RESUMEN

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

Asunto(s)

Homeostasis , Isoindoles , Pruebas de Sensibilidad Microbiana , Compuestos de Organoselenio , Oxidación-Reducción , Estreptomicina , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Animales , Ratones , Homeostasis/efectos de los fármacos , Estreptomicina/farmacología , Antituberculosos/farmacología , Antituberculosos/química , Mycobacterium marinum/efectos de los fármacos , Azoles/farmacología , Azoles/química , Relación Dosis-Respuesta a Droga , Antibacterianos/farmacología , Antibacterianos/química , Relación Estructura-Actividad , Estructura Molecular , Ratones Endogámicos BALB C

RESUMEN

Novel anticancer strategies reduce side effects on healthy tissues by elevating the lethal abilities of cancer cells. The development of effective particles with good bioavailability and selectivity remains problematic. For undesirable features, green chemistry is used to synthesize the best compounds, or natural-based particles are improved. Photodynamic therapy (PDT), modelled on phthalocyanines (Pcs), still delivers second-generation sensitizers which are complemented with metal ions, such as Zn2+, Al3+, or Ga3+. Gallium octacarboxyphthalocyanine hydroxide (Ga(OH)PcOC), was designed for skin cancer treatment, and was used as a pro-apoptotic and pro-oxidative agent on normal skin cell lines, fibroblasts (NHDF), and keratinocytes (HaCaT), with promising selectivity against melanoma cancer cells (Me45) in vitro. Compared to the previous reported findings, where the ZnPcOC acted on the skin cell lines at higher doses, the sensitivities to the Ga(OH)PcOC allows for an effective reduction of the sensitizer dose. The effective dose, for a novel Ga(OH)PcOC particle, was significantly reduced from 30 µM to 6 µM on Me45 cancer cells, tested using 24 h MTT viability, as well as cytometric pro-oxidative and pro-apoptotic assays. The promising photosensitizer did not reduce viability in normal fibroblasts and keratinocytes without reactive oxygen species (ROS) elevation or apoptosis induction. The improvement to the previous findings is better Ga-based photosensitizer selectivity against the cancer Me45 cells, then observed in Zn-based compounds.

Asunto(s)

Antineoplásicos , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Galio , Indoles , Fármacos Fotosensibilizantes , Neoplasias Cutáneas , Humanos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Galio/química , Galio/farmacología , Estructura Molecular , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Isoindoles/farmacología , Isoindoles/química , Isoindoles/síntesis química , Fotoquimioterapia , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacos , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Hidróxidos/química , Hidróxidos/farmacología

RESUMEN

Recombinant high-density lipoprotein (rHDL) as anti-atherosclerosis (AS) vehicle has unique advantages including multiple anti-atherogenic functions and homing features to plaques. However, rHDL may be converted into dysfunctional forms due to complex treatment during preparation. Herein, oxidation-induced dysfunction of non-split HDL and rHDL was initially investigated. It was found that although both non-split HDL and rHDL showed oxidative dysfunction behavior, non-split HDL demonstrated superior oxidation defense compared to rHDL due to its intact composition and avoidance of overprocessing such as split and recombination. Unfortunately, in vivo oxidative stress could compromise the functionality of HDL. Therefore, surface engineering of non-split HDL and rHDL with cascade antioxidant enzyme analogues Ebselen and mitochondrial-targeted TPGS-Tempo was conducted to construct a dual-line defense HDL nano system (i.e., T@E-HDLs/rHDL), aiming to restore plaque redox balance and preserving the physiological function of HDL. Results indicated that both T@E-HDLs and rHDLs performed without distinction and exhibited greater resistance to oxidative stress damage as well as better functions than unmodified HDLs in macrophage foam cells. Overall, the modification of dual antioxidants strategy bridges the gap between non-split HDL and rHDL, and provides a promising resolution for the dilemmas of oxidative stress in plaques and HDL self dysfunction.

Asunto(s)

Antioxidantes , Lipoproteínas HDL , Estrés Oxidativo , Proteínas Recombinantes , Estrés Oxidativo/efectos de los fármacos , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacología , Antioxidantes/farmacología , Proteínas Recombinantes/farmacología , Animales , Humanos , Ratones , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Oxidación-Reducción/efectos de los fármacos , Isoindoles/farmacología , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química

RESUMEN

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

Asunto(s)

Acetilcolinesterasa , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Relación Estructura-Actividad , Simulación de Dinámica Molecular , Humanos , Isoindoles/química , Isoindoles/farmacología , Isoindoles/síntesis química , Estructura Molecular

RESUMEN

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Asunto(s)

Compuestos de Bifenilo , Lignanos , Micelas , Compuestos de Organoselenio , Daño por Reperfusión , Daño por Reperfusión/prevención & control , Daño por Reperfusión/tratamiento farmacológico , Compuestos de Bifenilo/química , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacología , Lignanos/farmacología , Lignanos/química , Lignanos/administración & dosificación , Humanos , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/administración & dosificación , Isoindoles/farmacología , Isoindoles/administración & dosificación , Isoindoles/química , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas/administración & dosificación , Azoles/química , Azoles/farmacología , Azoles/administración & dosificación , Animales , Riñón/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/administración & dosificación , Tamaño de la Partícula , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Portadores de Fármacos/química , Estrés Oxidativo/efectos de los fármacos

RESUMEN

In this study, (E)-4-{4-[(1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl]phenoxy}phthalonitrile (4) and its phthalocyanine derivatives (5-8) were synthesized for the first time. Aggregation behaviors of the novel soluble phthalocyanines in organic solvents were investigated. In addition, the efficiency of 1O2 production of (5) and ZnPc (6) was investigated. The singlet oxygen quantum yields (ΦΔ) for 2HPc (5) and ZnPc (6) were found to be 0.58 and 0.83, respectively. Additionally, novel phthalocyanines (5-8) were investigated for their ability to inhibit enzymes. They exhibited a highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and α-glycosidase (α-Gly) enzymes. Ki values are in the range of 2.60 ± 9.87 to 11.53 ± 6.92 µM, 3.35 ± 0.53 to 15.47 ± 1.20 µM, and 28.60 ± 4.82 to 40.58 ± 7.37 nM, respectively. The calculations of the studied molecule at the B3LYP, HF, and M062X levels in the 6-31G basis sets were made using the Gaussian package program. Afterward, the interactions occurring in the docking calculation against a protein that is the crystal structure of hCA I (PDB ID: 2CAB), the crystal structure of hCA II (PDB ID: 5AML), and the crystal structure of α-Gly (PDB ID: 1R47), were examined. Following that, Protein-Ligand Interaction Profiler (PLIP) analysis was used to look at the interactions that occurred during the docking calculation in further detail.

Asunto(s)

Inhibidores de Anhidrasa Carbónica , Indoles , Isoindoles , Humanos , Isoindoles/síntesis química , Isoindoles/farmacología , Isoindoles/química , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Relación Estructura-Actividad , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Estructura Molecular , Simulación del Acoplamiento Molecular , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica I/antagonistas & inhibidores , Anhidrasa Carbónica I/metabolismo , Oxígeno Singlete/metabolismo , Relación Dosis-Respuesta a Droga

RESUMEN

While research has identified several inhibitors of the main protease (Mpro) of SARS-CoV-2, a significant portion of these compounds exhibit reduced activity in the presence of reducing agents, raising concerns about their effectiveness in vivo. Furthermore, the conventional biosafety level 3 (BSL-3) for cellular assays using viral particles poses a limitation for the widespread evaluation of Mpro inhibitor efficacy in a cell-based assay. Here, we established a BSL-1 compatible cellular assay to evaluate the in vivo potential of Mpro inhibitors. This assay utilizes mammalian cells expressing a tagged Mpro construct containing N-terminal glutathione S-transferase (GST) and C-terminal hemagglutinin (HA) tags and monitors Mpro autodigestion. Using this method, GC376 and boceprevir effectively inhibited Mpro autodigestion, suggesting their potential in vivo activity. Conversely, carmofur and ebselen did not exhibit significant inhibitory effects in this assay. We further investigated the inhibitory potential of selenoneine on Mpro using this approach. Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases.

Asunto(s)

Antivirales , Azoles , Proteasas 3C de Coronavirus , Isoindoles , Compuestos de Organoselenio , Prolina , SARS-CoV-2 , Antivirales/farmacología , Antivirales/química , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Azoles/farmacología , Azoles/química , Prolina/análogos & derivados , Prolina/farmacología , Prolina/química , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Células HEK293 , Lactamas , Leucina/análogos & derivados , Ácidos Sulfónicos

RESUMEN

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid ß oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid ß oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid ß-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Asunto(s)

Isoindoles , Metabolismo de los Lípidos , Hígado , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Compuestos de Organoselenio , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Receptor Toll-Like 4 , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor Toll-Like 4/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Ratones , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Isoindoles/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Azoles/farmacología , Azoles/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Dieta Alta en Grasa , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an r2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design; with the potential to guide experimental synthesis and enzyme assay testing.

Asunto(s)

Antivirales , Proteasas 3C de Coronavirus , Diseño de Fármacos , Isoindoles , Aprendizaje Automático , Simulación de Dinámica Molecular , Compuestos de Organoselenio , Inhibidores de Proteasas , Relación Estructura-Actividad Cuantitativa , SARS-CoV-2 , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Isoindoles/química , Isoindoles/farmacología , Isoindoles/síntesis química , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/síntesis química , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Humanos , Azoles/química , Azoles/farmacología , Azoles/síntesis química , COVID-19/virología , Dominio Catalítico

RESUMEN

A series of naphtho[1,8-ef]isoindole-7,8,10(9H)-trione derivatives as novel theranostic agents for photodynamic therapy and multi-subcellular organelles localization were designed and synthesized. Most of them possess moderate fluorescence quantum yield and long wavelength absorption simultaneously, which made them possible for dual effects of imaging and therapy. Notably, compounds 7 b and 7 d exhibited significant light-toxicity but slight dark-toxicity. Confocal fluorescence microscopy experiments demonstrated that compound 7 b can locate and image in special multi-subcellular organelles. All the research results implied that naphtho[1,8-ef] isoindole-7,8,10(9H)-trione derivatives can be applied as a new series of theranostic agents with the characteristics of photodynamic therapy and multi-subcellular organelles imaging.

Asunto(s)

Orgánulos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Nanomedicina Teranóstica , Humanos , Orgánulos/efectos de los fármacos , Orgánulos/metabolismo , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Estructura Molecular , Isoindoles/química , Isoindoles/farmacología , Isoindoles/síntesis química , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Células HeLa , Proliferación Celular/efectos de los fármacos , Naftalenos/química , Naftalenos/farmacología , Naftalenos/síntesis química , Relación Dosis-Respuesta a Droga

RESUMEN

The World Health Organization (WHO) identifies several bunyaviruses as significant threats to global public health security. Developing effective therapies against these viruses is crucial to combat future outbreaks and mitigate their impact on patient outcomes. Here, we report the synthesis of some isoindol-1-one derivatives and explore their inhibitory properties over an indispensable metal-dependent cap-snatching endonuclease (Cap-ENDO) shared among evolutionary divergent bunyaviruses. The compounds suppressed RNA hydrolysis by Cap-ENDOs, with IC50 values predominantly in the lower µM range. Molecular docking studies revealed the interactions with metal ions to be essential for the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold activity. Calorimetric analysis uncovered Mn2+ ions to have the highest affinity for sites within the targets, irrespective of aminoacidic variations influencing metal cofactor preferences. Interestingly, spectrophotometric findings unveiled sole dinuclear species formation between the scaffold and Mn2+. Moreover, the complexation of two Mn2+ ions within the viral enzymes appears to be favourable, as indicated by the binding of compound 11 to TOSV Cap-ENDO (Kd = 28 ± 3 µM). Additionally, the tendency of compound 11 to stabilize His+ more than His- Cap-ENDOs suggests exploitable differences in their catalytic pockets relevant to improving specificity. Collectively, our results underscore the isoindolinone scaffold's potential as a strategic starting point for the design of pan-antibunyavirus drugs.

Asunto(s)

Diseño de Fármacos , Endonucleasas , Simulación del Acoplamiento Molecular , Endonucleasas/metabolismo , Endonucleasas/antagonistas & inhibidores , Isoindoles/síntesis química , Isoindoles/farmacología , Isoindoles/química , Relación Estructura-Actividad , Estructura Molecular , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Bunyaviridae/efectos de los fármacos , Bunyaviridae/metabolismo , Relación Dosis-Respuesta a Droga , Humanos

RESUMEN

Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1G93A mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1G93A mice clearly indicating functional improvement.

Asunto(s)

Esclerosis Amiotrófica Lateral , Azoles , Isoindoles , Compuestos de Organoselenio , Superóxido Dismutasa-1 , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Animales , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Isoindoles/farmacología , Ratones , Azoles/farmacología , Humanos , Ratones Transgénicos , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico

RESUMEN

Type 2 diabetes (T2DM) is a progressive metabolic disease associated with high blood sugar levels that affects 537 million people worldwide. This study aim is to investigate the potential for use in the treatment of T2DM by examining the in vitro glucosidase inhibitory effects of novel synthesized metallophthalocyanines. For this reason, we have synthesized cobalt(II), copper(II) phthalocyanines (3PY-ON-CoQ, 3PY-ON-CuQ) that are both water-soluble and do not aggregate in water. These compounds were characterized by using various spectroscopic methods. The α-glucosidase inhibitory properties of 3PY-ON-CoQ and 3PY-ON-CuQ were carried out using the spectrophotometric method. Then, Lineweaver-Burk and Dixon plots were examined to determine the inhibitory type and constant (Ki). The IC50 values of 3PY-ON-CoQ and 3PY-ON-CuQ were 6.85 ± 1.25 µM and 55.09 ± 2.64 µM, respectively. Both compounds displayed mixed inhibitory effects on α-glucosidase according to Lineweaver-Burk plots. The Ki values of 3PY-ON-CoQ and 3PY-ON-CuQ were calculated as 6.30 ± 1.55 µM and 54.25 ± 1.20 µM, respectively. The results of this work may lead to the discovery of new compounds for the treatment of T2DM.

Asunto(s)

Cobalto , Cobre , Inhibidores de Glicósido Hidrolasas , Indoles , Isoindoles , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Cobre/química , Indoles/química , Indoles/farmacología , Isoindoles/química , Isoindoles/farmacología , alfa-Glucosidasas/metabolismo , Cobalto/química , Solubilidad , Agua/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química

RESUMEN

An efficient and practical one-pot synthesis of isoindolines from readily available starting materials was achieved under mild conditions by implementing an isoindole umpolung strategy. A variety of isoindolines were prepared with good to excellent yields. Biological screens of these identified compounds demonstrated that they are potent potentiators of colistin for multi-drug resistant Acinetobacter baumannii.

Asunto(s)

Acinetobacter baumannii , Antibacterianos , Colistina , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Acinetobacter baumannii/efectos de los fármacos , Colistina/farmacología , Colistina/síntesis química , Colistina/química , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Isoindoles/síntesis química , Isoindoles/farmacología , Isoindoles/química , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Inhibition of poly (ADP-ribose) polymerase-1 (PARP1), a DNA repair enzyme, has proven to be a successful strategy for the treatment of various cancers. With the appropriate selection conditions and protein design, DNA-encoded library (DEL) technology provides a powerful avenue to identify small molecules with the desired mechanism of action towards a target of interest. However, DNA-binding proteins, such as PARP1, can be challenging targets for DEL screening due to non-specific protein-DNA interactions. To overcome this, we designed and screened a PARP1 catalytic domain construct without the autoinhibitory helical domain. This allowed us to interrogate an active, functionally-relevant form of the protein resulting in the discovery of novel isoindolinone PARP1 inhibitors with single-digit nanomolar potency. These inhibitors also demonstrated little to no PARP1-DNA trapping, a property that could be advantageous in the clinic.

Asunto(s)

ADN , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , ADN/química , ADN/metabolismo , Relación Estructura-Actividad , Descubrimiento de Drogas , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Dosis-Respuesta a Droga , Isoindoles/química , Isoindoles/farmacología , Isoindoles/síntesis química , Dominio Catalítico

RESUMEN

This review discusses the possible methods for improving therapeutic efficacies of phthalocyanine (Pcs) -based therapeutic probes in photo- and sono-dynamic therapies under hypoxic conditions. Herein, the structural design strategies including varying the central metal, position substituents and the effects of adjuvant used in supplementing the therapeutics activities of Pcs or formation of NPs are discussed for cancer therapies in hypoxic conditions. Different mechanisms induced for cell death influenced by the compositions of the Pcs-probes are discussed. The focus mainly highlights the oxygen (O2) -dependent mechanisms including methods of supplementing tumour microenvironment O2-concentrations to promote PDT or SDT therapies. Alternatively, O2-independent mechanisms mainly used to evade hypoxia by stimulating anticancer processes that don't require O2 to initiate cell death, such as the Fenton reaction or thermal ablation effects.

Asunto(s)

Indoles , Isoindoles , Fotoquimioterapia , Fármacos Fotosensibilizantes , Hipoxia Tumoral , Indoles/farmacología , Indoles/uso terapéutico , Humanos , Isoindoles/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fotoquimioterapia/métodos , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos

RESUMEN

This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.

Asunto(s)

Antipsicóticos , Esquizofrenia , Humanos , Clorhidrato de Lurasidona/efectos adversos , Esquizofrenia/tratamiento farmacológico , Serotonina , Isoindoles/farmacología , Tiazoles/farmacología , Antipsicóticos/efectos adversos , Aumento de Peso

RESUMEN

In this study, synthesis of novel isoindole-1,3-dione analogues bearig halo, hydroxy, and acetoxy groups at the position 4,5,6 of the bicyclic imide ring was performed to examine their potential anticancer effects against some cell lines. A multistep chemical pathway was used to synthesize the derivatives. The cytotoxic effect of trisubstituted isoindole derivatives were evaluated by determining cellular viability using the MTT assay against A549, PC-3, HeLa, Caco-2, and MCF-7 cell lines. The C-2 selective ring-opening products were obtained from the ring-opening reaction of 5-alkyl/aryl-2-hydroxyhexahydro-4H-oxireno[2,3-e]isoindole-4,6(5H)-diones with nucleophiles such as chloride (Cl- ) and bromide (Br- ) ions. In addition, the ring-opening products halodiols were converted to their related acetates. The anticancer activity of synthesized isoindole-1,3-dione derivatives was investigated against HeLa, A549, MCF-7, PC3, and Caco-2 cells in vitro and resulted in varies cytotoxic effect depend on the group attached to the isoindole molecule. Furthermore, the evaluation of the antimicrobial action of trisubstituted isoindole derivatives against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was assessed and found out selective inhibition of the both bacterial growth via different trisubstituted isoindole derivatives. The results of this work encourage further research on the potential utilization of trisubstituted isoindole derivatives as cytotoxic and antimicrobial agents.

Asunto(s)

Antiinfecciosos , Antineoplásicos , Humanos , Células CACO-2 , Isoindoles/química , Isoindoles/farmacología , Antibacterianos/química , Antineoplásicos/química , Antiinfecciosos/farmacología , Relación Estructura-Actividad , Estructura Molecular

Asunto(s)

Antipsicóticos , Retención Urinaria , Humanos , Clorhidrato de Lurasidona/efectos adversos , Retención Urinaria/inducido químicamente , Antipsicóticos/efectos adversos , Isoindoles/farmacología

RESUMEN

Screening of 25 analogs of Ebselen, diversified at the N-aromatic residue, led to the identification of the most potent inhibitors of Sporosarcina pasteurii urease reported to date. The presence of a dihalogenated phenyl ring caused exceptional activity of these 1,2-benzisoselenazol-3(2H)-ones, with Ki value in a low picomolar range (<20 pM). The affinity was attributed to the increased π-π and π-cation interactions of the dihalogenated phenyl ring with αHis323 and αArg339 during the initial step of binding. Complementary biological studies with selected compounds on the inhibition of ureolysis in whole Proteus mirabilis cells showed a very good potency (IC50 < 25 nM in phosphate-buffered saline (PBS) buffer and IC90 < 50 nM in a urine model) for monosubstituted N-phenyl derivatives. The crystal structure of S. pasteurii urease inhibited by one of the most active analogs revealed the recurrent selenation of the Cys322 thiolate, yielding an unprecedented Cys322-S-Se-Se chemical moiety.

Asunto(s)

Inhibidores Enzimáticos , Ureasa , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Bacterias/metabolismo , Isoindoles/farmacología , Azoles/farmacología