Raoni S.B. Gonçalves

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.

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.

Heterogeneous Catalysis by Covalent Organic Frameworks (COF): Pd(OAc)2@COF‐300 in Cross‐Coupling Reactions

COF‐300, an imine‐linked, crystalline, and microporous covalent organic framework, modified by coordination of Pd(OAc)2 to its walls, afforded a hybrid material, Pd(OAc)2@COF‐300, which was used as an efficient heterogeneous catalyst for cross‐coupling reactions. This material showed excellent catalytic activity for the phosphine‐free Suzuki–Miyaura, Heck, and Sonogashira cross‐coupling reactions with low palladium loadings (0.1u2005molu2009% Pd). X‐ray photoelectron spectroscopy analysis of the catalyst after the reaction showed that PdII is converted to Pd0, which is trapped within the COFs nanopores. This was confirmed by high‐resolution transmission electron microscopy. Moreover, promising results were obtained using Pd(OAc)2@COF‐300 under continuous‐flow conditions for a Suzuki–Miyaura cross‐coupling reaction.

Synthesis and Antitubercular Activity of Heteroaromatic Isonicotinoyl and 7-Chloro-4-Quinolinyl Hydrazone Derivatives

Two series of N’(E)-heteroaromatic-isonicotinohydrazide derivatives (3a-f and 4a-b) and 1-(7-chloroquinolin-4-yl)-2-[(heteroaromatic)methylene]hydrazone derivatives (5a-f and 6a-b) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Several compounds were noncytotoxic and exhibited significant minimum inhibitory concentration (MIC) activity (3.12, 2.50, 1.25, or 0.60 μg/mL), which can be compared to that of the first-line drugs ethambutol (3.12 μg/mL) and rifampicin (2.0 μg/ml). These results can be considered an important starting point for the rational design of new leads for anti-TB compounds.

Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection

Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5-8u2009µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB.

Simultaneous Analysis of Isoniazid and Its Impurities by CZE

An alternative methodology for simultaneous determination of isoniazid, isonicotinic acid, 4-cyanopyridine, ethyl isonicotinate and isonicotinamide by capillary zone electrophoresis, within an analysis time of 11xa0min, is proposed. An electrolyte composed by 50xa0mmolxa0L−1 of acetic acid/sodium acetate buffer and 12.5xa0mmolxa0L−1 of Cu2+, an analyte dilution in 1xa0mmolxa0L−1 of Brij 35 and 12.5xa0mmolxa0L−1 of Cu2+ and +20xa0kV voltage were optimized. After evaluating some figures of merit, such as linearity, precision, recovery and quantification limit, the method was successfully applied to the isoniazid analysis in tablets. The contents found were 99.3xa0mg of isoniazid and 0.3xa0mg of isonicotinic acid, corresponding to 0.3xa0% of impurity regarding the content of the active ingredient in the pharmaceutical formulation.

2-{1-[2,8-Bis(trifluoro-meth-yl)quinolin-4-yl]-3,5,6,7,8,8a-hexa-hydro-1H-1,3-oxazolo[3,4-a]pyridin-3-yl}phenol.

In the title mefloquine–oxazolidine derivative, C24H20F6N2O2, the oxazoline ring adopts an envelope conformation (the flap atom is N) and the piperidine ring has a chair conformation. The oxazoline and benzene residues lie away from the C6 ring of the quinoline group and, to a first approximation, to one side of the plane through the ten atoms (r.m.s. deviation = 0.025u2005Å). An intramolecular O—H⋯N(piperidine) hydrogen bond is present. The crystal packing features C—H⋯O, C—H⋯F and C—H⋯π(hydroxybenzene) interactions.

Further study of oxazolidines derived from mefloquine and arenealdehydes: diastereoisomers and polymorphs

Abstract The reaction between racemic erythro [(R*,S*)-2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol] and 2-formyl-5-nitrothiene in toluene generates a reaction mixture containing two diastereoisomers of 4-[3-(5-nitrothien-2-yl)-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline, 6, – namely (2S*,3R*,4S*5R*)-6 (6a) and (2R*,3S*,4S*,5R*)-6 (6b) in a ratio of 5:1 as indicated by 1H NMR spectroscopy (using the 1,3-oxazolidine ring numbering scheme for the chiral centres). Isolation of each product from the mefloquine/2-formyl-5-nitrothiene reaction mixture was achieved by fractional crystallisation of an ethanol solution, but not by column chromatography on silica, which led to the destruction of the minor product, 6b. A second polymorphic form, [monoclinic, P21/c] of (2S*,3R*,4S*,5R*)-4-[3-(2-hydroxyphenyl-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (monoclinic-7) has been isolated from MeOH solution: the previously reported orthorhombic form, space group Fdd2, had been isolated from an ethanolic solution.

Crystal structures of three isomeric 4-[3-(dichlorophenyl)-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolines: importance of cage-type and π(quinoline)⋯π(quinoline) dimeric motifs

Abstract The crystal structures of three isomeric 4-[3-(dichlorophenyl)-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolines, (5: X2 = 2,3-, 2,4- and 2,5-Cl2) have been determined and have been compared to those of related compounds. The crystallographic asymmetric unit of each of (5: X2 = 2,4-Cl2) and (5: X2 = 3,4-Cl2) consists of a single molecule, while that of (5: X2 = 2,3-Cl2) contains two independent molecules – Molecule A and Molecule B. Each of the three compounds crystallizes in the triclinic space group, P1̅. The supramoleular arrangements of the three compounds are generated from combinations of some of C–H⋯X (X = F, Cl, and O), C–X⋯π (X = H, F and Cl) and π⋯π interactions. The presence and significance of two centrosymmetric structural dimeric motives – cage-type dimers, formed (i) from the intermeshing of “F”-shaped monomers, and (ii) π(quinoline)⋯π(quinoline) interactions, reported to arise frequently in other 4-[3-aryl-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolone compounds, were investigated. Both (5: X2 = 2,4-Cl2) and (5: X2 = 3,4-Cl2) exhibit cage-type dimers. In the cases of molecule B of (5: X2 = 2,3-Cl2) and (5: X2 = 3,4-Cl2), the π(quinoline)⋯π(quinoline) interactions are strong, but are much weaker in molecule A of (5: X2 = 2,3-Cl2) and (5: X2 = 2,4-Cl2).

Crystal structures of mefloquine-oxazolidine derivatives, 4-[3-(halophenyl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]- 2,8-bis(trifluoromethyl)quinolines

Abstract Crystal structures are reported for five racemic 4-{3-(halophenyl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1- yl}-2,8-bis(trifluoromethyl)quinolines, 2, namely (2: X = 2-F, 3-Br, 4-Cl, 4-Br and 4-F), prepared from mefloquine and XC6H5CHO. In each case, the compound crystallizes in the triclinic space group, P1̄, with Z = 2. All molecules have ‘‘F’’ shapes with the X-phenyl and quinoline rings lying on one side of the best plane through the fused oxazolidine- piperidine rings. Differences in the conformations of the molecules are indicated by the differences in the interplanar angles. In each case, the supramolecular arrangements are made up from combinations of π ... π and some of C-H...X and C-X... π (X = halo) interactions. Two similar structural sub-sets found in the crystal structures of the five derivatives are centrosymmetric π ... π-linked dimers and centrosymmetric cage-like dimers. The cage-like dimers, formed by the intermeshing of the rings of the monomers, are generated from different weak intermolecular interactions, which include C-H...X and C-X... π (X = halo) interactions. Comparisons are made between the activities of the mefloquine- oxazolidine derivatives in in-vitro tests against the multidrug-resistant tuberculosis strain and conformations, as measured by interplanar angles.