RESUMEN
A series of 2,5-bis(alkyl/arylamino)-1,4-benzoquinones (1-12) were investigated inâ vitro for their potential to inhibit the activity of jack bean urease. Compounds 1-6, 8, 9, 11 and 12 effectively inhibited the jack bean urease activity by 90.8 % when tested at 5â µm, whereas 7 and 10 had relatively little effect. The IC50 for most compounds was in the nanomolar range (31.4â nm and 36.0â nm for 2 and 8, respectively). The mechanism of enzyme inhibition shown by 2 and 8 is typical of mixed-type inhibitors, whose affinity for the active site is over 6- and 2-fold higher (Ki =30.0 and 22.8â nm, for 2 and 8, respectively) than that of an allosteric site. Molecular docking studies revealed that both 2 and 8 establish hydrogen bonds with the amino acids residues Asp494, Met588, His593 and Ala636 in the active site of jack bean urease. These results indicate that such aminoquinones are useful leads for the development of more efficient urease inhibitors of wider utility.
Asunto(s)
Benzoquinonas/química , Inhibidores Enzimáticos/química , Ureasa/antagonistas & inhibidores , Sitio Alostérico , Benzoquinonas/metabolismo , Benzoquinonas/farmacología , Canavalia/enzimología , Dominio Catalítico , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Cinética , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Ureasa/metabolismoRESUMEN
Aiming to obtain new potent leishmanicidal and cytotoxic compounds from natural sources, the triterpene hederagenin was converted into several new 1,2,3-triazolyl derivatives tethered at C-23 and C-28. For this work hederagenin was isolated from fruits of Sapindus saponaria and reacted with propargyl bromide to afford as a major product bis-propargylic derivative 1 in 74%. Submitting this compound to Huisgen 1,3-dipolar cycloaddition reactions with several azides afforded the derivatives 2-19 with yields in the range of 40-87%. All compounds have been screened for in vitro cytotoxic activity in a panel of five human cancer cell lines by a SRB assay. The bioassays showed that compound 19 was the most cytotoxic against all human cancer cell lines with EC50 = 7.4-12.1 µM. Moreover, leishmanicidal activity was evaluated through the in vitro effect in the growth of Leishmania infantum, and derivatives 1, 2, 5 and 17 were highly effective preventing proliferation of intracellular amastigote forms of L. infantum (IC50 = 28.8, 25.9, 5.6 and 7.4 µM, respectively). All these compounds showed a higher selectivity index and low toxicity against two strains of kidney BGM and liver HepG2 cells. Compound 5 has higher selectivity (1780 times) in comparison with the commercial antimony drug and is around 8 times more selective than the most active compound previously reported hederagenin derivative. Such high activity associated with low toxicities make the new bis-traiazolyl derivatives promising candidates for the treatment of leishmaniasis. In addition, hederagenin and some derivatives (2, 5 and 17) showed interaction in the binding site of the enzyme CYP51Li.
Asunto(s)
Antiprotozoarios/farmacología , Ácido Oleanólico/análogos & derivados , Triazoles/química , Animales , Antiprotozoarios/uso terapéutico , Espectroscopía de Resonancia Magnética con Carbono-13 , Células Cultivadas , Perros , Células Hep G2 , Humanos , Leishmaniasis/tratamiento farmacológico , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
Abenquines are natural quinones, produced by some Streptomycetes, showing the ability to inhibit cyanobacterial growth in the 1 to 100 µM range. To further elucidate their biological significance, the synthesis of several analogues (4f-h, 5a-h) allowed us to identify some steric and electronic requirements for bioactivity. Replacing the acetyl by a benzoyl group in the quinone core and also changing the amino acid moiety with ethylpyrimidinyl or ethylpyrrolidinyl groups resulted in analogues 25-fold more potent than the natural abenquines. The two most effective analogues inhibited the proliferation of five cyanobacterial strains tested, with IC50 values ranging from 0.3 to 3 µM. These compounds may be useful leads for the development of an effective strategy for the control of cyanobacterial blooms.
Asunto(s)
Cianobacterias , Quinonas/aislamiento & purificación , Quinonas/farmacología , Streptomyces/química , Brassica rapa/efectos de los fármacos , Brassica rapa/crecimiento & desarrollo , Cianobacterias/química , Cianobacterias/efectos de los fármacos , Cianobacterias/genética , Relación Dosis-Respuesta a Droga , Concentración 50 Inhibidora , Estructura Molecular , Oryza/efectos de los fármacos , Oryza/crecimiento & desarrollo , Quinonas/química , Relación Estructura-ActividadRESUMEN
In this study, we explore the cytotoxic activity of four natural abenquines (2a-d) and fourteen synthetic analogues (2e-j and 3a-h) against a panel of six human cancer cell lines using a SRB assay. It was found that most of the compounds revealed higher levels of cytotoxic activities than naturally occurring abenquines. The analogues carrying ethylpyrrolidinyl and ethylpyrimidinyl with either an acetyl group (2h-i) or a benzoyl group (3f-g), were the most potent against all human cancer cell lines and displayed EC50 between a range of 0.6-3.4µM. Notably, of the compounds tested, compound 2i proved the most cytotoxic against both ovarian (A2780) and breast (MCF7) cells, showing EC50=0.6 and 0.8µM respectively. Likewise, the analogues 2i, 3f and 3g showed strong activity against cell HT29 with EC50=0.9µM for these compounds.
Asunto(s)
Antineoplásicos/farmacología , Quinonas/farmacología , Células 3T3 , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Quinonas/químicaRESUMEN
Although quinones present a large array of biological activities, a few studies on the herbicidal potential of 2,5-bis(alkyl/arylamino)-1,4-benzoquinones have been reported to date. In this work, starting from benzoquinone, 13 2,5-bis(alkyl/arylamino)-1,4-benzoquinones were prepared in 46 - 93% yield. The products were fully characterized by spectroscopic analyses and their phytotoxicity against Cucumis sativus and Sorghum bicolor seedlings was investigated. At 100 ppm, compounds caused 10 - 88% growth inhibition of the dicotyledonous species, whereas the monocotyledon was less affected. Most compounds exerted little inhibitory effect on a cyanobacterial model strain. However, at 100 µm, compounds 8 - 10 caused about 50% inhibition of algal growth, and compounds 1 and 2 reduced cell viability in the 1 - 10 µm range. The ability of benzoquinone derivatives to interfere with the light-driven ferricyanide reduction by isolated spinach chloroplasts was evaluated. Some substances showed a moderate effect as uncouplers, but no relationship was found between this property and their biological activity, indicating that the herbicidal effect is not associated with the inhibition of the photosynthetic electron transport chain. Phytotoxic compounds were not toxic to insects, strengthening the possibility that they may serve as lead for the development of eco-friendly herbicides.