RESUMEN
Starting from 2-hydroxy-1,4-naphthoquinone (lawsone), we synthesized eight new 6H-dibenzo[b,h]xanthene derivatives selectively under solvent-free conditions. Spectroscopic investigations confirmed that only the isomer 6H-dibenzo[b,h]xanthene was obtained in all eight cases. Computational studies provide a rationalization for the selective appearance of these isomers having as an intermediate an addition product.
RESUMEN
The aim of this work was to develop and characterize nanoparticles as carriers of lapazine, a phenazine derived from ß-lapachone; its antimycobacterial activity is described for the first time as a potential treatment for tuberculosis. The lapazine was synthesized, and by using gas chromatography coupled to a flame ionization detector, it was possible to evaluate its purity degree of almost 100%. For better elucidation of the molecular structure, mass spectroscopy and 1H NMR were carried out and compared to the literature values. Lapazine was assayed in vitro against H37Rv Mycobacterium tuberculosis and a rifampicin-resistant strain, with minimum inhibitory concentration values of 3.00 and 1.56 µg mL(-1), respectively. The nanoparticles showed a polydispersity index of 0.16,mean diameter of 188.5 ± 1.7 mm, zeta potential of -15.03 mV, and drug loading of 54.71 mg g(-1) for poly-ε-caprolactone (PCL) nanoparticles and a polydispersity index of 0.318,mean diameter of 197.4 ± 2.7 mm, zeta potential of -13.43 mV and drug loading of 137.07 mg g(-1) for poly(DL-lactide-co-glycolide) (PLGA) nanoparticles. These results indicate that both polymeric formulations have good characteristics as potential lapazine carriers in the treatment of tuberculosis.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Ácido Láctico/química , Nanopartículas/química , Fenazinas/síntesis química , Fenazinas/farmacología , Poliésteres/química , Ácido Poliglicólico/química , Antituberculosos/química , Liberación de Fármacos , Cinética , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Nanopartículas/ultraestructura , Tamaño de la Partícula , Fenazinas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Electricidad Estática , Difracción de Rayos XRESUMEN
Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-ß-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 µM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10-15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites.
Asunto(s)
Antiprotozoarios/síntesis química , Reacción de Cicloadición/métodos , Naftoquinonas/síntesis química , Triazoles/síntesis química , Alquinos/química , Animales , Antimonio/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Azidas/química , Catálisis , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cobre/química , Resistencia a Medicamentos/efectos de los fármacos , Leishmania/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Macrófagos Peritoneales/citología , Macrófagos Peritoneales/efectos de los fármacos , Ratones , Naftoquinonas/química , Naftoquinonas/farmacología , Pruebas de Sensibilidad Parasitaria , Especificidad de la Especie , Triazoles/química , Triazoles/farmacologíaRESUMEN
Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 µg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Azoles/farmacología , Imidazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Naftoquinonas/farmacología , Oxazoles/farmacología , Antituberculosos/química , Azoles/síntesis química , Azoles/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Oxazoles/síntesis química , Oxazoles/química , Relación Estructura-ActividadRESUMEN
New oxirane derivatives were synthesized using six naphthoquinones as the starting materials. Our biological results showed that these oxiranes acted as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. In particular, oxirane derivative 14 showed low cytotoxicity in a mammalian cell line and exhibited better activity against epimastigote forms of T.cruzi than the current drug used to treat Chagas disease, benznidazole.
Asunto(s)
Óxido de Etileno/farmacología , Naftoquinonas/química , Naftoquinonas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Óxido de Etileno/análogos & derivados , Óxido de Etileno/química , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/síntesis química , Trypanosoma cruzi/citología , Trypanosoma cruzi/crecimiento & desarrollo , Células VeroRESUMEN
Several quinonoid and phenazine compounds were synthesized in moderate to high yields and showed activity against H(37)Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The cytotoxity of the compounds were evaluated against human peripheral blood mononuclear cells (PBMC) and these substances emerge as promising antitubercular prototypes.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Fenazinas/síntesis química , Quinonas/síntesis química , Antituberculosos/química , Células Cultivadas , Farmacorresistencia Microbiana , Isoniazida/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Fenazinas/química , Fenazinas/farmacología , Quinonas/química , Quinonas/farmacología , Rifampin/farmacología , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja , Difracción de Rayos XRESUMEN
Thirty two compounds were synthesized in moderate to high yields and showed activity against cancer cells HL-60 (leukemia), MDA-MB435 (melanoma), HCT-8 (colon) and SF295 (central nervous system), with IC(50) below 2 µM for some compounds. The ß-lapachone-based 1,2,3-triazoles showed the best cytoxicity profile and emerge as promising anticancer prototypes. Insights about the reactive oxygen species (ROS) mechanism of anticancer action for some compounds were obtained by addition of 1-bromoheptane that deplete reduced glutathione (GSH) content and by using N-acetylcysteine that protects cells against apoptotic cellular death, as well by analysis of thiobarbituric acid reactive substances (TBARS) formation, and oxidative DNA damage after treatment detected by the comet assay with the bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (ENDOIII).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzoquinonas/síntesis química , Benzoquinonas/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzoquinonas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Roturas del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 InhibidoraRESUMEN
A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-ß-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 µg/ml and 1c = 16 µg/ml) and the non-substituted derivative (1a = 8 µg/ml) were promising compared to chloramphenicol (12 µg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-ß-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.
Asunto(s)
Antibacterianos/farmacología , Enterococcus faecalis/efectos de los fármacos , Naftoquinonas/farmacología , Antibacterianos/química , Antibacterianos/toxicidad , Enterococcus faecalis/aislamiento & purificación , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Naftoquinonas/química , Naftoquinonas/toxicidad , Relación Estructura-ActividadRESUMEN
In continuing our screening program of naphthoquinone activity against Trypanosoma cruzi, the aetiological agent of Chagas' disease, new beta-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-beta-lapachones, 3-alkoxy-nor-beta-lapachones and imidazole anthraquinones were synthesised and evaluated against bloodstream trypomastigote forms of the parasite. Compounds 2,2-dimethyl-3-(2,4-dibromophenylamino)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, IC(50)/24h 24.9+/-7.4 and 4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione with 23.4+/-3.8 microM showed a trypanosomicidal activity higher than benznidazole. These results demonstrate the potential of naphthoquinone derivatives as novel structures for the development of alternative drugs for Chagas' disease.
Asunto(s)
Antraquinonas , Antiparasitarios , Naftoquinonas , Triazoles , Trypanosoma cruzi/efectos de los fármacos , Animales , Antraquinonas/síntesis química , Antraquinonas/química , Antraquinonas/farmacología , Antiparasitarios/síntesis química , Antiparasitarios/química , Antiparasitarios/farmacología , Cristalografía por Rayos X , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Ratones , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Naftoquinonas/farmacología , Pruebas de Sensibilidad Parasitaria , Quinonas/síntesis química , Quinonas/química , Quinonas/farmacología , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacologíaRESUMEN
Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimethoxy substituted naphthoquinones showed the best cytoxicity profile, while the ortho-nitro and the 2,4-dimethoxy substituted ones were more selective than doxorubicin and similar to the precursor lapachones, thus emerging as promising new lead compounds in anticancer drug development.
Asunto(s)
Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Naftoquinonas/química , Naftoquinonas/toxicidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We report here an alternative to the MCPBA or ozonolysis-based oxidation methods of quinoxaline-featuring compounds prepared from beta-lapachones. The use of peracetic acid allowed a simple preparation of the corresponding macrolactones by cleavage of the ring system. These lactones were evaluated for their antimycobacterial potential and compound 4 turned out to have an MIC of 0.62 microg per mL on Mycocabteriumtuberculosis H37Rv. These results justify further research into its value as a potential lead for an original treatment of tuberculosis.
Asunto(s)
Antituberculosos/síntesis química , Lactonas/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Fenazinas/química , Pruebas de Sensibilidad Microbiana , Oxidación-Reducción , Quinoxalinas , Relación Estructura-ActividadRESUMEN
Six new nor-beta-lapachones have been synthesized from reaction of 3-bromo-nor-beta-lapachone with arylamines. These derivatives have potent anticancer properties against several cell lines. Here, we report complete unambiguous assignments of (1)H and (13)C chemical shifts of the new compounds. The assignments were made using a combination of one- and two-dimensional NMR techniques ((1)H, (13)C, (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC).
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Quinonas/química , Aminas/química , Antineoplásicos/química , Isótopos de Carbono , Furanos/química , Naftalenos/químicaRESUMEN
New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Antiprotozoarios/química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Naftoquinonas/química , Pruebas de Sensibilidad Parasitaria , EstereoisomerismoRESUMEN
[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.
Asunto(s)
Naftoquinonas/química , Triazoles/síntesis química , Triazoles/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Azidas/química , Cationes/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Triazoles/química , Tripanocidas/químicaRESUMEN
Several arylamino derivatives of nor-beta-lapachone were synthesized in moderate to high yields and found to show very potent cytotoxicity against six neoplastic cancer cells: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (breast), HL-60 (leukaemia), PC-3 (prostate), and B-16 (murine melanoma), with IC(50) below 1 microg/mL. Their cytotoxicities were compared to doxorubicin and with their synthetic precursors, beta-lapachone and nor-beta-lapachone. The activity against a normal murine fibroblast L-929 showed that some of the compounds were selective against cancer cells. The absence of hemolytic activity (EC(50)>200 microg/mL), performed with erythrocyte suspensions, suggests that the cytotoxicity of the compounds was not related to membrane damage of mouse erythrocytes. For comparison purposes, one isomeric compound based on nor-alpha-lapachone was also synthesized and showed lower activity than the related ortho-derivative. The modified arylamino quinones appear as interesting new lead compounds in anti-cancer drug development.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Naftoquinonas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
This work describes the application of counter-current chromatography (CCC) as a useful, fast and economic alternative for the isolation and purification of heterocyclic derivatives from lapachol and beta-lapachone, two naturally occurring compounds from Tabebuia species, and nor-beta-lapachone, a synthetic congener of lapachol. The discussed data comprise four examples of purification of synthetic reactions with different solvent systems - the mixture of the oxazole and the imidazole from beta-lapachone; the quinoxaline from nor-beta-lapachone; and the purification of the N-oxides from the quinoxaline and the phenazine from nor-beta-lapachone from their respective not fully reacted substrates by means of aqueous reversed- and normal-phase elution modes and non-aqueous solvent systems. Traditional purification of these reaction products by silica gel column chromatography demanded a large amount of solvent and time and, in some cases, serious degradation of the products occurred, leading to low yield of the reaction. High-speed counter-current chromatography (HSCCC) was used as an alternative to optimize the process and raise the yield of the reactions.
Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Distribución en Contracorriente/métodos , Naftoquinonas/química , Factor de Transcripción Activador 6/genética , Cromatografía en Capa Delgada , Ciclización , Imidazoles/química , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/aislamiento & purificación , Oxazoles/química , Quinoxalinas/químicaRESUMEN
We synthesized new naphthoimidazoles from beta-lapachone with an aromatic moiety linked to the imidazole ring, using phenylic and heterocyclic aldehydes. The most active compound against Trypanosoma cruzi had a p-methyl group linked to the phenyl ring, presenting an EC(50) value of 15.5 +/- 2.9 microM. No reliable correlation could be established with the biological activity and the structure of in the phenylic series. For the heterocyclic series, activity was associated with a three bond-distance from nitrogen to the imidazole ring, in accordance with our previous work.
Asunto(s)
Antiinfecciosos/química , Imidazoles/síntesis química , Naftoquinonas/química , Parasitemia/tratamiento farmacológico , Piranos/síntesis química , Tripanocidas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Animales , Imidazoles/química , Imidazoles/farmacología , Ratones/parasitología , Modelos Moleculares , Conformación Molecular , Piranos/química , Piranos/farmacología , Relación Estructura-Actividad , Tripanocidas/farmacologíaRESUMEN
The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.
Asunto(s)
Antimaláricos/farmacología , Naftoquinonas/farmacología , Fenazinas/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/química , Antimaláricos/uso terapéutico , Relación Dosis-Respuesta a Droga , Malaria/tratamiento farmacológico , Ratones , Naftoquinonas/química , Naftoquinonas/uso terapéutico , Fenazinas/química , Fenazinas/uso terapéutico , Plasmodium berghei/fisiología , Plasmodium falciparum/fisiologíaRESUMEN
An intensive effort has been directed toward finding alternative drugs for treatment of Chagas' disease, caused by Trypanosoma cruzi, and prophylaxis of blood in endemic areas. Our research comprises the synthesis and trypanocidal screening of derivatives from naphthoquinones. Herein a new phenazine, obtained from the reaction of beta-lapachone with aniline, has its structure established by physical data and X-ray analysis. It was 9 times more active against T. cruzi trypomastigotes than crystal violet.
Asunto(s)
Fenazinas/síntesis química , Tripanocidas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Compuestos de Anilina/química , Animales , Cristalografía por Rayos X , Fenazinas/química , Fenazinas/farmacología , Tripanocidas/química , Tripanocidas/farmacologíaRESUMEN
The reactions of isomeric dilydronaphthofuran-quinones of the alfa ß type, 1 and 5, respectively, with NBS, under visible light, gave products. These reactions represent a new route to structural types represented by naphthol [1,2-b] furan and naphtho [2,3-b] furan quinones and lead to a new assessment of biosynthetic theory concerning the furan ring in plants