RESUMEN
Angiogenesis, the formation of new blood vessels, stimulates tumor growth and spread by delivering oxygen and nutrients, and is a key component of metastasis. This work aimed to evaluate the anti-angiogenic properties of a new synthesized compound. Rat aorta angiogenesis assay was used to evaluate the ability of the carbothioamide derivative to inhibit blood vessels sprouting. The tetrazolium (MTT) assay was used to evaluate the anti-proliferative effect of the synthetic compound on human umbilical vein endothelial cell line (HUVECs) and A549 lung cancer cells line. The (2, 2-diphenyl-1-picrylhydrazyl) DPPH was used to investigate the free radical scavenging action. The study showed that the compound has anti-angiogenic activity with IC50 56.9 µg/mL, moreover the compound managed to inhibit the proliferation of HUVECs and A549 cells (IC50 76.3 µg/mL and 45.5 µg/mL, respectively), and The IC50 concentration for free radical scavenging activity of the compound was 27.8 µg/ml. The study concluded that the compound has significant anti-angiogenic activity may be related to its significant anti-proliferative effect against HUVECs, these pharmacological effect may attributed to its potent free radical scavenging activity.
Asunto(s)
Inhibidores de la Angiogénesis , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proliferación Celular/efectos de los fármacos , Ratas , Inhibidores de la Angiogénesis/farmacología , Animales , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células A549 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Antineoplásicos/farmacología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Hidrazinas/farmacología , Tioamidas/farmacología , Tioamidas/química , MasculinoRESUMEN
A significant reason for developing innovative insecticidal active agents is the exponential rise in resistance to traditional chemical pesticides. Exploring new classes of insecticidal compounds with distinct mechanisms of action is one way to address this difficulty. So that, novel aryl thioamides derivatives 3-15 has been synthesized viaone-pot, three-component reaction of aroyl chloride, ammonium thiocyanate, and aromatic amines in dry acetone. The newly synthesized compounds' structures were validated by various spectroscopic methods, including elemental analysis, 1H-NMR, 13C NMR, and infrared spectroscopy. Under laboratory circumstances, the synthesized compounds showed good and broad-spectrum insecticidal activities toward S. littorali. When compared to other synthetic target compounds, 2,4-dichloro-N-[(3-fluorophenyl)carbamothioyl]benzamide 11, 2,4-dichloro-N-[(3-fluorophenyl)carbamothioyl]benzenecarbothioamide 13 showed good insecticidal activity, with 46.33â mg/L and LC50 values of 49.25â mg/L for 2nd instar larvae. Furthermore, the compound 3 was the least toxic in controlling the second and fourth instar larvae of S. littoralis on tomato leaves. Additionally, several histopathological and biochemical features of the some synthesized compounds under laboratory circumstances were also examined.
Asunto(s)
Diseño de Fármacos , Insecticidas , Spodoptera , Tioamidas , Animales , Insecticidas/farmacología , Insecticidas/síntesis química , Insecticidas/química , Spodoptera/efectos de los fármacos , Relación Estructura-Actividad , Tioamidas/química , Tioamidas/farmacología , Tioamidas/síntesis química , Larva/efectos de los fármacos , Estructura Molecular , Hormonas Juveniles/farmacología , Hormonas Juveniles/química , Hormonas Juveniles/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
Malaria continues to be a significant burden, particularly in Africa, which accounts for 95% of malaria deaths worldwide. Despite advances in malaria treatments, malaria eradication is hampered by insecticide and antimalarial drug resistance. Consequently, the need to discover new antimalarial lead compounds remains urgent. To help address this need, we evaluated the antiplasmodial activity of twenty-two amides and thioamides with pyridine cores and their non-pyridine analogues. Twelve of these compounds showed in vitro anti-proliferative activity against the intraerythrocytic stage of Plasmodium falciparum, the most virulent species of Plasmodium infecting humans. Thiopicolinamide 13i was found to possess submicromolar activity (IC50 = 142 nM) and was >88-fold less active against a human cell line. The compound was equally effective against chloroquine-sensitive and -resistant parasites and did not inhibit ß-hematin formation, pH regulation or PfATP4. Compound 13i may therefore possess a novel mechanism of action.
Asunto(s)
Antimaláricos , Plasmodium falciparum , Piridinas , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/farmacología , Antimaláricos/química , Humanos , Piridinas/farmacología , Piridinas/química , Amidas/farmacología , Línea Celular , Concentración 50 Inhibidora , Resistencia a Medicamentos , Descubrimiento de Drogas , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Tioamidas/farmacología , Tioamidas/química , Pruebas de Sensibilidad ParasitariaRESUMEN
Short, synthetic peptides that are displayed by major histocompatibility complex I (MHC I) can stimulate CD8 T cells in vivo to destroy virus-infected or cancer cells. The development of such peptides as vaccines that provide protective immunity, however, is limited by rapid proteolytic degradation. Introduction of unnatural amino acid residues can suppress MHC I antigen proteolysis, but the modified peptides typically display lower affinity for MHC I and/or diminished ability to activate CD8 T cells relative to native antigen. Here, we report a new strategy for modifying MHC I antigens to enhance resistance to proteolysis while preserving MHC I affinity and T cell activation properties. This approach, replacing backbone amide groups with thioamides, was evaluated in two well-characterized antigens presented by HLA-A2, a common human MHC I. For each antigen, singly modified thioamide analogues retained affinity for HLA-A2 and activated T cells specific for the native antigen, as measured via interferon-γ secretion. In each system, we identified a highly potent triply substituted thioamide antigen ("thio-antigen") that displayed substantial resistance to proteolytic cleavage. Collectively, our results suggest that thio-antigens may represent a general and readily accessible source of potent vaccine candidates that resist degradation.
Asunto(s)
Antígeno HLA-A2 , Tioamidas , Humanos , Tioamidas/farmacología , Tioamidas/metabolismo , Péptidos/metabolismo , Linfocitos T CD8-positivos , Complejo Mayor de HistocompatibilidadRESUMEN
Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present a series of four Ag(I) coordination compounds bearing as ligands the CH3-substituted thiadiazole-based thioamide 5-methyl-1,3,4-thiadiazole-2-thiol (mtdztH) and phosphines, i.e., [AgCl(mtdztH)(PPh3)2] (1), [Ag(mtdzt)(PPh3)3] (2), [AgCl(mtdztH)(xantphos)] (3), and [AgmtdztH)(dppe)(NO3)]n (4), where xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dppe = 1,2-bis(diphenylphosphino)ethane, and the assessment of their in vitro antibacterial and anti-cancer efficiency. Among them, diphosphine-containing compounds 3 and 4 were found to exhibit broad-spectrum antibacterial activity characteristics against both Gram-(+) and Gram-(-) bacterial strains, showing high in vitro bioactivity with IC50 values as low as 4.6 µΜ. In vitro cytotoxicity studies against human ovarian, pancreatic, lung, and prostate cancer cell lines revealed the strong cytotoxic potential of 2 and 4, with IC50 values in the range of 3.1-24.0 µΜ, while 3 and 4 maintained the normal fibroblast cells' viability at relatively higher levels. Assessment of these results, in combination with those obtained for analogous Ag(I) complexes bearing similar heterocyclic thioamides, suggest the pivotal role of the substituent groups of the thioamide heterocyclic ring in the antibacterial and anti-cancer efficacy of the respective Ag(I) complexes. Compounds 1-4 exhibited moderate in vitro antioxidant capacity for free radicals scavenging, as well as reasonably strong ability to interact with calf-thymus DNA, suggesting the likely implication of these properties in their bioactivity mechanisms. Complementary insights into the possible mechanism of their anti-cancer activity were provided by molecular docking calculations, exploring their ability to bind to the overexpressed fibroblast growth factor receptor 1 (FGFR1), affecting cancer cells' functionalities.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Proliferación Celular , Complejos de Coordinación/química , Simulación del Acoplamiento Molecular , Plata/química , Tioamidas/farmacologíaRESUMEN
In recent years, there has been an increasing interest in the study of Ag(I) coordination compounds as potent antibacterial and anticancer agents. Herein, a series of Ag(I) complexes bearing phosphines and heterocyclic thioamide ligands with highly electronegative NH2- and CF3-group substituents, i.e. [AgCl(atdztH)(xantphos)] (1), [Ag(µ-atdztH)(DPEphos)]2(NO3)2 (2), [Ag(atdzt)(PPh3)3] (3), [Ag(µ-atdzt)(DPEphos)]2 (4), and [Ag(µ-mtft)(DPEphos)]2 (5), where atdztH = 5-amino-1,3,4-thiadiazole-2-thiol, mtftH = 4-methyl-5-(trifluoromethyl)-1,2,4-triazol-3-thiol, xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and DPEphos = bis(2-diphenylphosphino-phenyl)ether, were synthesized, and their in vitro antibacterial and anticancer properties were evaluated. Complexes 1-4 bearing the NH2-substituted thioamide exhibited moderate-to-high activity against S. aureus, B. subtilis, B. cereus and E. coli bacterial strains. A high antiproliferative activity was also observed for 1-3 against SKOV-3, Hup-T3, DMS114 and PC3 cancer cell lines (IC50 = 4.0-11.7 µM), as well as some degree of selectivity against MRC-5 normal cells. Interestingly, 5 bearing the CF3-substituted thioamide is completely inactive in all bioactivity studies. Binding of 1-3 to drug-carrier proteins BSA and HSA is reasonably strong for their uptake and subsequent release to possible target sites. The three complexes show a significant in vitro antioxidant ability for scavenging free radicals, suggesting likely implication of this property in the mechanism of their bioactivity, but a low potential to destroy the double-strand structure of CT-DNA by intercalation. Complementary insights into possible bioactivity mechanisms were provided by molecular docking calculations, exploring the ability of complexes to bind to bacterial DNA gyrase, and to the overexpressed in the aforementioned cancer cells Fibroblast Growth Factor Receptor 1, affecting their functionalities.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Escherichia coli , Ligandos , Simulación del Acoplamiento Molecular , Plata/química , Plata/farmacología , Staphylococcus aureus , Tioamidas/farmacologíaRESUMEN
A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh3)2] (1), [Ag(dmp2SH)(PPh3)2]NO3 (2), [Ag(dmp2SΗ)(xantphos)]NO3 (3), [Ag(µ-dmp2S)(PPh3)]2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(µ-dmp2S)(DPEphos)]2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC50 = 1.6-4.5 µM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC50 = 0.32-3.00 µΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein.
Asunto(s)
Antiinfecciosos/farmacología , Complejos de Coordinación/química , Plata/química , Tioamidas/química , Antibacterianos/farmacología , Antiinfecciosos/química , Antineoplásicos/farmacología , Antioxidantes/farmacología , Bacterias/efectos de los fármacos , Quinasa 6 Dependiente de la Ciclina/metabolismo , ADN/metabolismo , Girasa de ADN/metabolismo , Células HeLa , Humanos , Ligandos , Células MCF-7 , Pruebas de Sensibilidad Microbiana/métodos , Modelos Moleculares , Simulación del Acoplamiento Molecular/métodos , Fosfinas/química , Plata/farmacología , Tioamidas/farmacología , Xantenos/químicaRESUMEN
Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wnt/ß-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Daño del ADN , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Glioblastoma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina/biosíntesis , Temozolomida/farmacología , Proteínas Supresoras de Tumor/metabolismo , Animales , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Sinergismo Farmacológico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Piperazinas/farmacología , Piridinas/farmacología , Serina/antagonistas & inhibidores , Tioamidas/farmacología , Carga Tumoral/efectos de los fármacos , Proteínas Supresoras de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Background: 2-Indolinone-based hydrazinecarbothioamides carrying a 3-phenylsulfonamide moiety (7-9) were designed by replacement of donepezil's pharmacophore group indanone with a 2-indolinone ring. Method: Compounds 7-9 were synthesized by reaction of N-(3-sulfamoylphenyl)hydrazinecarbothioamide (6) with 1H-indolin-2,3-diones (1-3). Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects of compounds 7-9 were assayed. Molecular modeling studies of 5-chloro-1,7-dimethyl-substituted compound 8e were carried out to determine the possible binding interactions at the active site of AChE. Results: Compound 8e showed the strongest inhibition against AChE (Ki = 0.52 ± 0.11 µM) as well as the highest selectivity (SI = 37.69). The selectivity for AChE over BuChE of compound 8e was approximately 17-times higher than donepezil and 26-times higher than galantamine. Conclusion: Further development of compounds 7-9 may present new promising agents for Alzheimer's treatment.
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Hidrazinas/farmacología , Oxindoles/farmacología , Tioamidas/farmacología , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Modelos Moleculares , Estructura Molecular , Oxindoles/química , Tioamidas/síntesis química , Tioamidas/químicaRESUMEN
Histone deacylase 11 and human sirtuins are able to remove fatty acid-derived acyl moieties from the ε-amino group of lysine residues. Specific substrates are needed for investigating the biological functions of these enzymes. Additionally, appropriate screening systems are required for identification of modulators of enzymatic activities of HDAC11 and sirtuins. We designed and synthesized a set of activity probes by incorporation of a thioamide quencher unit into the fatty acid-derived acyl chain and a fluorophore in the peptide sequence. Systematic variation of both fluorophore and quencher position resulted "super-substrates" with catalytic constants of up to 15,000,000 M-1s-1 for human sirtuin 2 (Sirt2) enabling measurements using enzyme concentrations down to 100 pM in microtiter plate-based screening formats. It could be demonstrated that the stalled intermediate formed by the reaction of Sirt2-bound thiomyristoylated peptide and NAD+ has IC50 values below 200 pM.
Asunto(s)
Colorantes Fluorescentes/química , Histona Desacetilasas/metabolismo , Tomografía de Emisión de Positrones , Sirtuinas/metabolismo , Tioamidas/química , Transporte de Electrón , Colorantes Fluorescentes/farmacología , Histona Desacetilasas/química , Histona Desacetilasas/genética , Humanos , Estructura Molecular , Procesos Fotoquímicos , Sirtuinas/antagonistas & inhibidores , Sirtuinas/química , Tioamidas/farmacologíaRESUMEN
Serine is involved in the regulation of hepatic lipid metabolism. However, whether exogenous or endogenous serine deficiency affects lipid accumulation in the liver and related mechanisms is unclear. Here, we investigated the effects of serine deficiency on hepatic fat accumulation in mice fed a serine-deficient diet or in mice supplemented with the D-3-phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503. Both treatments produced an increase in body weight and liver weight and higher triglyceride content in the liver. Both treatments also exacerbated hepatic inflammatory responses and oxidative stress. Importantly, NCT-503 supplementation significantly inhibited PHGDH activity and decreased the serine content in the liver. Dietary serine deficiency significantly affected the colonic microbiota, characterized by a decreased ratio of Firmicutes/Bacteroidetes and decreased proportion of Bifidobacterium. Dietary serine deficiency additionally resulted in significantly decreased colonic and serum acetate and butyrate levels. The collective results indicate that NCT-503 supplementation may contribute to overaccumulation of hepatic lipid, by causing hepatic serine deficiency, while dietary serine deficiency may produce similar outcomes by affecting the gut-microbiota-liver axis.
Asunto(s)
Hígado Graso/etiología , Hígado/metabolismo , Serina/deficiencia , Triglicéridos/metabolismo , Acetatos/metabolismo , Animales , Bacterias/crecimiento & desarrollo , Bacterias/metabolismo , Butiratos/metabolismo , Colon/microbiología , Modelos Animales de Enfermedad , Disbiosis , Inhibidores Enzimáticos/farmacología , Hígado Graso/metabolismo , Hígado Graso/microbiología , Hígado Graso/patología , Microbioma Gastrointestinal , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo , Fosfoglicerato-Deshidrogenasa/antagonistas & inhibidores , Fosfoglicerato-Deshidrogenasa/metabolismo , Piperazinas/farmacología , Piridinas/farmacología , Tioamidas/farmacología , Aumento de PesoRESUMEN
The small-molecule inhibitor of phosphoglycerate dehydrogenase, NCT-503, reduces incorporation of glucose-derived carbons into serine in vitro. Here we describe an off-target effect of NCT-503 in neuroblastoma cell lines expressing divergent phosphoglycerate dehydrogenase (PHGDH) levels and single-cell clones with CRISPR-Cas9-directed PHGDH knockout or their respective wildtype controls. NCT-503 treatment strongly reduced synthesis of glucose-derived citrate in all cell models investigated compared to the inactive drug control and independent of PHGDH expression level. Incorporation of glucose-derived carbons entering the TCA cycle via pyruvate carboxylase was enhanced by NCT-503 treatment. The activity of citrate synthase was not altered by NCT-503 treatment. We also detected no change in the thermal stabilisation of citrate synthase in cellular thermal shift assays from NCT-503-treated cells. Thus, the direct cause of the observed off-target effect remains enigmatic. Our findings highlight off-target potential within a metabolic assessment of carbon usage in cells treated with the small-molecule inhibitor, NCT-503.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfoglicerato-Deshidrogenasa/antagonistas & inhibidores , Piperazinas/farmacología , Piridinas/farmacología , Tioamidas/farmacología , Sistemas CRISPR-Cas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclo del Ácido Cítrico/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas/métodos , Glucosa/metabolismo , Humanos , Metabolómica , Fosfoglicerato-Deshidrogenasa/genéticaRESUMEN
Urease is potential target for various human's health complications, such as peptic ulcer, gastric cancer and kidney stone formation. The present study was based on synthesis of new hybrid pharmacophore N-substituted hydrazine-carbothioamides as potential urease inhibitors. Presented method gave excellent yield in range of 85-95% for hydrazine-carbothioamides derivatives (3a-s) after reaction of mono- and disubstituted hydrazides (1a-k) and substituted isothiocyanates (2a-d). All newly derivatives were characterized by advanced spectroscopic techniques (FTIR, 1HNMR, 13CNMR, EMS) and were assessed for their urease inhibition potential. All analogs except for 3k, 3l and 3m demonstrated strong inhibitory potential for urease with IC50 values of 8.45 ± 0.14 to 25.72 ± 0.23 µM as compared to standard thiourea (IC50 21.26 ± 0.35 µM). The structure-activity relationship and mode of interaction was established by molecular docking studies. It was revealed that the N-substituted hydrazine-carbothioamides interacted with nickel atoms present in the active site of urease and supported the correlations with the experimental findings. Therefore, the afforded hydrazine-carbothioamides derivatives are interesting hits for urease inhibition studies with future prospects of modification and optimization.
Asunto(s)
Inhibidores Enzimáticos/química , Hidrazinas/química , Relación Estructura-Actividad Cuantitativa , Tioamidas/química , Ureasa/antagonistas & inhibidores , Sitios de Unión , Inhibidores Enzimáticos/farmacología , Hidrazinas/farmacología , Simulación del Acoplamiento Molecular , Unión Proteica , Tioamidas/farmacología , Ureasa/química , Ureasa/metabolismoRESUMEN
Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer's heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 µM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 µM, respectively. Various informative structure-activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Colinesterasas/metabolismo , Hidrazinas/farmacología , Tioamidas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Compuestos Heterocíclicos/farmacología , Humanos , Microondas , Simulación del Acoplamiento Molecular , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
New hydrazinecarbothioamides with a phenylsulfonyl group were synthesized and their structures were identified by different spectroscopic data (1 H NMR, 13 C NMR, two-dimensional NMR, mass spectrometry, elemental analysis, and single-crystal X-ray analysis). The mechanism describing the formation of the products was also discussed. The antidiabetic activity of the isolated products was investigated histochemically. The synthesized sulfonylalkylthiosemicarbazide exhibited antihyperglycemic activity in streptozotocin-induced diabetic mice. Compounds 5a and 5c significantly lowered the blood glucose level to 103.3 ± 1.8 and 102 ± 3.9 mg/dl, respectively. Also, they caused a significant decrease in malondialdehyde levels and normalized the glutathione levels in streptozotocin-induced diabetic mice, compared with the diabetic group. The results suggest that the synthesized hydrazinocarbothioamides may effectively inhibit the development of oxidative stress in diabetes.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Hidrazinas/farmacología , Hipoglucemiantes/farmacología , Tioamidas/farmacología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Hidrazinas/síntesis química , Hidrazinas/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Estreptozocina , Relación Estructura-Actividad , Tioamidas/síntesis química , Tioamidas/químicaRESUMEN
BACKGROUND: Mixed ligand-metal complexes are efficient chelating agents because of their flexible donor ability. Mixed ligand complexes containing hetero atoms sulphur, nitrogen and oxygen have been probed for their biological significance. METHODS: Nine mixed ligand-metal complexes of 2-(butan-2-ylidene) hydrazinecarbothioamide (2- butanone thiosemicarbazone) with pyridine, bipyridine and 2-picoline as co-ligands were synthesized with Cu, Co and Zn salts. The complexes were tested against MDA-MB231 (MDA) and A549 cell lines. Antibacterial activity was tested against Staphylococcus aureus and Escherichia coli. The drug character of the complexes was evaluated on parameters viz. physicochemical properties, bioactivity scores, toxicity assessment and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile using various automated softwares. Molecular docking was performed against Ribonucleotide Reductase (RR) and topoisomerase II (topo II). RESULTS: The mixed ligand-metal complexes were synthesized by condensation reaction for 4-5 h. The characterization was done by elemental analysis, 1H-NMR, FT-IR, molar conductance and UV spectroscopic techniques. Molecular docking results showed that [Cu(C5H11N3S)(py)2(CH3COO)2], [Zn(C5H11N3S)(bpy)(SO4)] and [Zn(C5H11N3S)(2-pic)2(SO4)] displayed the lowest binding energies with respect to RR. Against topo II [Cu(C5H11N3S)(py)2(CH3COO)2], [Cu(C5H11N3S)(bpy)(CH3COO)2] and [Zn(C5H11N3S)(2-pic)2(SO4)] had the lowest energies. The druglikness assessment was done using Leadlikeness and Lipinski's rules. Not more than two violations were obtained in case of each filtering rule showing drug-like character of the mixed ligand complexes. Some of the complexes exhibited positive bioactivity scores and almost all the complexes were predicted to be safe with no hazardous effects as predicted by the toxicity assessment. Ames test predicted the non-mutagenic nature of the complexes. CONCLUSION: In vitro activity evaluation showed that [Zn(C5H11N3S)(py)2(SO4)], [Co(C5H11N3S(bpy) (Cl)2] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against MDA. Against A549 [Co(C5H11N3S)(py)2(Cl)2], [Cu(C5H11N3S)(py)2(CH3COO)2] and [Co(C5H11N3S(bpy)(Cl)2] were active. Antibacterial evaluation showed that [Co(C5H11N3S)(bpy)(Cl)2], [Zn(C5H11N3S)(2-pic)2(SO4)] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against S. aureus. Against E. coli, [Zn(C5H11N3S)(2- pic)2(SO4)] showed activity at 18-20 mg dose range.
Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Hidrazinas/farmacología , Simulación del Acoplamiento Molecular , Tioamidas/farmacología , Células A549 , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Simulación por Computador , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Ligandos , Pruebas de Sensibilidad Microbiana , Tioamidas/síntesis química , Tioamidas/químicaRESUMEN
The present research paper reports the convenient synthesis, successful characterization, in vitro antibacterial, antifungal, antioxidant potency and biocompatibility of N-acyl-morpholine-4-carbothioamides (5a-5j). The biocompatible derivatives were found to be highly active against the tested bacterial and fungal strains. Moreover, some of the screened N-acyl-morpholine-4-carbothioamides exhibited excellent antioxidant potential. Docking simulation provided additional information about possibilities of their inhibitory potential against RNA. It has been predicted by in silico investigation of the binding pattern that compounds 5a and 5j can serve as the potential surrogate for design of novel and potent antibacterial agents. The results for the in vitro bioassays were promising with the identification of compounds 5a and 5j as the lead and selective candidate for RNA inhibition. Results of the docking computations further ascertained the inhibitory potential of compound 5a. Based on the in silico studies, it can be suggested that compounds 5a and 5j can serve as a structural model for the design of antibacterial agents with better inhibitory potential. Binding mode of compound 5j inside the active site of RNA in 3D space. 5j displayed highest antibacterial potential than the reference drug ampicillin with ZOI 10.50 mm against Staphylococcus aureus. 5j also displayed highest antifungal potential than the reference drug amphotericin B with ZOI 18.20 mm against Fusarium solani.
Asunto(s)
Antibacterianos , Antifúngicos , Antioxidantes , Morfolinas , Tioamidas , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Aspergillus flavus/efectos de los fármacos , Aspergillus flavus/crecimiento & desarrollo , Aspergillus niger/efectos de los fármacos , Aspergillus niger/crecimiento & desarrollo , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Compuestos de Bifenilo/química , Células Cultivadas , Eritrocitos/efectos de los fármacos , Fusarium/efectos de los fármacos , Fusarium/crecimiento & desarrollo , Hemólisis/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Picratos/química , ARN/química , Tioamidas/síntesis química , Tioamidas/química , Tioamidas/farmacologíaRESUMEN
Poly (ADP-ribose) polymerases (PARPs) play a key role in DNA repair. In this study we designed a novel small-molecular compound, (E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamide (DHC-1), which was a potent and selective PARP-1 inhibitor. DHC-1 selectively inhibited PARP-1 activity with an IC50 value of 41.12 ± 13.28 nM. Cytotoxicity results showed that DHC-1 selectively inhibited the proliferation of BRCA1-deficient breast cancer HCC-1937 and BRCA2-deficient pancreatic cancer Capan-1 cells. Mechanism studies found that DHC-1 stabilized PARP-1-DNA complexes and inhibited PAR formation in BRCA2-/- Capan-1 cells. Further experiments found that DHC-1 induced DNA double-strand damage in BRCA2-/- Capan-1 cells, which was demonstrated by accumulation of γ-H2AX foci. Flow cytometry experiments revealed that DHC-1 induced G2/M phase arrest and activate mitochondrial-induced apoptotic pathways. Interestingly, we also found that DHC-1 enhanced cell proliferation inhibitory effect of oxaliplatin (OXA). The further in vivo nude mouse studies showed that DHC-1 inhibited the growth of Capan-1 xenografts and showed a similar mechanism to that in vitro. Collectively, our results demonstrate that DHC-1 may be an excellent candidate for treatment of BRCA-deficient pancreatic cancers.
Asunto(s)
Antineoplásicos/farmacología , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Compuestos de Bencilideno/farmacología , Hidrazinas/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Tioamidas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Compuestos de Bencilideno/química , Compuestos de Bencilideno/uso terapéutico , Neoplasias de la Mama , Ciclo Celular , Línea Celular Tumoral , Femenino , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidrazinas/química , Hidrazinas/uso terapéutico , Ratones , Ratones Desnudos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Tioamidas/química , Tioamidas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Organometallic metal(arene) anticancer agents were believed to confer low selectivity for potential cellular targets. However, the ruthenium(arene) pyridinecarbothioamide (plecstatin-1) showed target selectivity for plectin, a scaffold protein and cytolinker. We employed a three-dimensional cancer spheroid model and showed that plecstatin-1 limited spheroid growth, induced changes in the morphology and in the architecture of tumour spheroids by disrupting the cytoskeletal organization. Additionally, we demonstrated that plecstatin-1 induced oxidative stress, followed by the induction of an immunogenic cell death signature through phosphorylation of eIF2α, exposure of calreticulin, HSP90 and HSP70 on the cell membrane and secretion of ATP followed by release of high mobility group box-1.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Muerte Celular Inmunogénica/efectos de los fármacos , Rutenio/farmacología , Antineoplásicos/química , Neoplasias Colorrectales/patología , Células HCT116 , Células HT29 , Humanos , Rutenio/química , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patología , Tioamidas/química , Tioamidas/farmacología , Células Tumorales CultivadasRESUMEN
Cancer is a major cause of death. Thus, the incidence and mortality rate of cancer is globally important. Regarding vast problems caused by chemotherapy drugs, efforts have progressed to find new anti-cancer drugs. Pyrazole derivatives are known as components with anti-cancer properties. In here, Fe3O4 nanoparticles were first functionalized with (3-chloropropyl) trimethoxysilane, then 2-((pyrazol-4-yl) methylene) hydrazinecarbothioamide (P) was anchored on the surface of magnetic nanoparticles (PL). The synthesized nano-compounds were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, Zeta potential, dynamic light scattering, and energy-dispersive x-ray spectrometry analyses. The cytotoxicity effect was evaluated using MTT assay, apoptosis test by Flow cytometry, cell cycle analysis, Caspase-3 activity assay and Hoechst staining on MCF-7 cell line. The high toxicity for tumor cells and low toxicity on normal cells (MCF10A) was considered as an important feature (selectivity index, 10.9). Based on results, the IC50 for P and PL compounds were 157.80 and 131.84â µM/ml respectively. Moreover, apoptosis inducing, nuclear fragmentation, Caspase 3 activity and induction of cell rest in sub-G1 and S phases, were also observed. The inhibitory effect of PL was significantly higher than P, which could be due to the high penetrability of Fe3O4 nanoparticles.