RESUMEN
Sustainability in chemistry heavily relies on heterogeneous catalysis. Enzymes, the main catalyst for biochemical reactions in nature, are an elegant choice to catalyze reactions due to their high activity and selectivity, although they usually suffer from lack of robustness. To overcome this drawback, enzyme-decorated nanoporous heterogeneous catalysts were developed. Three different approaches for Candida antarctica lipaseâ B (CAL-B) immobilization on a covalent organic framework (PPF-2) were employed: physical adsorption on the surface, covalent attachment of the enzyme in functional groups on the surface and covalent attachment into a linker added post-synthesis. The influence of the immobilization strategy on the enzyme uptake, specific activity, thermal stability, and the possibility of its use through multiple cycles was explored. High specific activities were observed for PPF-2-supported CAL-B in the esterification of oleic acid with ethanol, ranging from 58 to 283â U mg-1 , which was 2.6 to 12.7â times greater than the observed for the commercial Novozyme 435.
Asunto(s)
Enzimas Inmovilizadas/química , Proteínas Fúngicas/química , Lipasa/química , Estructuras Metalorgánicas/química , Adsorción , Biocatálisis , Candida/enzimología , Esterificación , Modelos Moleculares , Nanoporos/ultraestructura , Ácido Oléico/químicaRESUMEN
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 (0.5-8 µg/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.
Asunto(s)
Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Mefloquina/farmacología , Mefloquina/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Oxazoles/farmacología , Oxazoles/uso terapéutico , Animales , Carga Bacteriana , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Reposicionamiento de Medicamentos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
A series of 23 racemic mefloquine-oxazolidine derivatives, 4-[3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolines, derived from (R*, S*)-(±)-mefloquine and arenealdehydes, have been evaluated for their activity against four cancer cell lines (HCT-8, OVCAR-8, HL-60, and SF-295). Good cytotoxicities have been determined with IC50 values ranging from 0.59 to 4.79 µg/mL. In general compounds with aryl groups having strong electron-releasing substituents, such as HO and MeO, or electron-rich heteroaryl groups, for example imidazol-2-y-l, are active. However, other factors such as steric effects may play a role. As both the active and non-active conformations of the mefloquine-oxazolidine derivatives are similar, it is concluded that molecular conformations do not play a significant role either. This study is the first to evaluate mefloquine derivatives as antitumor agents. The mefloquine-oxazolidine derivatives are considered to be useful leads for the rational design of new antitumor agents.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Mefloquina/química , Oxazoles/química , Quinolinas/química , Quinolinas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Quinolinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Functionalized 3-trifluoromethyl-2-isoxazolines and 3-trifluoromethylisoxazoles were easily prepared from trifluoromethyl aldoxime 2 under mild conditions by using DIB as oxidant. Theoretical studies of the reactivity of trifluoroacetonitrile oxide 4 toward olefins and alkynes were carried out. The 3-trifluoromethyl-2-isoxazolines were ring-opened with NaBH4 and NiCl2 to yield the corresponding trifluoromethylated γ-amino alcohols.
RESUMEN
A series of twenty-three N-acylhydrazones derived from isoniazid (INH 1-23) have been evaluated for their in vitro antibacterial activity against INH- susceptible strain of M. tuberculosis (RG500) and three INH-resistant clinical isolates (RG102, RG103 and RG113). In general, derivatives 4, 14, 15 and 16 (MIC=1.92, 1.96, 1.96 and 1.86 µM, respectively) showed relevant activities against RG500 strain, while the derivative 13 (MIC=0.98 µM) was more active than INH (MIC=1.14 µM). However, these derivatives were inactive against RGH102, which displays a mutation in the coding region of inhA. These results suggest that the activities of these compounds depend on the inhibition of this enzyme. However, the possibility of other mechanisms of action cannot be excluded, since compounds 2, 4, 6, 7, 12-17, 19, 21 and 23 showed good activities against katG-resistant strain RGH103, being more than 10-fold more active than INH.
RESUMEN
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.
Asunto(s)
Aldehídos/química , Antituberculosos/química , Antituberculosos/farmacología , Etambutol/farmacología , Mefloquina/química , Mycobacterium tuberculosis/efectos de los fármacos , Oxazoles/química , Animales , Antituberculosos/síntesis química , Células Cultivadas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Etambutol/química , Mefloquina/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Mycobacterium tuberculosis/aislamiento & purificación , Oxazoles/farmacologíaRESUMEN
The title mol-ecule, C(25)H(22)F(6)N(2)O(3), adopts an open conformation whereby the quinoline and carboxyl-ate ester groups are orientated in opposite directions but to the same side of the piperidine ring so that the mol-ecule has an approximate U-shape. The piperidine ring adopts a distorted boat conformation. In the crystal, inversion dimers linked by pairs of O-Hâ¯O hydrogen bonds generate R(2) (2)(14) loops.
RESUMEN
The title mol-ecule, C(22)H(24)F(6)N(2)O(3), adopts a folded conformation whereby the carboxyl-ate residue lies over the quinolinyl residue, with the dihedral angle between the carbamate and quinoline planes being 41.64â (7)°. Helical supra-molecular C(7) chains sustained by O-Hâ¯O hydrogen bonds propagating along the a-axis direction feature in the crystal packing. The F atoms of one of the CF(3) groups are disordered over two orientations; the major component has a site occupancy of 0.824â (7).
RESUMEN
The title mefloquine derivative has been crystallized as its 1:1 methanol solvate, C(19)H(18)F(6)N(2)O(2)·CH(3)OH. Each of the meth-ine-hydroxyl residue [the C-C-C-O torsion angle is -16.35â (17) °] and the piperidinyl group [distorted chair conformation] lies to one side of the quinolinyl ring system. The hydroxyl and carbonyl groups lie to either side of the mol-ecule, enabling their participation in inter-molecular inter-actions. Thus, the hydroxyl and carbonyl groups of two centrosymmetrically related mol-ecules are bridged by two methanol mol-ecules via O-Hâ¯O hydrogen bonds, leading to a four-mol-ecule aggregate. These are linked into a supra-molecular chain along the a axis via C-Hâ¯O inter-actions involving the hydroxyl-O atom. The chains assemble into layers that inter-digitate along the c axis being connected by C-Hâ¯F inter-actions.
RESUMEN
In the title mefloquine-oxazolidine derivative, C(24)H(20)F(6)N(2)O(2), 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 C(6) ring of the quinoline group and, to a first approximation, to one side of the plane through the ten atoms (r.m.s. deviation = 0.025â Å). An intra-molecular O-Hâ¯N(piperidine) hydrogen bond is present. The crystal packing features C-Hâ¯O, C-Hâ¯F and C-Hâ¯π(hy-droxy-benzene) inter-actions.
RESUMEN
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.
Asunto(s)
Antituberculosos/farmacología , Mefloquina/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxazoles/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Cristalografía por Rayos X , Diseño de Fármacos , Mefloquina/síntesis química , Mefloquina/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Oxazoles/síntesis química , Oxazoles/química , Relación Estructura-ActividadRESUMEN
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 microg/mL), which can be compared to that of the first-line drugs ethambutol (3.12 microg/mL) and rifampicin (2.0 microg/ml). These results can be considered an important starting point for the rational design of new leads for anti-TB compounds.