RESUMO
Four new 2,4-distyrylquinolines and one 2-styryl-4-[2-(thiophen-2-yl)vinyl]quinoline have been synthesized using indium trichloride condensation reactions between aromatic aldehydes and the corresponding 2-methylquinolines, which were themselves prepared using Friedländer annulation reactions between mono- or diketones and (2-aminophenyl)chalcones: the products have all been fully characterized by spectroscopic and crystallographic methods. 2,4-Bis[(E)-styryl]quinoline, C25H19N, (IIa), and its dichloro analogue, 2-[(E)-2,4-dichlorostyryl]-4-[(E)-styryl]quinoline, C25H17Cl2N, (IIb), exhibit different orientations of the 2-styryl unit relative to the quinoline nucleus. In each of the 3-benzoyl analogues {2-[(E)-4-bromostyryl]-4-[(E)-styryl]quinolin-3-yl}(phenyl)methanone, C32H22BrNO, (IIc), {2-[(E)-4-bromostyryl]-4-[(E)-4-chlorostyryl]quinolin-3-yl}(phenyl)methanone, C32H21BrClNO, (IId), and {2-[(E)-4-bromostyryl]-4-[(E)-2-(thiophen-2-yl)vinyl]quinolin-3-yl}(phenyl)methanone, C30H20BrNOS, (IIe), the orientation of the 2-styryl unit is similar to that in (IIa), but the orientation of the 4-arylvinyl units show considerable variation. The thiophene unit in (IIe) is disordered over two sets of atomic sites having occupancies of 0.926â (3) and 0.074â (3). There are no hydrogen bonds of any kind in the structure of (IIa), but in (IId), a single C-H...O hydrogen bond links the molecules into cyclic centrosymmetric R22(20) dimers. A combination of C-H...N and C-H...π hydrogen bonds links the molecules of (IIb) into a three-dimensional framework structure. A combination of three C-H...π hydrogen bonds links the molecules of (IIc) into sheets, and a combination of C-H...O and C-H...π hydrogen bonds forms sheets in (IIe). Comparisons are made with the structures of some related compounds.
RESUMO
Seven styrylquinolines were synthesized in this study. Two of these styrylquinolines are new and were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, and normal cells (HaCaT). According to the results, compounds 3a and 3d showed antiproliferative activity in SW480 and SW620 cells, but their effect seemed to be caused by different mechanisms of action. Compound 3a induced apoptosis independent of ROS production, as evidenced by increased levels of caspase 3, and had an immunomodulatory effect, positively regulating the production of different immunological markers in malignant cell lines. In contrast, compound 3d generated a pro-oxidant response and inhibited the growth of cancer cells, probably by another type of cell death other than apoptosis. Molecular docking studies indicated that the most active compound, 3a, could efficiently bind to the proapoptotic human caspases-3 protein, a result that could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. The obtained results suggest that these compounds have chemopreventive potential against CRC, but more studies should be carried out to elucidate the molecular mechanisms of action of each of them in depth.
Assuntos
Adenocarcinoma , Anticarcinógenos , Antineoplásicos , Neoplasias do Colo , Humanos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Caspase 3/metabolismo , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Anticarcinógenos/farmacologia , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteínas Reguladoras de Apoptose , Proliferação de CélulasRESUMO
In this study, we report the synthesis and evaluation of in vitro and in vivo antitrypanosomal activity of styrylquinoline-like compounds (SQ) 3a-h. Synthesis was carried out by using quinaldine and 8- hydroxyquinaldine with a variety of aromatic aldehydes. The structure of SQs was corroborated by one and two-dimension NMR spectroscopy. In vitro antitrypanosomal activity on T. cruzi Talahuen strain was evaluated using ß-galactosidase enzymatic method; cytotoxicity on U-937 cells was assessed by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method. On the other hand, in vivo therapeutical response to 3a-f compounds was evaluated in BALB/c mice (Mus musculus) experimentally infected with T. cruzi blood trypomastigotes and then orally administered with 100 mg/kg weight day for 20 days. All of the compounds showed in vitro activity with EC50 values ranging between 4.6 ± 0.1 µg/mL (14.4 µM) and 36.6 ± 6.1 µg/mL (91 µM). Furthermore, treatment with 3a-f compounds for 20 days resulted in improvement in all of the mice, with a 83-96% decrease in parasitic load at day 90 post-treatment. Treatment with benznidazol (BZ) managed to cure 100% of the mice at the end of treatment. None of the treatments affected the weight of the animals or alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine levels in serum. These results suggest a therapeutic potential of 3a-f compounds as treatment for the infection.
RESUMO
BACKGROUND: Many 2-substituted quinolines and especially 2-arylvinyl derivatives isolated from plants or prepared by synthesis have been designed from ethnopharmacological studies. OBJECTIVE: In order to explore new aspects of the structure-antituberculosis activity relationship, a series of styrylquinoline derivatives was prepared. METHOD: A series of styrylquinoline derivatives was prepared from quinaldic acid and a variety of arylbenzaldehydes under eco-friendly conditions via Knoevenagel reaction and trifluoroacetic acid (TFA) as catalyst. RESULTS: The products were obtained in short reaction times and good yields and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). CONCLUSION: Three compounds had activity under aerobic conditions.
Assuntos
Antituberculosos/farmacologia , Quinolinas/farmacologia , Estirenos/farmacologia , Antituberculosos/síntese química , Química Verde , Micro-Ondas , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/síntese química , Estereoisomerismo , Estirenos/síntese químicaRESUMO
Actualmente la quimioterapia de la leishmaniasis es promisoria, sin embargo aun no se dispone de un medicamento adecuado. Varias quinolinas sustituidas han presentado actividad in vitro contra agentes causales de leishmaniasis cutánea, leishmaniasis visceral, tripanosomiasis africana y enfermedad de Chagas. En este trabajo se sintetizan seis 2-arilquinolinas derivadas de la galipeina mediante condensación de Perkin a partir de quinaldina y aldehídos aromáticos. La actividad leishmanicida se evalúa en amastigotes axénicos y la actividad citotóxica en células U-937. Todos los compuestos muestran ser activos contra leishmania panamensis pero también contra células mamíferas. Los compuestos estirilquinolinas 2-[(E)-2-(2,5-dimetoxifenil)etenil]quinolina (1), 2-[(E)-2-(2,3-dimetoxifenil)etenil]quinolina (2) y N-{4-[(E)-2-quinolin-2-iletenil]fenil}acetamida (3) son mas activos sobre amastigotes axénicos (CE50 = 3,7; 4,5 y 19,1μg/mL) e intracelulares (CE50 = 1,4; 1,8 y 1,7μg/mL), en comparación con los derivados hidrogenados 2-[2-(2,5-dimetoxifenil)etil]quinolina (1a), 2-[2-(2,3-dimetoxifenil)etil]quinolina (2a) y N-[4-(2-quinolin-2-iletil)fenil]acetamida (3a) (CE50= 31,1; 23,6 y 59,3μg/mL). Todos los compuestos muestran también actividad contra células U-937 con CE50 de 3,7; 6,2 y 4,5μg/mL para las estirilquinolinas 1, 2 y 3, respectivamente y CE50 de 16,0; 12,9 y 20,2μg/mL para los derivados hidrogenados 1a, 2a y 3a, respectivamente. Aunque el proceso de hidrogenación produjo una disminución tanto de la actividad leishmanicida como de la actividad citotóxica, la actividad leishmanicida mostrada por los compuestos de tipo 2-estirilquinolinas les confiere un potencial como moléculas candidatas para el desarrollo de compuestos anti-leishmania.
The search of new treatments for leishmaniasis is an active task nowadays, since there is a lack of non-toxic, cheap and non-resistant medication. In the literature several quinolines have shown in vitro activity against agents of cutaneous leishmaniasis, visceral leishmaniasis, African trypanosomiasis and Chagas diseases. Six 2-styrylquinolines derived from galipeine were synthesized by Perkin condensation of quinaldine with aromatic aldehydes. Leishmanicidal activity was estimated for leishmania panamensis at the amastigote form and cytotoxic activity against U-937 cells. All compounds showed activity against both L. panamensis and U-937 cells. (E)-2-(2,5-dimethoxyphenyl)ethenyl)quinoline (1), (E)-2-(2,3-dimethoxyphenyl)ethenyl)quinoline (2) and (E)-N-[4-(2-quinolin-2-yl-ethenyl)phenyl]acetamide (3) were more active against axenic (EC50= 3.7, 4.5 and 19.1μg/mL) and intracellular amastigotes (EC50= 1.4, 1.8 and 1.7μg/ml, respectively), in comparison with hydrogenated derivatives 2-[2-(2,5-dimethoxyphenyl)ethyl]quinoline (1a), 2-[2-(2,3-dimethoxyphenyl)ethyl]quinoline (2a) and N-[4-(2-quinolin-2-ylethyl)phenyl]acetamide (3a) (CE50= 31.1, 23.6 and 59.3μg/mL, respectively). All compounds were also active against the U-937 cells. Styrylquinolines 1, 2 and 3 showed a LC50 of 3.7, 6.2 and 4.5μg/mL, respectively and the hydrogenated derivatives 1a, 2a and 3a showed a LC50 of 16.0. 12.9 and 20.2μg/mL, respectively. Although hydrogenation reduced the leishmanicidal and cytotoxic activities, the activity showed against leishmania parasites suggests this compound series has potential as drug candidates for the treatment of leishmaniasis.