RESUMEN
In this work we have collected a set of 30 trypanosomicidal naphthoquinones and developed pharmacophoric and 3D-QSAR models as tools for the design of new potential anti-Chagasic compounds. Firstly, qualitative information was obtained from SAR and pharmacophoric models identifying some fragments around the 2-aryloxynaphthoquinone scaffold important for the antiparasitic activity. Then, 3D-QSAR CoMFA and CoMSIA models were developed. The models showed adequate statistical parameters where the steric, electrostatic, and hydrophobic features explain the trypanosomicidal effect. Therefore, to validate our models, we carried out the design, synthesis, and biological evaluation on T. cruzi epimastigotes of five new compounds (33a-e). According to CoMFA model, three out of five compounds showed pIC50 values within one logarithmic unit of deviation. The two compounds that did not fit the predictions were those with high lipophilicity, which agreed with the SAR and pharmacophore models. Docking and molecular dynamic studies were performed on T. cruzi trypanothione reductase, in a proposed binding site for this type of naphthoquinone. Interestingly, 33a-e showed the same interaction pattern as a naphthoquinone inhibitor (2). Finally, predicted drug-likeness properties indicated that 33a-e have optimal oral bioavailability. Thus, this study provides new in silico models for obtaining novel trypanosomicidal compounds.
Asunto(s)
Enfermedad de Chagas , Naftoquinonas , Trypanosoma cruzi , Antiparasitarios , Enfermedad de Chagas/tratamiento farmacológico , Humanos , Modelos Moleculares , Naftoquinonas/farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
A new series of heteroaryl nitrones were synthesized and evaluated as free radical traps due to the results showed in our previous report. The physicochemical characterization of these new nitrones by electron spin resonance (ESR) demonstrated their high capability to trap and stabilize different atom centered free radicals generated by the Fenton reaction. Additionally, we intensely studied them in terms of their physicochemical properties. Kinetic studies, including the use of a method based on competition and the hydroxyl adduct decay, gave the corresponding rate constants and half-lives at the physiological pH of these newly synthesized nitrones. New nitrones derived from quinoxaline 1,4-dioxide heterocycles were more suitable than DMPO to trap hydroxyl free radicals with a half-life longer than two hours. We explain some of the results using computational chemistry through density functional theory (DFT).
RESUMEN
The objective of this work was to develop a novel (99m) Tc complex bearing the 5-nitroimidazol-1-yl moiety with recognised selectivity towards hypoxic tissue, as a potential radiopharmaceutical for imaging tumour hypoxia. The new metronidazole derivative (2-amine-3-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio]propanoic acid) (L) containing adequate groups to coordinate technetium through the formation of a Tc(I)-tricarbonyl complex was synthesised with adequate yield (33%) and characterised by spectroscopy. Labelling was performed by substitution of three labile water molecules of the technetium tricarbonyl precursor, fac-[(99m)Tc(CO)3 (H2O)3](+) with the ligand. A radiochemical purity higher than 90% was achieved and remained unchanged for more than 4 h. The complex has a high stability in plasma, a moderate plasma protein binding and a moderate hydrophilicity. In vitro cell uptake studies showed a ratio between the activity taken up by cells in hypoxia/normoxia of 1.6 ± 0.4 (p < 0.5). Biodistribution in normal mice showed rapid depuration and low uptake in all organs and tissues except liver. Biodistribution in mice bearing induced tumours showed a low tumour uptake, but tumour/muscle ratio was favourable thanks to depuration. Comparison with biological results of other metronidazole derivatives clearly shows that modifications of the chelator are very important and contribute to improve the biological behaviour.
Asunto(s)
Imagen Molecular/métodos , Nitroimidazoles/química , Compuestos de Organotecnecio , Radiofármacos/síntesis química , Animales , Transporte Biológico , Proteínas Sanguíneas/metabolismo , Hipoxia de la Célula , Línea Celular Tumoral , Fenómenos Químicos , Técnicas de Química Sintética , Estabilidad de Medicamentos , Femenino , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Compuestos de Organotecnecio/síntesis química , Compuestos de Organotecnecio/metabolismo , Compuestos de Organotecnecio/farmacocinética , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
The metabolism of six anti-Trypanosoma cruzi 5-phenylethenylbenzofuroxans (PhEBfx) was studied in vitro using rat hepatic microsomal and cytosolic fractions as a mammalian model and whole cells of T. cruzi as a parasitic model. Some of the expected metabolites were synthesized to provide authentic chromatographic standards. The metabolites were identified using high-performance liquid chromatography (HPLC) in comparison with the authentic standards and their proportions were determined. Their structures were confirmed using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. The behaviour of the six PhEBfx in the three different systems was similar. The main metabolites, formed by reductive processes, were the corresponding o-nitroanilines. Two of the test compounds were studied for extended time periods in the rat liver preparations and their terminal metabolites were identified as o-phenylendiamine derivatives.
Asunto(s)
Compuestos de Anilina/metabolismo , Benzoxazoles/metabolismo , Hepatocitos/metabolismo , Microsomas Hepáticos/metabolismo , Oxadiazoles/metabolismo , Trypanosoma cruzi/metabolismo , Animales , Benzoxazoles/química , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Oxadiazoles/química , RatasRESUMEN
In order to get insight into the trypanocidal mechanism of action of a series of 5-nitrofuryl containing thiosemicarbazones some studies related to their bioreduction were performed. Electron spin resonance spectra of radicals generated in T. cruzi by compounds' bioreduction were analyzed. Three different patterns of ESR signals were observed for the different assayed compounds. These results were in agreement with the changes in the T. cruzi-oxygen uptake promoted by these compounds. On the other hand, free-radical scavenger properties, measured as oxygen radical absorbance capacity (ORAC), did not seem to correlate with the trypanocidal activity.
Asunto(s)
Nitrofuranos/química , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Animales , Espectroscopía de Resonancia por Spin del Electrón , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Humanos , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Tiosemicarbazonas/química , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/metabolismoRESUMEN
Alpha-tocopherol is a very well-known potent antioxidant and radical scavenger in chemical and biological systems. Its structure has served as starting point for design and synthesis of more potent antioxidant analogues with regard to its potential clinical and nutritional applications in human health. Furthermore, in recent years, intense research has been made not only in the development of hybrid compounds with classical drug moieties in a single molecule, but also in the preparation of label analogues with application in tocopherol metabolism studies. In the present review principal progresses in these aspects are outlined.
Asunto(s)
Antioxidantes/química , Vitamina E/análogos & derivados , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Modelos Químicos , Estructura Molecular , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Vitamina E/químicaRESUMEN
The synthesis and evaluation as hypoxic selective cytotoxins of new derivatives of 2-amino or 2-hydroxyphenazine 5,10-dioxide are described. The compounds were developed as structural analogs of other bioreductive compounds and its in vitro cytotoxicities on V79 cells under hypoxic and aerobic conditions were determined. To gain insight into its mechanism of action electrochemical behavior, interaction with DNA experiments and QSAR studies were performed.
Asunto(s)
Citotoxinas/química , Citotoxinas/farmacología , Fenazinas/química , Fenazinas/toxicidad , Relación Estructura-Actividad Cuantitativa , Animales , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Cricetinae , Citotoxinas/síntesis química , ADN/química , Electroquímica , Estructura Molecular , Fenazinas/síntesis química , Análisis EspectralRESUMEN
The synthesis and evaluation of a series of oxotechnetium and oxorhenium complexes containing a nitroaromatic moiety as potential radiopharmaceuticals for targeting tumour hypoxia is presented. 99mTc labelling was performed in high yield (>85%) and radiochemical purity (>90%). Their structure was corroborated by means of the rhenium complexes. Reduction potentials were in the range for bioreducible compounds. 99mTc complexes III-VI were selected for "in vivo" experiments in view of the results of cytotoxicity studies. Biodistribution in normal animals was characterized by high initial blood, lung and liver uptake, fast blood and soft tissue depuration and preferential excretion via the hepatobiliary system. Initial tumour uptake was moderate but tumour/muscle ratios for complexes III and IV, were favourable at all time points. Although the results are encouraging further development is still necessary in order to achieve higher tumour uptake and lower gastrointestinal activity.
Asunto(s)
Nitrobencenos/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Compuestos de Organotecnecio/síntesis química , Compuestos de Organotecnecio/farmacología , Renio/química , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , China , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Cámaras gamma , Hipoxia , Ligandos , Ratones , Estructura Molecular , Neoplasias Experimentales , Compuestos Organometálicos/química , Compuestos de Organotecnecio/química , Sensibilidad y Especificidad , Relación Estructura-Actividad , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Furoxan derivatives with in vitro cytotoxic activity were investigated as antitumoral agents in vivo. The compounds were tested in murine models of both CCRFS-180 II sarcoma and mammary adenocarcinoma. Two of the furoxan derivatives considered here, 3-formyl-4-phenyl-1,2,5-oxadiazole N2-oxide and 3-carbonitrile-4-phenyl-1,2,5-oxadiazole N2-oxide, present in vivo antitumoral activity. They were able to produce more than 90% of tumoral necrosis under the experimental protocol of administration and posology employed. NO-releasing capacity of furoxans may explain the anti-neoplastic activity of these compounds.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Animales , Antineoplásicos/toxicidad , Línea Celular Tumoral , Fenómenos Químicos , Química Farmacéutica , Química Física , Femenino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Oxadiazoles/toxicidad , Quinoxalinas/farmacología , Sarcoma Experimental/tratamiento farmacológico , Sarcoma Experimental/patologíaRESUMEN
Several new 1,2,5-oxadiazole N-oxide derivatives and some deoxygenated analogues were synthesized to be tested as potential selective hypoxic cell cytotoxins. Compounds prepared were designed in order to gain insight into the mechanism of action of this kind of cytotoxin. Compounds were tested in oxia and hypoxia and they proved to be non-selective. 3-Cyano-N(2)-oxide-4-phenyl-1,2,5-oxadiazole showed the best cytotoxic activity in oxia. The cytotoxicity observed for these derivatives could be explained in terms of the electronic characteristics of the 1,2,5-oxadiazole substituents. Electrochemical and ESR studies were performed on the more cytotoxic derivative.
Asunto(s)
Antineoplásicos/síntesis química , Oxadiazoles/química , Oxadiazoles/síntesis química , Aerobiosis/fisiología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Hipoxia de la Célula/fisiología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Clonales , Cricetinae , Citotoxinas/farmacología , Relación Estructura-ActividadRESUMEN
The cytotoxicity of 18 new 1,2,6-thiadiazin-3,5-dione 1,1-dioxides was evaluated. This group of products was previously assayed against epimastigotes of Trypanosoma cruzi and some of them showed a high antiprotozoal activity. Thereafter 13 compounds with a high anti-epimastigote activity and low cytotoxicity were selected to be assayed against amastigotes. Some of the products showed the same or even lower cytotoxicity than nifurtimox and benznidazole, but most of them were very toxic for macrophages at 100 microg/ml. Only one of the compounds had an anti-amastigote activity similar to that of reference drugs at 10 microg/ml, but unfortunately this disappeared at lower concentrations.
Asunto(s)
Antiprotozoarios/farmacología , Tiadiazinas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Ratones , Pruebas de Sensibilidad ParasitariaRESUMEN
The physico-chemical properties of some 5-nitro-2-furaldehyde semicarbazones (nitrofurazones) and thiophene analogues were compared with their in vitro and in vivo trypanocidal activity against Trypanosoma cruzi (Tulahuen strain). 3D-QSAR models were obtained by applying the SIMCA methodology to the electrostatic and steric fields (CoMFA fields) of the molecules. Nitrofurazones bearing N4 substituents. which cover a range of 14-17 A from the nitro group with a thickness of about 6 A when considering the extended conformer. produced complete survival in infected mice. The in vitro model allows larger N4 substituents than the SURVival model, but they must not bear positive centres in the region 15-16 A from the nitro group. Moreover, the in vitro model is in agreement with the active site of trypanothione reductase (TR). Both models can be of use in the design of novel drugs bearing an amide-like group at a distance of 7-9 A from an easily reducible group.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Nitrofurazona/química , Nitrofurazona/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Sitios de Unión/efectos de los fármacos , Enfermedad de Chagas/parasitología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ratones , Modelos Moleculares , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Nitrofurazona/síntesis química , Relación Estructura-Actividad Cuantitativa , Tripanocidas/síntesis química , Trypanosoma cruzi/enzimologíaRESUMEN
N-oxide-containing compounds have been developed as prodrugs that are selectively bioactivated in the hypoxic cells in tumors. This selectivity is based on the net reduction of the N-oxide moiety in the absence of oxygen, in a one or two-electron process, by reductive enzymes. A wide range of N-oxides have been studied and some of them are currently in clinical use. This review covers the principal families of compounds under study and in clinical trials.
Asunto(s)
Hipoxia de la Célula/efectos de los fármacos , Citotoxinas/síntesis química , Óxidos de Nitrógeno/síntesis química , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Citotoxinas/química , Citotoxinas/farmacología , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Neoplasias/patología , Óxidos de Nitrógeno/farmacología , Relación Estructura-ActividadRESUMEN
Several new 1,2,5-oxadiazole N-oxide derivatives were synthesized to be tested both as potential selective hypoxic cell cytotoxins and as DNA-binding agents. The compounds prepared included bis(1,2,5-oxadiazole N-oxide) derivatives and oxadiazole rings linked to naphthyl residues. The compounds were tested for their cytotoxicity in oxia and hypoxia and they proved to be non-selective and less active than the parent compounds 3-formyl-4-phenyl-1,2,5-oxadiazole N2-oxide (3) and 3-chloromethyl-4-phenyl-1,2,5-oxadiazole N2-oxide (4). The DNA-affinity assays showed that the compounds tested have poor affinity for this biomolecule.
Asunto(s)
Hipoxia de la Célula/fisiología , Supervivencia Celular/efectos de los fármacos , Citotoxinas/síntesis química , ADN/química , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Óxidos/síntesis química , Óxidos/farmacología , Aerobiosis , Animales , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Células Clonales , Citotoxinas/química , Citotoxinas/farmacología , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Oxadiazoles/química , Óxidos/química , Relación Estructura-ActividadRESUMEN
As part of an ongoing program on the chemistry and biological activity of N-oxide-containing molecules, a number of novel 1,2, 5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline N,N'-dioxide derivatives were synthesized and evaluated for their herbicidal activity. Many of these compounds exhibited moderate to good herbicidal pre-emergence activity against Triticum aestivum. Dose-response studies were done on the more representative compounds (12, 20, and 26). The most active compound, butylcarbamoylbenzo[1,2-c]1,2,5-oxadiazole N-oxide, 26, displayed herbicidal activity at concentrations as low as 24 g/ha.
Asunto(s)
Herbicidas/síntesis química , Óxidos/síntesis química , Relación Dosis-Respuesta a Droga , Herbicidas/farmacología , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Óxidos/farmacologíaRESUMEN
Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure-activity relationship studies were carried out using voltammetric response and lipophilic-hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic-hydrophilic properties and trypanocidal activity, high R(M) values being associated with low in vivo effects.
Asunto(s)
Aldehídos/síntesis química , Furaldehído/análogos & derivados , Compuestos de Sulfhidrilo/síntesis química , Tripanocidas/síntesis química , Aldehídos/farmacología , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Fenómenos Químicos , Química Física , Cromatografía en Capa Delgada , Electroquímica , Furaldehído/síntesis química , Furaldehído/farmacología , Lípidos/química , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Espectrofotometría Infrarroja , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacosRESUMEN
In a search for antichagasic drugs, 14 new 4-(nitroarylidene)-1,2,6-thiadiazin-3,5-dione 1,1-dioxide derivatives were synthesized and tested in vitro against the epimastigote form of Trypanosoma cruzi and some of them showed important antiprotozoan activity. Attempts to synthesize new 4-(nitroarylidene)-3,5-diamino-1,2,6-thiadiazine 1,1-dioxides were unsuccessful. The antichagasic properties of nitroarylidene-malononitrile and nitroarylidene-cyanoacetamide derivatives, thus obtained, were also tested. The cytotoxic properties against Vero cells of compounds which showed remarkable in vitro antichagasic activity were evaluated. All compounds tested exhibited high toxicity percentages at 100 micrograms/ml. However, compound 3c showed in vitro antichagasic and cytotoxic properties such as nifurtimox at the dose of 10 micrograms/ml.
Asunto(s)
Tiadiazinas/síntesis química , Tripanocidas/síntesis química , Animales , Chlorocebus aethiops , Humanos , Espectroscopía de Resonancia Magnética , Nifurtimox/química , Nifurtimox/farmacología , Nifurtimox/toxicidad , Nitroimidazoles/química , Nitroimidazoles/farmacología , Nitroimidazoles/toxicidad , Espectrofotometría Infrarroja , Tiadiazinas/farmacología , Tiadiazinas/toxicidad , Tripanocidas/farmacología , Tripanocidas/toxicidad , Trypanosoma cruzi/efectos de los fármacos , Células VeroRESUMEN
The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.
Asunto(s)
Óxidos N-Cíclicos/síntesis química , Oxadiazoles/síntesis química , Tripanocidas/síntesis química , Animales , Línea Celular , Cricetinae , Cricetulus , Óxidos N-Cíclicos/química , Electroquímica , Espectroscopía de Resonancia por Spin del Electrón , Fibroblastos , Concentración 50 Inhibidora , Oxadiazoles/química , Relación Estructura-Actividad , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacosRESUMEN
Synthesis and biological evaluation of new 1,2,5-oxadiazole N-oxide derivatives with potential cytotoxic effects are described. From the series of compounds tested, compounds 2 and 6 proved to be very active, although non-selective.
Asunto(s)
Antineoplásicos/síntesis química , Óxidos N-Cíclicos/síntesis química , Oxadiazoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Cricetinae , Cricetulus , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Modelos Moleculares , Oxadiazoles/química , Oxadiazoles/farmacología , Células Tumorales Cultivadas , Difracción de Rayos XRESUMEN
Several novel semicarbazones derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde, and tested in vitro as potential anti-trypanosomal agents. The compounds were prepared in good to excellent yields in 2-3 steps from readily available starting materials. Some derivatives were found to be active against Trypanosoma cruzi with an activity similar to that of Nifurtimox.