of the isomeric series having R = NO(2), with several monosubstituted analogues containing 2-pyridyl or 3-pyridyl units rather than 4-pyridyl, and with a number of examples having two or three substituents in the aryl ring: some 30 structures in all are discussed.

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.

Copper(II) complexes with 2-pyridineformamide-derived thiosemicarbazones: spectral studies and toxicity against Artemia salina.

The copper(II) complexes [Cu(H2Am4DH)Cl2] (1), [Cu(H2Am4Me)Cl2] (2), [Cu(H2Am4Et)Cl2] (3) and [Cu(2Am4Ph)Cl] (4) with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me), N(4)-ethyl (H2Am4Et) and N(4)-phenyl (H2Am4Ph) derivatives were studied by means of infrared and EPR spectral techniques. The crystal structure of 4 was determined. The studied compounds proved to be toxic to Artemia salina, suggesting that they could present cytotoxic activity against solid tumors. Among the free thiosemicarbazones H2Am4Ph presented higher toxicity than all other compounds, which showed comparable effects. In the case of complexes 2 and 3 toxicity is probably attributable to the complex as an entity or to a synergistic effect involving the thiosemicarbazone and copper. H2Am4Ph and complexes 2 and 3 revealed to be the most promising compounds as potential antineoplasic agents.

Synthesis and antitubercular activity of new mefloquine-oxazolidine derivatives.

In this work, we report the synthesis and the antitubercular evaluation of 16 new mefloquine derivatives, formed from reactions between mefloquine and benzaldehydes, with the activity expressed as the minimum inhibitory concentration (MIC) in μM. The compounds were non-cytotoxic and exhibited an important activity (12.6 μM). The appreciable activity of these compounds can be considered an important finding for the rational design of new leads for anti-TB compounds.