RESUMEN
Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.
Asunto(s)
Pirazoles , Tiadiazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , HumanosRESUMEN
Climate change forces agriculture to face the rapidly growing virulence of biotrophic fungal pathogens, which in turn drives researchers to seek new ways of combatting or limiting the spread of diseases caused by the same. While the use of agrochemicals may be the most efficient strategy in this context, it is important to ensure that such chemicals are safe for the natural environment. Heterocyclic compounds have enormous biological potential. A series of heterocyclic scaffolds (1,3,4-thiadiazole, 1,3-thiazole, 1,2,4-triazole, benzothiazine, benzothiadiazine, and quinazoline) containing 2,4-dihydroxylaryl substituents were investigated for their ability to inhibit the growth and development of biotrophic fungal pathogens associated with several important cereal diseases. Of the 33 analysed compounds, 3 were identified as having high inhibitory potential against Blumeria and Puccinia fungi. The conducted research indicated that the analysed compounds can be used to reduce the incidence of fungal diseases in cereals; however, further thorough research is required to investigate their effects on plant-pathogen systems, including molecular studies to determine the exact mechanism of their activity.
Asunto(s)
Grano Comestible , Compuestos Heterocíclicos , Enfermedades de las Plantas , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Grano Comestible/microbiología , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Hongos/efectos de los fármacos , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Tiadiazoles/farmacología , Tiadiazoles/químicaRESUMEN
The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE-/- mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.
Asunto(s)
Apoptosis , Aterosclerosis , Células Espumosas , Canales Iónicos , Macrófagos , Fagocitosis , Animales , Canales Iónicos/metabolismo , Canales Iónicos/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Ratones , Células Espumosas/metabolismo , Células Espumosas/patología , Humanos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Tiofenos/farmacología , Masculino , Especies Reactivas de Oxígeno/metabolismo , Placa Aterosclerótica/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Mitocondrias/metabolismo , Pirazinas , TiadiazolesRESUMEN
Targeting Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.
Asunto(s)
Aterosclerosis , Imagen Óptica , ARN Interferente Pequeño , Animales , Humanos , Ratones , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/terapia , Rayos Infrarrojos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Nanopartículas/química , Placa Aterosclerótica/diagnóstico por imagen , ARN Interferente Pequeño/química , ARN Interferente Pequeño/uso terapéutico , Tiadiazoles/química , Tiadiazoles/farmacología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/química , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismoRESUMEN
Implementing sustainable crop protection practices is crucial to protect global harvests and ensure high-quality food supplies. While priming is an established method in seed production for the fortification of plants against various stresses, it is not yet a standard practice in transplant cultivation. Thus, we evaluated the long-term effects of thermopriming-a heat-based priming technique-on the growth, development, and fruit yield of tomato plants. Following a recovery period of about six weeks for thermoprimed plants without stress inducers, we subjected them to subsequent salt stress to ascertain the persistence of the priming effects. Additionally, we compared the efficacy of thermopriming with benzothiadiazole (BTH), a chemical elicitor, in enhancing plant resilience to abiotic stress. While BTH application negatively impacted both plant growth and fruit health, thermopriming showed no such adverse effects on these parameters. Instead, thermopriming initially enhanced the plant defense mechanisms by increasing the accumulation of protective phenols and flavonoids in the leaves. Interestingly, while thermopriming did not alter the response to salt stress, it notably strengthened the overall resilience of the plants. Our findings underscore both the potential and temporal constraints of thermopriming memory. Nonetheless, primed plants exhibited temporarily increased stress tolerance, offering a means to safeguard the offspring.
Asunto(s)
Agricultura , Productos Agrícolas , Calor , Estrés Salino , Solanum lycopersicum , Solanum lycopersicum/efectos de los fármacos , Solanum lycopersicum/crecimiento & desarrollo , Productos Agrícolas/efectos de los fármacos , Productos Agrícolas/crecimiento & desarrollo , Agricultura/métodos , Estrés Salino/fisiología , Tiadiazoles/farmacología , Hojas de la Planta/química , Hojas de la Planta/efectos de los fármacos , Frutas/química , Frutas/efectos de los fármacosRESUMEN
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO (NtPPO) and herbicidal activity were evaluated. Among them, compounds B11 (Ki = 9.05 nM) and B20 (Ki = 10.23 nM) showed significantly better inhibitory activity against NtPPO than that against flumiclorac-pentyl (Ki = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to NtPPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.
Asunto(s)
Amaranthus , Diseño de Fármacos , Inhibidores Enzimáticos , Herbicidas , Simulación del Acoplamiento Molecular , Oxadiazoles , Ftalimidas , Malezas , Protoporfirinógeno-Oxidasa , Tiadiazoles , Herbicidas/química , Herbicidas/farmacología , Herbicidas/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Malezas/efectos de los fármacos , Malezas/enzimología , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/síntesis química , Relación Estructura-Actividad , Ftalimidas/química , Ftalimidas/farmacología , Ftalimidas/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Protoporfirinógeno-Oxidasa/antagonistas & inhibidores , Protoporfirinógeno-Oxidasa/química , Protoporfirinógeno-Oxidasa/metabolismo , Amaranthus/química , Amaranthus/efectos de los fármacos , Proteínas de Plantas/química , Proteínas de Plantas/antagonistas & inhibidores , Estructura Molecular , Nicotiana/químicaRESUMEN
Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
Asunto(s)
Antineoplásicos , Benzotiazoles , Proliferación Celular , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Tiadiazoles , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Humanos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacología , Benzotiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Sorafenib/farmacología , Sorafenib/química , Estructura Molecular , Simulación por Computador , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [125I]ITA-3, with moderate binding affinity (IC50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [125I]ITA-3, we developed a potential PET tracer, [18F]FITA-2 (radiochemical yield >25%, molar activity >110 GBq/µmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC50 = 245 nM), good brain uptake (SUVpeak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [18F]FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.
Asunto(s)
Tomografía de Emisión de Positrones , Tiadiazoles , alfa-Sinucleína , Tomografía de Emisión de Positrones/métodos , alfa-Sinucleína/metabolismo , Humanos , Animales , Tiadiazoles/química , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Tiadiazoles/farmacocinética , Ratas , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Radiofármacos/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Radioisótopos de Flúor/química , Imidazoles/química , Imidazoles/farmacocinética , Imidazoles/síntesis química , Masculino , Ratas Sprague-Dawley , Descubrimiento de Drogas , Relación Estructura-ActividadRESUMEN
Muscarinic receptors are G protein-coupled receptors (GPCRs) that play a role in various physiological functions. Previous studies have shown that these receptors, along with other GPCRs, are voltage-sensitive; both their affinity toward agonists and their activation are regulated by membrane potential. To our knowledge, whether the effect of antagonists on these receptors is voltage-dependent has not yet been studied. In this study, we used Xenopus oocytes expressing the M2 muscarinic receptor (M2R) to investigate this question. Our results indicate that the potencies of two M2R antagonists, atropine and scopolamine, are voltage-dependent; they are more effective at resting potential than under depolarization. In contrast, the M2R antagonist AF-DX 386 did not exhibit voltage-dependent potency.Furthermore, we discovered that the voltage dependence of M2R activation by acetylcholine remains unchanged in the presence of two allosteric modulators, the negative modulator gallamine and the positive modulator LY2119620. These findings enhance our understanding of GPCRs' voltage dependence and may have pharmacological implications.
Asunto(s)
Antagonistas Muscarínicos , Oocitos , Receptor Muscarínico M2 , Xenopus laevis , Animales , Receptor Muscarínico M2/antagonistas & inhibidores , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M2/agonistas , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Antagonistas Muscarínicos/farmacología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Oocitos/fisiología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Atropina/farmacología , Escopolamina/farmacología , Acetilcolina/metabolismo , Acetilcolina/farmacología , Femenino , Sulfonamidas , TiadiazolesRESUMEN
The 5-heterocyclic 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were obtained as potential biologically active compounds. Lipophilicity is one of the most important physicochemical properties of compounds and was already taken into account during the drug candidates design and development. The lipophilicity of compounds was determined using the computational (log P) and chromatography (log kw, RMw) methods. The experimental ones included the reverse-phase column high performance liquid chromatography RP (HPLC) with C8, C18, phosphatidylcholine (IAM), and cholesterol stationary phases and the thin layer chromatography (RP-HPTLC) with C8 and C18 stationary phases and various organic modifiers under the isocratic conditions. Descriptive statistics, correlation, and PCA analyses were used to compare the obtained results. For lipophilicity estimation of the tested compounds by HPTLC, dioxane and MeOH seem to be particularly beneficial as organic modifiers. The chromatographic lipophilicity parameters log kw (RMw) were well correlated and highly redundant (85%) compared with those calculated. Most compounds possess lipophilicity parameters within the recommended range for drug candidates.
Asunto(s)
Interacciones Hidrofóbicas e Hidrofílicas , Tiadiazoles , Tiadiazoles/química , Cromatografía Líquida de Alta Presión/métodos , Cromatografía en Capa Delgada/métodos , Simulación por Computador , Cromatografía de Fase Inversa/métodosRESUMEN
2,6-pyridine dicarboxylic acid (DPA) is an exceptional biomarker of notorious anthrax spores. Therefore, the rapid, sensitive, and selective quantitative detection of DPA is extremely significant and urgent. This paper reports a Zn(II) metal-organic framework with the formula of {[Zn6(NDA)6(DPBT)3] 2H2O·3DMF}n (MOF-1), which consists of 2,6-naphthalenedicarboxylic acid (2,6-NDA), 4,7-di(4-pyridyl)-2,1,3-benzothiadiazole (DPBT), and Zn(II) ions. Structural analysis indicated that MOF-1 is a three-dimensional (3D) network which crystallized in the monoclinic system with the C2/c space group, revealing high pH, solvent, and thermal stability. Luminescence sensing studies demonstrated that MOF-1 had the potential to be a highly selective, sensitive, and recyclable fluorescence sensor for the identification of DPA. Furthermore, fluorescent test paper was made to detect DPA promptly with color changes. The enhancement mechanism was established by the hydrogen-bonding interaction and photoinduced electron transfer transition between MOF-1 and DPA molecules.
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Biomarcadores , Estructuras Metalorgánicas , Tiadiazoles , Zinc , Estructuras Metalorgánicas/química , Zinc/química , Zinc/análisis , Tiadiazoles/química , Carbunco/diagnóstico , Ácidos Picolínicos/química , Ácidos Picolínicos/análisis , Bacillus anthracis , Modelos MolecularesRESUMEN
In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including 1H NMR, 13C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 ± 0.10 µM to 20.50 ± 0.20 µM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 µM to 20.70 ± 0.50 µM when compared with the standard drug Donepezil having IC50 = 6.70 ± 0.20 µM for AChE and 7.90 ± 0.10 µM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC50 = 3.20 ± 0.10 µM for AChE and 4.30 ± 0.50 µM for BuChE), analog-4 (IC50 = 4.30 ± 0.30 µM for AChE and 5.50 ± 0.20 µM for BuChE) and analog-5 (IC50 = 4.10 ± 0.30 µM for AChE and 4.60 ± 0.40 µM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Bencimidazoles , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Tiadiazoles , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Humanos , Relación Estructura-Actividad , Simulación por ComputadorRESUMEN
A photo/electrochemical coupling interface of Ru[dcbpy]32+-AMT/Au (AMT; 5-Amino-1,3,4-thiadiazole-2-thiol) was fabricated using a dehydration condensation sulfhydrating method. For the interface functional properties, a combined dual-signal recording (CDSR) method was applied to characterize the response characteristics, and a scanning electrochemical microscopy-electrochemiluminescence (SECM-ECL) imaging was developed to assess the interface distribution uniformity. The interface biosensing compatibility was validated by constructing a simple DNA sensor. The research results show that the interaction between the two functional parameters follows a synergistic effect mechanism in the coupling conditions and an interference effect mechanism in the detection condition. Under optimized conditions, the saturation dual-signal response values are 156.0 and 86.8 µA, respectively. The statistics and imaging comparison analysis validate good interface distribution uniformity and stability performance. The DNA sensor's dual-signal detection limits to the signal probe (SP) are â¼30 fM and 0.3 pM with linear ranges of 100.0 fM â¼ 1.0 nM and 1.0 pM â¼ 10.0 nM, respectively. The fabricated interface exhibits an effective bi-functional response performance compatible with biosensing. The proposed imaging method has a high technical fit for studying photo/electrochemical coupling interfaces and can also provide a reference for other similar coupling interface analyses.
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Técnicas Biosensibles , ADN , Oro , ADN/química , Oro/química , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Microscopía Electroquímica de Rastreo , Mediciones Luminiscentes/métodos , Tiadiazoles/química , Procesos Fotoquímicos , Rutenio/química , Complejos de Coordinación/químicaRESUMEN
Modern environmental organic chemistry is focused on developing cost-efficient, versatile, environmentally acceptable catalytic chemicals that are also highly effective. Herein, hybrid calcium-chitosan nanocomposite films was prepared by doping calcium oxide molecules into a chitosan matrix at weight percentage (15, 20, and 25 % wt. chitosancalcium) using an easy and affordable simple co-precipitation process. The CS-CaO nanocomposite's structure was elucidated using analytical techniques such as Fourier transform infrared (FTIR), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). Based on the X ray diffraction (XRD) measurements, the crystallinity was reduced by the incorporation of the CaO molecules. Also, from the calculation of the Debye-Scherrer equation on this X-ray diffraction (XRD) pattern, the crystallite size was found to be 17.2 nm for the nanocomposite film with 20 % wt. The energy dispersive spectroscopy graph demonstrated the presence of the distinctive Ca element signals within the chitosan, with the amount in a sample of 20 % wt. being discovered to be 21.32 % wt. For the synthesis of bis-hydrazono[1,2,4]thiadiazoles, the obtained CS-CaO nanocomposite could be employed as a potent heterogeneous recyclable catalyst. Better reaction yields, quicker reactions, softer reaction conditions, and green reusable efficient biocatalysts for several uses are just a few advantages of this approach.
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Compuestos de Calcio , Quitosano , Tecnología Química Verde , Nanocompuestos , Óxidos , Quitosano/química , Nanocompuestos/química , Compuestos de Calcio/química , Óxidos/química , Tiadiazoles/química , Difracción de Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , CatálisisRESUMEN
Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.
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Antipsicóticos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Antipsicóticos/efectos adversos , Antagonistas Muscarínicos/uso terapéutico , Antagonistas Muscarínicos/efectos adversos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/farmacología , Bencilatos/uso terapéutico , Bencilatos/efectos adversos , Combinación de Medicamentos , Animales , Agonistas Muscarínicos/uso terapéutico , Agonistas Muscarínicos/efectos adversos , Tiadiazoles/uso terapéutico , Tiadiazoles/efectos adversos , Tiadiazoles/farmacologíaRESUMEN
A photoacoustic (PA) imaging technique using the second near-infrared (NIR-II) window has attracted more and more attention because of its merits of deeper penetration depth and higher signal-to-noise (S/N) ratio than that using the first near-infrared (NIR-I) one. However, the design and development of high-performance PA imaging contrast agents in the NIR-II window is still a challenge. A semiconducting polymer, constructed by asymmetric units, exhibits regiorandom characteristics that effectively increase the distortion of the backbone. This increase in the degree of twist can regulate the twisted intramolecular charge transfer (TICT) effect, resulting in an enhancement of the PA signal. In this paper, an asymmetric structural acceptor strategy is developed to improve the PA signals of the resulting semiconducting polymer (PATQ-MP) in the NIR-II window with improved brightness, higher S/N ratio, and better photothermal conversion efficiency compared to polymers with the same main-chain structure containing a symmetric acceptor. DFT analysis showed that PATQ-MP containing an asymmetric acceptor monomer had a larger dihedral angle, which effectively improved the PA signal intensity by enhancing the TICT effect. The PEG-encapsulated PATQ-MP nanoparticles exhibit promising performance in the PA imaging of mouse tumors in vivo, demonstrating the clear identification of microvessels as small as 100 µm along with rapid metabolism within a span of 5 h. Therefore, this work provides a unique molecular design strategy for improving the signal intensity of PA imaging in the NIR-II window.
Asunto(s)
Técnicas Fotoacústicas , Polímeros , Semiconductores , Técnicas Fotoacústicas/métodos , Animales , Ratones , Polímeros/química , Quinoxalinas/química , Femenino , Humanos , Tiadiazoles/química , Rayos Infrarrojos , Ratones Desnudos , Ratones Endogámicos BALB C , Medios de Contraste/químicaRESUMEN
In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.
Asunto(s)
Diseño de Fármacos , Insecticidas , Simulación del Acoplamiento Molecular , Spodoptera , Tiadiazinas , Tiadiazoles , Animales , Insecticidas/química , Insecticidas/síntesis química , Insecticidas/farmacología , Spodoptera/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Tiadiazinas/química , Tiadiazinas/farmacología , Tiadiazinas/síntesis química , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Proteínas de Insectos/química , Bencenosulfonamidas , Estructura Molecular , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica II/químicaRESUMEN
Piezo1, a mechano-activated ion channel, has wide-ranging physiological and therapeutic implications, with the ongoing development of specific agonists unveiling cellular responses to mechanical stimuli. In our study, we systematically analyzed the chemical subunits in Piezo1 protein agonist Yoda1 to comprehend the structure-activity relationship and push forward next-generation agonist development. Preliminary screening assays for Piezo1 agonism were performed using the Piezo1-mCherry-transfected HEK293A cell line, keeping Yoda1 as a positive control. We introduce a novel Piezo1 agonist Yaddle1 (34, 0.40 µM), featuring a trifluoromethyl group, with further exploration through in vitro studies and density functional theory calculations, emphasizing its tetrel interactions, to act as an ambidextrous wedge between the domains of Piezo1. In contrast to the poor solubility of the established agonist Yoda1, our results showed that the kinetic solubility of Yaddle1 (26.72 ± 1.8 µM at pH 7.4) is 10-fold better than that of Yoda1 (1.22 ± 0.11 µM at pH 7.4). Yaddle1 (34) induces Ca2+ influx in human CD4+ T cell, suggesting its potential as a vaccine adjuvant for enhanced T cell activation.
Asunto(s)
Canales Iónicos , Linfocitos T , Humanos , Canales Iónicos/metabolismo , Células HEK293 , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Activación de Linfocitos/efectos de los fármacos , Pirazinas , TiadiazolesRESUMEN
Tuberculosis remains a global health threat, with increasing infection rates and mortality despite existing anti-TB drugs. The present work focuses on the research findings regarding the development and evaluation of thiadiazole-linked thiazole derivatives as potential anti-tuberculosis agents. We present the synthesis data and confirm the compound structures using spectroscopic techniques. The current study reports twelve thiazole-thiadiazole compounds (5 a-5 l) for their anti-tuberculosis and related bioactivities. This paper emphasizes compounds 5 g, 5 i, and 5 l, which exhibited promising MIC values, leading to further in silico and interaction analysis. Pharmacophore mapping data included in the present analysis identified tubercular ThyX as potential drug targets. The compounds were evaluated for anti-tubercular activity using standard methods, revealing significant MIC values, particularly compound 5 l, with the best MIC value of 7.1285â µg/ml. Compounds 5 g and 5 i also demonstrated moderate to good MIC values against M.â tuberculosis (H37Ra). Structural inspection of the docked poses revealed interactions such as hydrogen bonds, halogen bonds, and interactions containing Pi electron cloud, shedding light on conserved interactions with residues like Argâ 95, Cysâ 43, Hisâ 69, and Argâ 87 from the tubercular ThyX enzyme.