RESUMEN

Imidacloprid (IDP) is an active ingredient of the Admire brand pesticide used to control the vector (Asian citrus psyllid) that transmits the causative organism Candidatus Liberibacter asiaticus (CLas) for citrus greening or huanglongbing disease. Imidacloprid products are applied via soil drench where citrus roots are mostly concentrated which is between 0 and 60 cm depth. These soil depths exhibit different characteristics that may affect IDP leaching beyond the rooting zone. Representative soil samples were collected from Entisols and Ultisols, which are the dominant soil orders under citrus production in central Florida, at 15 cm increments up to 60 cm to estimate and understand the batch sorption, kinetics, equilibria, and degradation of IDP. Results showed that the equilibrium time for IDP at 0-15 cm depth (10 hours) was 2 times faster than at 15-60 cm (20 hours) for the Entisol. Nevertheless, all depths reached equilibrium within 24 hours for the Entisol. The 0-30 cm depth adsorbed 2 times more IDP than the 30-60 cm depth for both soils. Nevertheless, the adsorption coefficient was approximately ≤ 1 mL g-1 for both soils. The half-life of IDP in both soils ranged from 10 to 17 days. The Entisol showed higher adsorption than the Ultisol at both depths, probably due to relatively lower organic carbon (OC) content in the Ultisol compared to the Entisol. Thus, the Ultisol showed high IDP leaching vulnerability compared to the Entisol. Movement of IDP is affected by the amount of OC in the citrus critical zone.

Asunto(s)

Citrus , Neonicotinoides , Nitrocompuestos , Contaminantes del Suelo , Suelo , Neonicotinoides/química , Neonicotinoides/metabolismo , Nitrocompuestos/química , Nitrocompuestos/metabolismo , Florida , Suelo/química , Adsorción , Contaminantes del Suelo/química , Contaminantes del Suelo/metabolismo , Citrus/química , Cinética , Semivida , Insecticidas/química , Insecticidas/metabolismo , Imidazoles/química , Imidazoles/metabolismo

RESUMEN

Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Asunto(s)

Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química

RESUMEN

Carbonic anhydrase (CA) plays a crucial role in the CO2 capture processes by catalyzing the hydration of CO2. In this study, we synthesized a bioinspired carbonic anhydrase Zn-MOF (metal-organic framework) incorporating 2-aminoimidazole and Zn2+ as initial constituents. The synthesized Zn-MOF exhibited promising potential for efficiently catalyzing the CO2 hydration. Structural analyses such as SEM, XRD, and BET confirmed that the Zn-MOF crystal consisted of stacked grains with an average size of approximately 36 nm, forming a micron-sized spherical structure. Functionally, Zn-MOF exhibited effective catalytic activity toward both CO2 hydration and ester hydrolysis. The introduction of amino groups significantly enhanced the esterase activity of Zn-MOF to 0.28 U/mg at ambient temperature, which was twice that of ZIF-8. Furthermore, the introduction of amino groups resulted in remarkable hydrothermal stability, with the esterase activity reaching 0.72 U/mg after undergoing hydrothermal treatment at 80 °C for 12 h. Additionally, Zn-MOF exhibited enhanced capability in CO2 hydration at a pH value exceeding 8.5. After six repeated uses, ZIF-8 and Zn-MOF retained approximately 68 and 65% of their initial enzyme activity, respectively, underscoring the potential practical applicability of Zn-MOF in industrial CO2 capture processes. This work showcases the development of a novel Zn-MOF crystal as an efficient CA mimic, effectively emulating the active sites of natural CA using 2-aminoimidazole as a coordinating ligand for Zn2+ coordination. These findings not only advance the field of innovative enzyme mimics but also pave the way for further exploration of industrial CO2 capture catalysts.

Asunto(s)

Dióxido de Carbono , Anhidrasas Carbónicas , Imidazoles , Zinc , Anhidrasas Carbónicas/metabolismo , Anhidrasas Carbónicas/química , Imidazoles/química , Zinc/química , Dióxido de Carbono/química , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/síntesis química , Catálisis , Esterasas/química , Esterasas/metabolismo

RESUMEN

An efficient electrochemiluminescence (ECL) emitter, Ir(ppy)3-based molecules has recently been reported to exhibit aggregation-induced electrochemiluminescence (AIECL) phenomenon. However, it remains a significant challenge to control the aggregation states of these molecules and achieve uniform aggregates with intense ECL emission. In this work, a biosensor was developed to detect microcystin-LR (MC-LR) based on Ir(ppy)3-functionalized zeolitic imidazolate framework-8 (Ir-ZIF-8) as the ECL emitter and the trans-cleavage activity of CRISPR-Cas12a as the methodological strategy. The Ir-ZIF-8, a functional metal-organic framework (MOF), exhibited the AIECL phenomenon via the spatial domain-limiting effect of encapsulating Ir(ppy)3 into the mesopores of ZIF-8, while the porosity and highly ordered topological structure of ZIF-8 effectively limited the molecular motion of Ir(ppy)3. CRISPR-Cas12a was employed to indiscriminately cleave double-stranded DNA decorated with carboxy tetramethylrhodamine (TAMRA), which quenched the ECL signal of Ir-ZIF-8 by resonance energy transfer and then separated the quencher from Ir-ZIF-8 to reactivate the signal. The concentration of MC-LR was designed to correlate with both the quencher amount and the activity of Cas12a. Then, two linear regression equations for MC-LR detection were constructed to improve the accuracy of the biosensor, and the constructed biosensor showed remarkable reproducibility, stability, and selectivity. The accurate detection of MC-LR with limits of detection of 1.2 and 5.9 pg/mL was made possible by the high quenching efficiency of TAMRA and the effective cutting ability of the editable CRISPR-Cas12a system.

Asunto(s)

Técnicas Biosensibles , Sistemas CRISPR-Cas , Técnicas Electroquímicas , Mediciones Luminiscentes , Toxinas Marinas , Microcistinas , Microcistinas/análisis , Microcistinas/química , Toxinas Marinas/química , Sistemas CRISPR-Cas/genética , Técnicas Biosensibles/métodos , Zeolitas/química , Estructuras Metalorgánicas/química , Imidazoles/química , Límite de Detección , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Asociadas a CRISPR/química

RESUMEN

Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.

Asunto(s)

Acetolactato Sintasa , Amaranthus , Resistencia a los Herbicidas , Herbicidas , Imidazoles , Mutación Puntual , Acetolactato Sintasa/genética , Acetolactato Sintasa/metabolismo , Acetolactato Sintasa/química , Herbicidas/farmacología , Herbicidas/química , Resistencia a los Herbicidas/genética , Imidazoles/farmacología , Imidazoles/química , Amaranthus/efectos de los fármacos , Amaranthus/genética , Sorghum/genética , Sorghum/efectos de los fármacos , Simulación del Acoplamiento Molecular , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Ácidos Nicotínicos/farmacología , Niacina/análogos & derivados

RESUMEN

BACKGROUND: Biothiols are important for numerous cellular processes, such as resisting oxidative stress and protecting cell health. Their abnormal levels and molecular configurations have been associated with various diseases. So, establishing an effective and reliable method for the specific detection and enantiomeric discrimination of diverse biothiols is highly meaningful. RESULTS: We have developed a new NMR and CD probe using 1,4-dinitroimidazole, specifically targeting the thiol group. This probe allows for the specific detection and enantiomeric recognition of biothiols in complex mixtures. We achieved this by identifying the distinguishable 1H NMR signals of 2nd in imidazole-ring of the resulting 4NI-biothiols in the downfield region at 7-8 ppm and newly discovered induced CD signals within 290-430 nm. Using this probe, the limits of detection of Cys, GSH, and Hcy, the recovery rates, and the concentration of GSH extracted from HEK293T cells were determined by measuring the unique downfield 1H NMR signals. Moreover, Cys, GSH, and Hcy can be discriminated simultaneously in complicated samples at a pH range of 2-3.5. Furthermore, this probe can also be utilized to sense chiral thiol-drugs. SIGNIFICANCE: This method offers a cost-effective and accurate sensing solution for the specific detection of biothiols in complex mixtures, with stereochemical recognition.

Asunto(s)

Imidazoles , Compuestos de Sulfhidrilo , Humanos , Estereoisomerismo , Imidazoles/química , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/análisis , Células HEK293 , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Cisteína/análisis , Glutatión/análisis , Glutatión/química , Homocisteína/análisis , Límite de Detección , Estructura Molecular

RESUMEN

Gaussia luciferase (Gluc) is currently known as the smallest naturally secreted luciferase. Due to its small molecular size, high sensitivity, short half-life, and high secretion efficiency, it has become an ideal reporter gene and is widely used in monitoring promoter activity, studying protein-protein interactions, protein localization, high-throughput drug screening, and real-time monitoring of tumor occurrence and development. Although studies have shown that different Gluc mutations exhibit different bioluminescent properties, their mechanisms have not been further investigated. The purpose of this study is to reveal the relationship between the conformational changes of Gluc mutants and their bioluminescent properties through molecular dynamics simulation combined with neural relationship inference (NRI) and Markov models. Our results indicate that, after binding to the luciferin coelenterazine (CTZ), the α-helices of the 109-119 residues of the Gluc Mutant2 (GlucM2, the flash-type mutant) are partially unraveled, while the α-helices of the same part of the Gluc Mutant1 (GlucM1, the glow-type mutant) are clearly formed. The results of Markov flux analysis indicate that the conformational differences between glow-type and flash-type mutants when combined with luciferin substrate CTZ mainly involve the helicity change of α7. The most representative conformation and active pocket distance analysis indicate that compared to the flash-type mutant GlucM2, the glow-type mutant GlucM1 has a higher degree of active site closure and tighter binding. In summary, we provide a theoretical basis for exploring the relationship between the conformational changes of Gluc mutants and their bioluminescent properties, which can serve as a reference for the modification and evolution of luciferases.

Asunto(s)

Luciferasas , Cadenas de Markov , Simulación de Dinámica Molecular , Luciferasas/metabolismo , Luciferasas/genética , Luciferasas/química , Conformación Proteica , Mutación , Animales , Copépodos/enzimología , Copépodos/genética , Imidazoles/química , Imidazoles/metabolismo , Unión Proteica , Mediciones Luminiscentes , Pirazinas

RESUMEN

The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18-23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19-21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani, at a single concentration of 50 µM.

Asunto(s)

Imidazoles , Leishmania donovani , Tiadiazoles , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Leishmania donovani/efectos de los fármacos , Leishmania donovani/crecimiento & desarrollo , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , Relación Estructura-Actividad , Estructura Molecular

RESUMEN

The excessive utilization of antimicrobials in humans and animals has resulted in considerable environmental contamination, necessitating the development of high-performance antibiotic adsorption media. A significant challenge is the development of composite nanofibrous materials that are both beneficial and easy to fabricate, with the aim of improving adsorption capacity. Herein, a new kind of zeolitic imidazolate framework-8 (ZIF-8)-modified regenerated cellulose nanofibrous membrane (ZIF-8@RC NFM) was designed and fabricated by combining electrospinning and in situ surface modification technologies. Benefiting from its favorable surface wettability, enhanced tensile strength, interconnected porous structure, and relatively large specific surface area, the resulting ZIF-8@RC NFMs exhibit a relatively high adsorption capacity for tetracycline hydrochloride (TCH) of 105 mg g-1 within 3 h. Moreover, a Langmuir isotherm model and a pseudo-second-order model have been demonstrated to be more appropriate for the description of the TCH adsorption process of ZIF-8@RC-3 NFMs. Additionally, this composite fibrous material could keep a relatively stable adsorption capability under various ionic strengths. The successful fabrication of the novel ZIF-8@RC NFMs may shed light on the further development of wastewater adsorption treatment materials.

Asunto(s)

Celulosa , Nanofibras , Tetraciclina , Zeolitas , Tetraciclina/química , Nanofibras/química , Adsorción , Celulosa/química , Zeolitas/química , Imidazoles/química , Contaminantes Químicos del Agua/química , Estructuras Metalorgánicas/química , Membranas Artificiales , Purificación del Agua/métodos

RESUMEN

In the realm of intracellular drug delivery, overcoming the barrier of endosomal entrapment stands as a critical factor influencing the effectiveness of nanodrug delivery systems. This study focuses on the synthesis of an acid-sensitive fatty acid derivative called imidazole-stearic acid (IM-SA). Leveraging the proton sponge effect attributed to imidazole groups, IM-SA was anticipated to play a pivotal role in facilitating endosomal escape. Integrated into the lipid core of solid lipid nanoparticles (SLNs), IM-SA was paired with hyaluronic acid (HA) coating on the surface of SLNs loading with curcumin (CUR). The presence of IM-SA and HA endowed HA-IM-SLNs@CUR with dual functionalities, enabling the promotion of endosomal escape, and specifical targeting of liver cancer. HA-IM-SLNs@CUR exhibited a particle size of ∼228 nm, with impressive encapsulation efficiencies (EE) of 87.5 % ± 2.3 % for CUR. Drugs exhibit significant pH sensitive release behavior. Cellular experiments showed that HA-IM-SLN@CUR exhibits enhanced drug delivery capability. The incorporation of IM-SA significantly improved the endosomal escape of HA-IM-SLN@CUR, facilitating accelerated intracellular drug release and increasing intracellular drug concentration, exhibiting excellent growth inhibitory effects on HepG2 cells. Animal experiments revealed a 3.4-fold increase in CUR uptake at the tumor site with HA-IM-SLNs@CUR over the free CUR, demonstrating remarkable tumor homing potential with the tumor growth inhibition rate of 97.2 %. These findings indicated the significant promise of HA-IM-SLNs@CUR in the realm of cancer drug delivery.

Asunto(s)

Antineoplásicos , Curcumina , Endosomas , Nanopartículas , Tamaño de la Partícula , Curcumina/farmacología , Curcumina/química , Humanos , Nanopartículas/química , Animales , Endosomas/metabolismo , Endosomas/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Células Hep G2 , Liberación de Fármacos , Ratones , Lípidos/química , Sistemas de Liberación de Medicamentos , Proliferación Celular/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Propiedades de Superficie , Portadores de Fármacos/química , Ácidos Esteáricos/química , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Imidazoles/química , Imidazoles/farmacología , Ratones Desnudos , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Liposomas

RESUMEN

Copper(I) ions (Cu+) are used in olefin separations due to their olefin complexing ability and low cost, but their instability in the presence of water and gases limits their widespread use. Ionic liquids (ILs) have emerged as stabilizers of Cu+ ions and prevent their degradation, providing high olefin separation efficiency. There is limited understanding into the role that polymeric ionic liquids (PILs), which possess similar structural characteristics to ILs, have on Cu+ ion-olefin interactions. Moreover, copper ions with diverse oxidation states, including Cu+ and Cu2+ ions, have been rarely employed for olefin separations. In this study, gas chromatography (GC) is used to investigate the interaction strength of olefins to stationary phases composed of the 1-hexyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([C6MIM+][NTf2-]) IL and the poly(1-hexyl-3-vinylimidazolium [NTf2-]) (poly([C6VIM+][NTf2-])) PIL containing monovalent and divalent copper salts (i.e., [Cu+][NTf2-] and [Cu2+]2[NTf2-]). The chromatographic retention of alkenes, alkynes, dienes, and aromatic compounds was examined. Incorporation of the [Cu2+]2[NTf2-] salt into a stationary phase comprised of poly(dimethylsiloxane) resulted in strong retention of olefins, while its addition to the [C6MIM+][NTf2-] IL and poly([C6VIM+][NTf2-]) PIL allowed for the interaction strength to be modulated. Olefins exhibited greater affinities toward IL and PIL stationary phases containing the [Cu2+]2[NTf2-] salt compared to those with the [Cu+][NTf2-] salt. Elimination of water from both copper salts was observed to be an important factor in promoting olefin interactions, as evidenced by increased olefin retention upon exposure of the stationary phases to high temperatures. To evaluate the long-term thermal stability of the stationary phase, chromatographic retention of probes was measured on the [Cu2+]2[NTf2-]/[C6MIM+][NTf2-] IL stationary phase after its exposure to helium at a temperature of 110 °C.

Asunto(s)

Alquenos , Cobre , Líquidos Iónicos , Líquidos Iónicos/química , Alquenos/química , Alquenos/aislamiento & purificación , Cobre/química , Cromatografía de Gases/métodos , Polímeros/química , Imidazoles/química

RESUMEN

Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions.

Asunto(s)

Afatinib , Proteínas de Fusión bcr-abl , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/química , Afatinib/química , Afatinib/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Modelos Moleculares , Simulación por Computador , Mutación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Enlace de Hidrógeno , Antineoplásicos/química , Antineoplásicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Piridazinas

RESUMEN

The acquisition of new RNA functions through evolutionary processes was essential for the diversification of RNA-based primordial biology and its subsequent transition to modern biology. However, the mechanisms by which RNAs access new functions remain unclear. Do RNA enzymes need completely new folds to support new but related functions, or is reoptimization of the active site sufficient? What are the roles of neutral and adaptive mutations in evolutionary innovation? Here, we address these questions experimentally by focusing on the evolution of substrate specificity in RNA-catalyzed RNA assembly. We use directed in vitro evolution to show that a ligase ribozyme that uses prebiotically relevant 5'-phosphorimidazole-activated substrates can be evolved to catalyze ligation with substrates that are 5'-activated with the biologically relevant triphosphate group. Interestingly, despite catalyzing a related reaction, the new ribozyme folds into a completely new structure and exhibits promiscuity by catalyzing RNA ligation with both triphosphate and phosphorimidazole-activated substrates. Although distinct in sequence and structure, the parent phosphorimidazolide ligase and the evolved triphosphate ligase ribozymes can be connected by a series of point mutations where the intermediate sequences retain at least some ligase activity. The existence of a quasi-neutral pathway between these distinct ligase ribozymes suggests that neutral drift is sufficient to enable the acquisition of new substrate specificity, thereby providing opportunities for subsequent adaptive optimization. The transition from RNA-catalyzed RNA assembly using phosphorimidazole-activated substrates to triphosphate-activated substrates may have foreshadowed the later evolution of the protein enzymes that use monomeric triphosphates (nucleoside triphosphates, NTPs) for RNA synthesis.

Asunto(s)

Imidazoles , ARN Ligasa (ATP) , ARN Catalítico , ARN Catalítico/metabolismo , ARN Catalítico/química , ARN Catalítico/genética , Especificidad por Sustrato , Imidazoles/metabolismo , Imidazoles/química , ARN Ligasa (ATP)/metabolismo , ARN Ligasa (ATP)/química , ARN Ligasa (ATP)/genética , Evolución Molecular , Conformación de Ácido Nucleico , Dominio Catalítico

RESUMEN

This study reports a new series of 1,10-phenanthroline-substituted imidazolium salts (1a-f), examining their design, synthesis, structure and anticancer activities. The structures of these salts (1a-f) were characterized using 1H, 13C NMR, elemental analysis, mass spectrometry and Fourier transform infrared (FT-IR) spectroscopies. The salts' cytotoxic activities were tested against cancer cell lines, specifically MCF-7, MDA-MB-231 and non-tumorigenic MCF-10A mammary cells. The study compared the impact of aliphatic and benzylic groups in the salts' structure on their anticancer activity. Screening results revealed that compound 1c, in particular, showed promising inhibitory activity against the growth of MDA-MB-231 breast cancer cells, with an IC50 value of 12.8 ± 1.2 µM, indicating its potential as a chemotherapeutic agent. Cell apoptosis analysis demonstrated a tendency for compound 1c to induce early apoptosis in breast cancer cells. The stability/aquation of compound 1c was investigated using 1H NMR spectroscopy and its binding modes with DNA were explored via UV-Vis spectroscopy. Additionally, the study investigated the interaction residues and docking scores of compound 1c and the reference drug doxorubicin against Bax and Bcl-2 proteins using molecular docking.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Imidazoles , Fenantrolinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenantrolinas/química , Fenantrolinas/farmacología , Fenantrolinas/síntesis química , Sales (Química)/química , Sales (Química)/farmacología , Sales (Química)/síntesis química , Relación Estructura-Actividad , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología

RESUMEN

Bacterial infections have emerged as a significant contributor to global mortality and morbidity rates. Herein, we introduce a dual fluorescence "turn-on" supramolecular sensor array composed of three assembled complexes (C1-C3), formed from three positively charged fluorophores (A1-A3) and one cucurbit[7]uril (CB[7]). The ability of this three-element array to simultaneously recognize 10 bacterial species within just 30 s was remarkable, boasting an impressive 100% accuracy. Additionally, the array excelled at distinguishing among various bacterial mixtures and enabled the quantitative detection of common bacterial strains. Notably, it has been skillfully applied to differentiate 10 bacterial samples in urine, achieving excellent differentiation and showcasing promising potential for medical diagnostic applications.

Asunto(s)

Hidrocarburos Aromáticos con Puentes , Colorantes Fluorescentes , Imidazoles , Imidazoles/química , Hidrocarburos Aromáticos con Puentes/química , Colorantes Fluorescentes/química , Bacterias/aislamiento & purificación , Humanos , Espectrometría de Fluorescencia , Compuestos Heterocíclicos con 2 Anillos , Compuestos Macrocíclicos , Imidazolidinas

RESUMEN

Prenylation of amino acids is a critical step for synthesizing building blocks of prenylated alkaloid family natural products, where the corresponding prenyltransferase that catalyzes prenylation on free l-histidine (l-His) has not yet been identified. Here, we first discovered and characterized a prenyltransferase FunA from the antifungal agent fungerin pathway that efficiently performs C4-dimethylallylation on l-His. Crystal structure-guided engineering of the prenyl-binding pocket of FunA, a single M181A mutation, successfully converted it into a C4-geranyltransferase. Furthermore, FunA and its variant FunA-M181A show broad substrate promiscuity toward substrates that vary in substituents of the imidazole ring. Our work furthers our knowledge of free amino acid prenyltransferase and expands the arsenal of alkylation biocatalysts for imidazole-containing small molecules.

Asunto(s)

Dimetilaliltranstransferasa , Histidina , Histidina/química , Histidina/metabolismo , Dimetilaliltranstransferasa/metabolismo , Dimetilaliltranstransferasa/química , Dimetilaliltranstransferasa/genética , Ingeniería de Proteínas , Modelos Moleculares , Especificidad por Sustrato , Imidazoles/química , Imidazoles/metabolismo

RESUMEN

Five novel imidazole-functionalized chitosan derivatives 3a-3e were synthesized via addition reactions of chitosan with imidazole derivatives. The partial incorporation of imidazole moiety in chitosan were confirmed by FTIR, UV, 1H NMR, XRD, SEM and GPC. Meanwhile, the antifungal activity against three common plant pathogenic fungi: Phytophthora nicotianae (P. nicotianae), Fusarium graminearum (F. graminearum) and Rhizoctonia solani (R. solani), was assayed in vitro at 0.5 and 1.0 mg/mL by hyphal measurement, and the introduction of imidazole group can influence the antifungal activity. At 0.5 mg/mL, 3e inhibited P. nicotianae growth by 42 % and had an inhibitory index against R. solani of 50 %. Derivative 3e was more effective than unmodified chitosan whose antifungal index was 17 % against P. nicotianae and 22 % against R. solani. To our surprise, at 1.0 mg/mL, the inhibition rate of 3e against R. solani can reach 99 %, while the inhibition rate of chitosan is only 38 %. These results indicated that some imidazole chitosan derivatives with enhanced antifungal activities could serve as potential biomaterial for antifungal application.

Asunto(s)

Antifúngicos , Quitosano , Imidazoles , Pruebas de Sensibilidad Microbiana , Quitosano/química , Quitosano/farmacología , Quitosano/síntesis química , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Fusarium/efectos de los fármacos , Rhizoctonia/efectos de los fármacos , Phytophthora/efectos de los fármacos

RESUMEN

An antifungal agent, luliconazole, is commercially available in cream or gel form. The major limitation of these conventional formulations is less residence time at the infection site. The primary objective of this work was to develop luliconazole-loaded polyvinyl alcohol (Luz-PVA) nanofibers for mycotic skin conditions with a longer retention. Luz-PVA nanofibers were prepared by plate electrospinning and optimized for polymer concentration and process parameters. The optimized batch (Trial 5) was prepared by 10% PVA, processed at 22.4 kV applied voltage, and 14 cm plate and spinneret distance to yield thick, uniform, and peelable nanofibers film. There was no interaction observed between Luz and PVA in the FTIR study. DSC and XRD analysis showed that luliconazole was loaded into fabricated nanofibers with a reduced crystallinity. FESEM studies confirmed the smooth, defect-free mats of nanofibers. Luz-PVA nanofibers possessed a tensile strength of 21.8 N and a maximum elongation of 10.8%, representing the excellent elasticity of the scaffolds. For Luz-PVA nanofibers, the sustained and complete drug release was observed in 48 h. In antifungal activity using Candida albicans, the Luz-PVA nanofibers showed a greater zone of inhibition (30.55 ± 0.38 mm and 29.27 ± 0.31 mm) than marketed cream (28.06 ± 0.18 mm and 28.47 ± 0.24 mm) and pure drug (27.57 ± 0.17 mm and 27.50 ± 0.47 mm) at 1% concentration in Sabouraud dextrose agar and yeast malt agar, respectively. Therefore, Luz-PVA nanofibers exhibited good mechanical properties, longer retention time, and better antifungal activity than marketed products and, therefore, can be further examined preclinically as a potential treatment option for topical mycotic infection.

Asunto(s)

Antifúngicos , Candida albicans , Imidazoles , Pruebas de Sensibilidad Microbiana , Nanofibras , Alcohol Polivinílico , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efectos de los fármacos , Nanofibras/química , Alcohol Polivinílico/química , Imidazoles/química , Imidazoles/farmacología , Administración Tópica , Espectroscopía Infrarroja por Transformada de Fourier , Resistencia a la Tracción , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Difracción de Rayos X

RESUMEN

We have prepared a novel assembly with copper nanoclusters (CuNCs) and imidazolium-based gemini surfactants (different chain lengths). These novel mimic enzymes formed through the assembly of nanocluster-gemini surfactants have been utilized in creating colorimetric sensors to detect biomolecules. Yet, understanding the method for detecting glutathione (GSH) and its sensing mechanism using this specific assembly-based colorimetric sensor poses a significant challenge. Because of the role of surface ligands, the complexes of cysteine-capped CuNCs (Cys-CuNCs) and gemini surfactants exhibit strong amphiphilicity, enabling them to self-assemble like a molecular amphiphile. We have investigated the kinetics and catalytic capabilities of this Cys-CuNCs@gemini surfactant assembly through peroxidase-like activity. Additionally, a sensitive and simple-to-use colorimetric sensing approach for glutathione (GSH) is also disclosed here, demonstrating a low limit of detection, by using this peroxidase-like activity of Cys-CuNCs@gemini surfactant assemblies. Thus, the remarkable advantages of the Cys-CuNCs@gemini surfactant nanozyme make it suitable for the precise colorimetric detection of GSH, demonstrating excellent sensitivity and reliable selectivity. Additionally, it performs well in detecting GSH in various soft drinks.

Asunto(s)

Colorimetría , Cobre , Cisteína , Glutatión , Nanopartículas del Metal , Tensoactivos , Cobre/química , Glutatión/análisis , Glutatión/química , Colorimetría/métodos , Tensoactivos/química , Cisteína/análisis , Cisteína/química , Nanopartículas del Metal/química , Imidazoles/química , Peroxidasa/química , Peroxidasa/metabolismo

RESUMEN

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

Asunto(s)

Bencimidazoles , Compuestos de Bifenilo , Losartán , Telmisartán , Tetrazoles , Valsartán , Bencimidazoles/química , Bencimidazoles/análisis , Tetrazoles/química , Telmisartán/química , Valsartán/química , Losartán/química , Losartán/análisis , Compuestos de Bifenilo/química , Irbesartán/química , Irbesartán/análisis , Imidazoles/química , Benzoatos/química , Valina/química , Valina/análisis , Solventes/química , Estabilidad de Medicamentos