RESUMEN

The literature reports that thiazole and isatin nuclei present a range of biological activities, with an emphasis on anticancer activity. Therefore, our proposal was to make a series of compounds using the molecular hybridization strategy, which has been used by our research group, producing hybrid molecules containing the thiazole and isatin nuclei. After structural planning and synthesis, the compounds were characterized and evaluated in vitro against breast cancer cell lines (T-47D, MCF-7 and MDA-MB-231) and against normal cells (PBMC). The activity profile on membrane proteins involved in chemoresistance and tumorigenic signaling proteins was also evaluated. Among the compounds tested, the compounds 4c and 4a stood out with IC50 values of 1.23 and 1.39 µM, respectively, against the MDA-MB-231 cell line. Both compounds exhibited IC50 values of 0.45 µM for the MCF-7 cell line. Compounds 4a and 4c significantly decreased P-gp mRNA expression levels in MCF-7, 4 and 2 folds respectively. Regarding the impact on tumorigenic signaling proteins, compound 4a inhibited Akt2 in MDA-MB-231 and compound 4c inhibited the mRNA expression of VIM in MCF-7.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Isatina , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero , Tiazoles , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Isatina/farmacología , Isatina/química , Isatina/síntesis química , Línea Celular Tumoral , ARN Mensajero/metabolismo , ARN Mensajero/genética , Tiazoles/farmacología , Tiazoles/química , Femenino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Simulación del Acoplamiento Molecular , Células MCF-7 , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad

RESUMEN

BACKGROUND: Cancer is a disease characterized by the abnormal multiplication of cells and is the second leading cause of death in the world. The search for new effective and safe anticancer compounds is ongoing due to factors such as low selectivity, high toxicity, and multidrug resistance. Thus, heterocyclic compounds derived from isatin, thiazole and phthalimide that have achieved promising in vitro anticancer activity have been tested in vivo and in clinical trials. OBJECTIVE: This review focused on the compilation of promising data from thiazole, isatin, and phthalimide derivatives, reported in the literature between 2015 and 2022, with in vivo anticancer activity and clinical trials. METHOD: A bibliographic search was carried out in the PUBMED, MEDLINE, ELSEVIER, and CAPES PERIODIC databases, selecting relevant works for each pharmacophoric group with in vivo antitumor activity in the last 6 years. RESULTS: In our study, 68 articles that fit the scope were selected and critically analyzed. These articles were organized considering the type of antitumor activity and their year of publication. Some compounds reported here demonstrated potent antitumor activity against several tumor types. CONCLUSION: This review allowed us to highlight works that reported promising structures for the treatment of various cancer types and also demonstrated that the privileged structures thiazole, isatin and phthalimide are important in the design of new syntheses and molecular optimization of compounds with antitumor activity.

RESUMEN

BACKGROUND: Despite its homeostatic role, inflammation is involved in several pathologies, such as acute lung injury. Morita-Ballys-Hilman adducts (MBHA) are a group of synthetic molecules and present a wide range of biological activities, including anti-inflammatory action. Thus, this study aimed to assess whether ISACN, an MBHA, modulates inflammation during acute lung injury induced by lipopolysaccharide (LPS). METHODS: BALB/c mice were intraperitoneally treated with 24 mg/kg ISACN and challenged with LPS (2.5 mg/kg). On bronchoalveolar lavage fluid (BALF), we assessed the total and differential leukocyte count and measurement of protein leakage, cytokines (IL-1ß, IL-6, and TNF-α), and chemokine (CXCL-1). Additionally, lung histopathology was also performed (H&E staining). In vitro studies were conducted with peritoneal macrophages to assess the possible mechanism of action. They were cultured in the presence of ISACN (5 and 10 µM) and stimulated by LPS (1 µg/mL). RESULTS: ISACN reduced neutrophil migration, protein leakage, and inflammatory cytokines (IL-1ß, IL-6, and TNF-α) without interfering with the production of CXCL1. In addition, ISACN caused a decrease in LPS-induced lung injury as evident from histopathological changes. In peritoneal macrophages, ISACN diminishes the nitric oxide and cytokine levels (IL-1ß, IL-6, and TNF-α). The treatment with ISACN (10 µM) also reduced LPS-induced TLR4, CD69, iNOS overexpression, and the LPS-induced ERK, JNK, and p38 phosphorylation. CONCLUSION: Thus, this work showed for the first time the immunomodulatory action of MBHA in LPS-induced acute lung injury and provided new evidence for the mechanisms related to the anti-inflammatory effect of ISACN.

Asunto(s)

Acrilonitrilo , Lesión Pulmonar Aguda , Ratones , Animales , Lipopolisacáridos/toxicidad , Acrilonitrilo/efectos adversos , Acrilonitrilo/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Pulmón , Citocinas/metabolismo , Antiinflamatorios/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo

RESUMEN

Concerned about weed infestation, a major threat to food production and herbicide resistance that interferes in the mechanism of action of the main herbicides, we have synthesized eight isatin derivatives using the "Click Chemistry" approach through copper-catalyzed azide-alkyne cycloadditions (CuAAC). Sixteen isatin derivatives were evaluated for their phytotoxic activity against the seed culture of the model plants, Lactuca sativa and Allium cepa. Six of them showed phytotoxic activity similar to the positive control, trifluralin. Hypocotyl length measurement analysis in L. sativa revealed that triazole derivative 8 is more active than trifluralin. For A. cepa, root length measurement analyses revealed that 3, 10, 14, 16, and 17 were similar to the positive control trifluralin. Three-dimensional quantitative structure-activity relationship (3D-QSAR) comparative molecular field analysis (CoMFA) model construction using the acetolactate synthase (ALS) crystallographic structure displayed pki values of predicted inhibitory activity and contour maps revealing sterically bulky groups for 11, the CF3 group in ortho, and for 17, Br in ortho, favoring the inhibitory ALS activity.

Asunto(s)

Herbicidas , Isatina , Relación Estructura-Actividad Cuantitativa , Isatina/farmacología , Trifluralina , Herbicidas/química

RESUMEN

Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC50 values of 7.2, 6.4, and 7.3 µM, respectively, and were all more potent than imatinib (IC50 of 65.4 µM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC50 value of 35.8 µM (imatinib, IC50 = 0.08 µM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer.

Asunto(s)

Proliferación Celular/efectos de los fármacos , Mesilato de Imatinib/farmacología , Neoplasias/patología , Células A549 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/uso terapéutico , Células K562 , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico

RESUMEN

Isoniazid is a first-line drug for the treatment of tuberculosis, a bacterial disease caused by Mycobacterium tuberculosis. Its terminal amino group is highly reactive, leading to significant metabolic deactivation, drug interactions and hepatotoxicity. It is speculated that the activity of isoniazid derivatives is, in part, related to the cleavage of the protecting group. Therefore, this study aimed to evaluate the cleavage characteristics of previously developed isoniazid derivatives through kinetic studies by high-performance liquid chromatography with ultraviolet-diode array detectio to establish a comparison between the rates of the process and the respective activities against M. tuberculosis. Chromatographic separations were performed on an XDB C18 column coupled to an XDB C18 precolumn. The mobile phase consisted of ultrapure water and acetonitrile in gradient mode. The flow rate was 1.0 mL/min, the injection volume was 20 µL, and the detection wavelengths were 230 nm (derivatives and isatins) and 270 nm (isoniazid). Incubation of derivatives was carried out for 5 days in 10 mmol/L phosphate buffer solution (pH 3.0, 7.4, 8.0) or in fetal bovine serum at 37 °C. The incubation reduced the concentration of the derivatives and led to the formation of isoniazid in a first-order kinetic reaction. Isoniazid formation was logarithmically correlated with the minimum inhibitory concentration of the derivatives. The results showed that higher cleavage rates are associated with greater activities against M. tuberculosis, providing important information for the development of future generations of isoniazid derivatives and for screening drug candidates for the treatment of tuberculosis.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Hidrazinas/química , Isoniazida , Mycobacterium tuberculosis/efectos de los fármacos , Isoniazida/análisis , Isoniazida/química , Isoniazida/metabolismo , Isoniazida/farmacología , Cinética , Límite de Detección , Modelos Lineales , Pruebas de Sensibilidad Microbiana , Reproducibilidad de los Resultados

RESUMEN

BACKGROUND/AIM: To identify the best of three isatin-based scaffolds in terms of anticancer activity. MATERIALS AND METHODS: Synthesis of isatin-based scaffolds was performed through a reaction to form Schiff bases. In silico analyses consisted of a target prediction with the Swiss Target Prediction tool and a molecular docking by AutoDock Vina. Anticancer activity and cytotoxicity were determined using the WST1 viability assay. RESULTS: Three scaffolds (IA, IB, and IC) were synthesized and confirmed with good reaction yields. The Swiss Target Prediction tool showed a trend towards kinases. Molecular docking assays demonstrated higher affinity of IC towards CDK2. Anticancer activity assays identified IC as the most active against the cancer cell lines. Cytotoxicity results in non-cancer cells suggested a lack of selectivity. CONCLUSION: The scaffold IC was identified as the best in terms of anticancer activity and these effects may be due to inhibition of CDK2, as evidenced by molecular docking.

Asunto(s)

Antineoplásicos/farmacología , Quinasa 2 Dependiente de la Ciclina/metabolismo , Isatina/farmacología , Simulación del Acoplamiento Molecular/métodos , Neoplasias/tratamiento farmacológico , Bases de Schiff/química , Antineoplásicos/química , Apoptosis , Proliferación Celular , Humanos , Isatina/química , Neoplasias/metabolismo , Neoplasias/patología , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

Pain and inflammation are symptoms of various diseases, and they can be modulated by different pathways, thus highlighting the importance of investigating the therapeutic effects of novel compounds. Previous studies have shown that isatin-thiosemicarbazone exhibits antitumor, antifungal antibacterial and other biological properties. Based on the wide range of biological effects of these compounds, the aim of the present study was to investigate the central nervous system (CNS) performance, and the anti-nociceptive and anti-inflammatory activity of (Z)-2-(5-nitro-2-oxoindolin-3-ilidene)-N-hydroazinecarbothioamide (PA-Int5) in treated mice. Three doses of PA-Int5 were tested orally (1.0, 2.5 and 5.0 mg/kg) in the nociceptive and inflammatory animal models. Additionally, the potential sedative effects of PA-Int5 (5 mg/kg, oral gavage) were investigated using an open field and rotarod tests, to exclude any possible unspecific effects of the nociceptive assays. Anti-nociceptive activity was assessed using the acetic acid-induced abdominal contortion and formalin tests, whereas anti-inflammatory activity was assessed using a carrageenan-induced paw edema and zymosan-induced air-pouch models. PA-Int5 (5 mg/kg) induced anti-nociceptive activity in the abdominal contortion model. In the formalin test, PA-Int5 (at 2.5 and 5 mg/kg) reduced nociception in the second phase. At the higher dose tested, PA-Int5 did not affect spontaneous locomotion or motor coordination. The data revealed that at all doses tested, the compound significantly reduced paw edema following carrageenan administration. In the zymosan-induced air-pouch model, PA-Int5 potently inhibited leukocyte migration and protein levels at the site of inflammation. When combined, the results revealed, for the first time, that PA-Int5 exhibited anti-nociceptive and anti-inflammatory activities, and highlights its potential, as well that of other derivatives, as novel candidates for pain relief.

RESUMEN

Neglected diseases are a group of transmissible diseases that occur mostly in countries in tropical climates. Among this group, Chagas disease and leishmaniasis stand out, considered threats to global health. Treatment for these diseases is limited. Therefore, there is a need for new therapies against these diseases. In this sense, our proposal consisted of developing two series of compounds, using a molecular hybridization of the heterocyclic isatin and thiazole. The isatin and thiazole ring are important scaffold for several biological disorders, including antiparasitic ones. Herein, thiazolyl-isatin has been synthesized from respective thiosemicarbazone or phenyl-thiosemicarbazone, being some of these new thiazolyl-isatin toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 2e (IC50 = 4.43 µM), 2j (IC50 = 2.05 µM), 2l (IC50 = 4.12 µM) and 2m (1.72 µM) showed the best anti-T. cruzi activity for trypomastigote form presenting a selectivity index higher than Benznidazole (BZN). Compounds 2j, 2l and 2m were able to induce a significantly labelling compatible with necrosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with the compound 2m from IC50 concentrations, promoted changes in the shape, flagella and surface of body causing of the parasite dead. Concerning leishmanicidal evaluation against L. amazonensis and L. infantum, compounds 2l (IC50 = 7.36 and 7.97 µM, respectively) and 2m (6.17 and 6.04 µM, respectively) showed the best activity for promastigote form, besides showed a higher selectivity than Miltefosine. Thus, compounds 2l and 2m showed dual in vitro trypanosomicidal and leishmanicidal activities. A structural activity relationship study showed that thiazolyl-isatin derivatives from phenyl-thiosemicarbazone (2a-m) were, in general, more active than thiazolyl-isatin derivatives from thiosemicarbazone (1a-g). Crystallography studies revealed a different configuration between series 1a-g and 2a-m. The configuration and spatial arrangement divergent between the two sub-series could explain the improved biological activity profile of 2a-m sub-series.

Asunto(s)

Isatina/química , Isatina/farmacología , Leishmania/efectos de los fármacos , Tiazoles/química , Tripanocidas/química , Tripanocidas/farmacología , Diseño de Fármacos , Concentración 50 Inhibidora , Relación Estructura-Actividad

RESUMEN

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

Asunto(s)

Acetilcolinesterasa/efectos de los fármacos , Reactivadores de la Colinesterasa/farmacología , Isatina/farmacología , Piridinas/farmacología , Simulación por Computador , Técnicas In Vitro

RESUMEN

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. CONCLUSION: These findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Asunto(s)

Acetilcolinesterasa/metabolismo , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Indoles/farmacología , Malatión/toxicidad , Oxindoles/farmacología , Receptor trkB/metabolismo , Transducción de Señal , Animales , Antidepresivos/administración & dosificación , Antidepresivos/química , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Indoles/administración & dosificación , Indoles/química , Indoles/uso terapéutico , Masculino , Actividad Motora/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oxindoles/administración & dosificación , Oxindoles/química , Oxindoles/uso terapéutico , Ratas Wistar , Transducción de Señal/efectos de los fármacos

RESUMEN

An operationally simple and time-efficient approach has been developed for the synthesis of racemic N-substituted 3-(2-aryl-2-oxoethyl)-3-hydroxyindolin-2-ones by a piperidine-catalysed aldol reaction between aryl methyl ketones and N-alkylisatins. These aldol products were used successfully as strategic intermediates for the preparation of N-substituted (E)-3-(2-hetaryl-2-oxoethylidene)indolin-2-ones by a stereoselective dehydration reaction under acidic conditions. The products have all been fully characterized by 1H and 13C NMR spectroscopy, by mass spectrometry and, for a representative selection, by crystal structure analysis. In each of (RS)-1-benzyl-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]indolin-2-one, C24H21NO4, (Ic), and (RS)-1-benzyl-3-{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-3-hydroxyindolin-2-one, C25H24N2O3, (Id), inversion-related pairs of molecules are linked by O-H...O hydrogen bonds to form R22(10) rings, which are further linked into chains of rings by a combination of C-H...O and C-H...π(arene) hydrogen bonds in (Ic) and by C-H...π(arene) hydrogen bonds in (Id). The molecules of (RS)-1-benzyl-3-hydroxy-3-[2-oxo-2-(pyridin-4-yl)ethyl]indolin-2-one, C22H18N2O3, (Ie), are linked into a three-dimensional framework structure by a combination of O-H...N, C-H...O and C-H...π(arene) hydrogen bonds. (RS)-3-[2-(Benzo[d][1,3]dioxol-5-yl)-2-oxoethyl]-1-benzyl-3-hydroxyindolin-2-one, C24H19NO5, (If), crystallizes with Z' = 2 in the space group P-1 and the molecules are linked into complex sheets by a combination of O-H...O, C-H...O and C-H...π(arene) hydrogen bonds. In each of (E)-1-benzyl-3-[2-(4-fluorophenyl)-2-oxoethylidene]indolin-2-one, C23H16FNO2, (IIa), and (E)-1-benzyl-3-[2-oxo-2-(thiophen-2-yl)ethylidene]indolin-2-one, C21H15NO2S, (IIg), the molecules are linked into simple chains by a single C-H...O hydrogen bond, while those of (E)-1-benzyl-3-[2-oxo-2-(pyridin-4-yl)ethylidene]indolin-2-one, C22H16N2O2, (IIe), are linked by three C-H...O hydrogen bonds to form sheets which are further linked into a three-dimensional structure by C-H...π(arene) hydrogen bonds. There are no hydrogen bonds in the structures of either (E)-1-benzyl-3-[2-(4-methoxyphenyl)-2-oxoethylidene]indolin-2-one, C24H19NO3, (IIc), or (E)-1-benzyl-5-chloro-3-[2-(4-chlorophenyl)-2-oxoethylidene]indolin-2-one, C23H15Cl2NO2, (IIh), but the molecules of (IIh) are linked into chains of π-stacked dimers by a combination of C-Cl...π(arene) and aromatic π-π stacking interactions.

RESUMEN

Quaternary or spirocyclic 3-substituted-3-hydroxy-2-oxindole is considered a privileged scaffold. In other words, it is a molecular core present on several compounds with a wide spectrum of biological activities. Among its precursors, activated ketones (isatin nucleus) can be used as interesting starting points to Morita-Baylis-Hillman adducts derivatives, a class of compounds with good cytotoxic potential. In this paper, we present the synthesis, anti-proliferative activity against lung cancer cell line and a theoretical conformational study of 21 of Morita-Baylis-Hillman adducts from isatin derivatives, by DFT quantum chemical calculations, followed by a SAR and QSAR analysis. Besides, an efficient synthetic protocol and good biological activity profile were highlighted interesting observations about 1H NMR experimental spectra, molecular modeling results and crystallographic data available.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Técnicas de Química Sintética , Isatina/química , Isatina/farmacología , Modelos Teóricos , Espectroscopía de Protones por Resonancia Magnética , Antineoplásicos/síntesis química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Isatina/análogos & derivados , Isatina/síntesis química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad Cuantitativa

RESUMEN

The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE-reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)-5-chloro-3-(hydroxyimino) indolin-2-one oxime (Cℓ-HIN) and 2-(5-chloro-2-oxoindolin-3-ylidene)-hydrazinecarbothioamide (Cℓ-OXHS) was higher than 1000 µM while to 3-(phenylhydrazono) butan-2-one oxime (PHBO) was 38 µM. Our screening showed that Cℓ-HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Cℓ-HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Cℓ-HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase-1 (PON-1) activity among groups treated. In conclusion, Cℓ-HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Cℓ-HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.

Asunto(s)

Inhibidores de la Colinesterasa/toxicidad , Isatina/farmacología , Malatión/toxicidad , Oximas/farmacología , Animales , Artemia , Reactivadores de la Colinesterasa/administración & dosificación , Reactivadores de la Colinesterasa/química , Reactivadores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Descubrimiento de Drogas/métodos , Femenino , Insecticidas/toxicidad , Isatina/administración & dosificación , Isatina/química , Dosificación Letal Mediana , Masculino , Oximas/administración & dosificación , Oximas/química , Ratas , Ratas Wistar

RESUMEN

In this review we compare and discuss results of compounds already reported as anticancer agents based on isatin-derivatives, metalated as well as non-metallated. Isatin compounds can be obtained from plants, marine animals, and is also found in human fluids as a metabolite of amino acids. Its derivatives include imines, hydrazones, thiosemicarbazones, among others, already focused on numerous anticancer studies. Some of them have entered in pre-clinical and clinical tests as antiangiogenic compounds or inhibitors of crucial proteins. As free ligands or coordinated to metal ions, such isatin derivatives showed promising antiproliferative properties against different cancer cells, targeting different biomolecules or organelles. Binding to metal ions usually improves its biological properties, indicating a modulation by the metal and by the ligand in a synergistic process. They also reveal diverse mechanisms of action, being able of binding DNA, generating reactive species that cause oxidative damage, and inhibiting selected proteins. Strategies used to improve the efficiency and selectivity of these compounds comprise structural modification of the ligands, metalation with different ions, syntheses of mononuclear and dinuclear species, and use of inserted or anchored compounds in selected drug delivery systems.

RESUMEN

Several isatin derivatives have shown important biological activities, which have attracted interest from researchers. For this reason, the present study aimed to evaluate the anti-inflammatory and antinociceptive effects of the isatin derivative (Z)-2-(5-chloro-2-oxoindolin-3-ylidene)-N-phenyl-hydrazinecarbothioamide (COPHCT) in mice. Three doses of this compound were tested: 1.0, 2.5, and 5.0 mg/kg. The anti-inflammatory activity was assessed using the carrageenan-induced paw edema model and the zymosan-induced air pouch model. The evaluation of the antinociceptive effect was performed through the formalin test and the acetic acid-induced abdominal writhing test. The paw edema assay demonstrated that all doses of the compound showed a significant reduction of the edema in the second hour evaluated, but a better response was observed in the fourth hour. The zymosan-induced air pouch model indicated that the compound, in all doses, significantly reduced leukocyte migration and total protein concentration levels. In the formalin test, the doses 1.0, 2.5, and 5.0 mg/kg of COPHCT showed activity only in the second phase, with reduction in paw pain time of 73.61, 79.46, and 73.85%, respectively. The number of abdominal writhings decreased with the increasing dose, but only 5.0 mg/kg COPHCT exhibited a significant response, with a reduction of 24.88%. These results demonstrated the ability of this compound to interfere in the anti-inflammatory activity of edema, vascular permeability, and cell migration. In addition, its possible antinociceptive effect may be related to the dose used.

Asunto(s)

Animales , Masculino , Femenino , Ratas , Analgésicos/farmacología , Isatina/farmacología , Antiinflamatorios/farmacología , Extractos Vegetales , Carragenina , Edema

RESUMEN

Arboviruses have been spreading rapidly throughout the Western Hemisphere in recent decades. Among the arboviruses with high morbidity and mortality are the members of the Alphavirus and Flavivirus genera. Within the first genus, Chikungunya Virus (CHIKV) is considered one of the most challenging human arboviral infection worldwide, against which there is no specific antivirals. Flaviviruses are some of the main viruses responsible for encephalitis, haemorrhagic disease and developmental defects. Dengue virus (DENV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV) and Zika Virus (ZIKV) are examples of flaviviruses without clinically approved antiviral agents. Thus, the search for new antivirals becomes highly important. One of the strategies that can be employed to obtain new drugs is the identification and utilization of privileged structures. Isatin is an example of a privileged molecular framework, displaying a broad spectrum of biological activities, including antiviral action. Obtaining and studying the antiviral properties of isatin derivatives have helped to identify important agents with potential activity against different arboviruses. This article reviews some of these isatin derivatives, their structures and antiviral properties reported against this important group of viruses.

Asunto(s)

Antivirales/química , Antivirales/farmacología , Infecciones por Arbovirus/tratamiento farmacológico , Arbovirus/efectos de los fármacos , Isatina/química , Isatina/farmacología , Animales , Antivirales/uso terapéutico , Descubrimiento de Drogas/métodos , Humanos , Isatina/uso terapéutico

RESUMEN

BACKGROUND: Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry. OBJECTIVE: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold. METHOD: 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic intermediates were also evaluated for comparison. RESULTS: A series of compounds were prepared in good yields. Among the 37 compounds evaluated, 18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated alkyl chain (IC50 = 24.1, 38.6, and 83.2 µM; SI = 11.6, 11.8, and 14.0, respectively). To further elucidate the mechanism of action of these new compounds, the redox behaviour of some active and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase C (TcrPDEC). CONCLUSION: A class of thio/semicarbazones structurally simple and easily accessible was synthesized. Compounds containing thiosemicarbazone moieties showed the best results in the series, being more active than the corresponding semicarbazones. Our results indicated that the activity of these compounds does not originate from an oxidation-reduction pathway but probably from the interactions with trypanosomal enzymes.

Asunto(s)

Supervivencia Celular/efectos de los fármacos , Técnicas Electroquímicas/métodos , Semicarbazonas/síntesis química , Semicarbazonas/farmacología , Análisis Espectral/métodos , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Animales , Línea Celular , Ratones , Simulación del Acoplamiento Molecular , Semicarbazonas/química , Relación Estructura-Actividad , Tiosemicarbazonas/química , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacos

RESUMEN

The reaction in methanol of CuII acetate monohydrate with 5-fluoro-isatin 3-oxime deprotonated with KOH in a 1:2 molar ratio and recrystallization from pyridine yielded the title compound, [Cu(C8H4FN2O2)2(C5H5N)2]. In the centrosymmetric complex, the anionic form of the isatin oxime acts as a κ2N,O donor, building five-membered metallarings. The CuII cation is sixfold coordinated in a slightly distorted octa-hedral environment by two trans, equatorial, anionic isatin derivatives and two trans pyridine ligands in axial positions. The complexes are linked by hydrogen bonding into a three-dimensional network, which is also stabilized by π-π stacking inter-actions [centroid-to-centroid distance = 3.7352 (9) Å] and C-H⋯π contacts. The Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H⋯H (31.80%), H⋯C (24.30%), H⋯O (15.20%) and H⋯F (10.80%). This work is the second report in the literature of a crystal structure of a coordination compound with isatin 3-oxime ligands (coordination chemistry).

RESUMEN

The reaction between 5-fluoro-isatin and hydroxyl-amine hydro-chloride in acidic ethanol yields the title compound, C8H5FN2O2, whose mol-ecular structure matches the asymmetric unit and is nearly planar with an r.m.s. deviation for the mean plane through all non-H atoms of 0.0363 Å. In the crystal, the mol-ecules are linked by N-H⋯N, N-H⋯O and O-H⋯O hydrogen-bonding inter-actions into a two-dimensional network along the (100) plane, forming rings with R22 (8) and R12 (5) graph-set motifs. The crystal packing also features weak π-π inter-actions along the [100] direction [centroid-to-centroid distance 3.9860 (5) Å]. Additionally, the Hirshfeld surface analysis indicates that the major contributions for the crystal structure are the O⋯H (28.50%) and H⋯F (16.40%) inter-actions. An in silico evaluation of the title compound with the vascular endothelial growth factor receptor-2 (VEGFR-2) was carried out. The title compound and the selected biological target VEGFR-2 show the N-H⋯O(GLU94), (CYS96)N-H⋯O(isatine) and (PHE95)N-H⋯O(isatine) inter-molecular inter-actions, which suggests a solid theoretical structure-activity relationship.