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The development of coordination compounds with antineoplastic therapeutic properties is currently focused on non-covalent interactions with deoxyribonucleic acid (DNA). Additionally, the interaction profiles of these compounds with globular plasma proteins, particularly serum albumin, warrant thorough evaluation. In this study, we report on the interactions between biomolecules and complexes featuring hydrazone-type imine ligands coordinated with vanadium. The potential to enhance the therapeutic efficiency of these compounds through mitochondrial targeting is explored. This targeting is facilitated by the derivatization of ligands with triphenylphosphonium groups. Thus, this work presents the synthesis, characterization, interactions, and cytotoxicity of dioxidovanadium(V) complexes (C1-C5) with a triphenylphosphonium moiety. These VV-species are coordinated to hydrazone-type iminic ligands derived from (3-formyl-4-hydroxybenzyl)triphenylphosphonium chloride ([AH]Cl) and aromatic hydrazides ([H2L1]Cl-[H2L5]Cl). The structures of the five complexes were elucidated through single-crystal X-ray diffraction and vibrational spectroscopies, confirming the presence of dioxidovanadium(V) species in various geometries with degrees of distortion (τ = 0.03-0.50) and highlighting their zwitterionic characteristics. The molecular structural stability of C1-C5 in solution was ascertained using 1H, 19F, 31P, and 51V-nuclear magnetic resonance. Moreover, their interactions with biomolecules were evaluated using diverse spectroscopic methodologies and molecular docking, indicating moderate interactions (Kb ≈ 104 M-1) with calf thymus DNA in the minor groove and with human serum albumin, predominantly in the superficial IB subdomain. Lastly, the cytotoxic potentials of these complexes were assessed in keratinocytes of the HaCaT lineage, revealing that C1-C5 induce a reduction in metabolic activity and cell viability through apoptotic pathways.
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Antineoplásicos , Complejos de Coordinación , ADN , Compuestos Organofosforados , Vanadio , Humanos , Vanadio/química , Vanadio/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , ADN/metabolismo , ADN/química , Supervivencia Celular/efectos de los fármacos , Hidrazinas/química , Hidrazinas/farmacología , Animales , Simulación del Acoplamiento Molecular , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Estructura Molecular , Ligandos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
This study characterized four corrole derivatives, namely Cbz-Cor, MetCbz-Cor, PTz-Cor, and PTzEt-Cor, examining their photophysical, electrochemical, photobiological, and biomolecule-binding properties. Experimental photophysical data of absorption and emission elements correlated with a theoretical analysis obtained through time-dependent density functional theory (TD-DFT). As for the photophysical properties, we observed lower fluorescence quantum yields and discernible differences between the excited and ground states, as indicated by Stokes shift values. Natural Transition Orbit (NTO) plots presented high occupied molecular orbital - low unoccupied molecular orbital (HOMO-LUMO) densities around the tetrapyrrolic macrocycle in all examples. Our findings demonstrate that corroles maintain stability in solution and offer photostability (<20 %), predominantly in DMSO(5 %)/Tris-HCl (pH 7.4) buffer solution. Furthermore, the singlet oxygen (1O2) quantum yield and log POW values underscore their potential application in photoinactivation approaches, as these corroles serve as effective ROS generators with more lipophilic features. We also evaluated their biomolecular binding capacity towards salmon sperm DNA and human serum albumin using spectroscopic techniques and molecular docking analysis for sustenance. Concerning biomolecule interaction profiles, the corrole derivatives showed a propensity for interacting in the minor grooves of the double helix DNA due to secondary forces, which were more pronounced in site III of the human serum protein.
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Carbazoles , ADN , Fenotiazinas , Albúmina Sérica Humana , ADN/química , Fenotiazinas/química , Humanos , Carbazoles/química , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Porfirinas/química , Animales , Unión Proteica , Salmón , Simulación del Acoplamiento Molecular , Oxígeno Singlete/química , Oxígeno Singlete/metabolismoRESUMEN
Glucose interacts with human serum albumin (HSA, the main protein responsible for the biodistribution of drugs in the bloodstream) and consequently affects the binding capacity of exogenous compounds. Thus, in this work, the interactive profile between HSA and the anti-inflammatory drug nimesulide (NMD, used mainly by patients with diabetic neuropathy to relieve acute or chronic pains) was characterized in nonglycemic, normoglycemic (80 mg/dL), and hyperglycemic (320 mg/dL) conditions by biophysics techniques. There is a spontaneous and ground-state association HSA:NMD under physiological conditions. Therefore, the Stern-Volmer constant (Ksv) can also be used to estimate the binding affinity. The Ksv values for nonglycemic, normoglycemic, and hyperglycemic conditions are around 104 M-1, indicating a moderate affinity of NMD to albumin that was slightly improved by glucose levels. Additionally, the binding is enthalpically and entropically driven mainly into subdomains IIA or IIIA. The binding perturbs weakly the α-helix content of albumin, however, glucose potentially stabilizes the tertiary structure, decreasing the structural perturbation upon NMD binding and improves the complex HSA:NMD stability. Overall, the biophysical characterization indicated that glucose levels might slightly positively impact the pharmacokinetic profile of NMD, allowing NMD to achieve its therapeutical potential without affecting drastically its effective dosages.
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Glucosa , Albúmina Sérica Humana , Sulfonamidas , Humanos , Albúmina Sérica Humana/química , Distribución Tisular , Unión Proteica , Antiinflamatorios no Esteroideos/farmacología , Sitios de Unión , Espectrometría de Fluorescencia , Termodinámica , Dicroismo Circular , Simulación del Acoplamiento MolecularRESUMEN
This study presents the synthesis of novel glycoconjugates by connecting benzazole and carbohydrate units with a 1,2,3-triazole linker. A simple synthetic route employing a copper(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) was utilized. The synthesized compounds exhibit excited-state intramolecular proton transfer (ESIPT), resulting in longer wavelength emission with a significantly large Stokes shift (â¼10 000 cm-1). These compounds show potential as chemical sensors due to their ability to detect Cu2+ ions, causing a decrease in fluorescence emission (turn-off effect). Additionally, they demonstrate strong interaction with proteins, exemplified by their interaction with bovine serum albumin (BSA) as a model protein.
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Cobre , Albúmina Sérica Bovina , Albúmina Sérica Bovina/química , Cobre/química , Glicoconjugados , TriazolesRESUMEN
Crotalicidin is a cathelicidin-related anti-infective (antimicrobial) peptide expressed in the venom glands of the South American rattlesnake Crotalus durissus terrificus. Congener peptides of crotalicidin, named vipericidins, are found in other pit vipers inhabiting South America. Crotalicidin is active against bacteria and pathogenic yeasts and has anti-proliferative activity for some cancer cells. The structural dissection of crotalicidin produced fragments (e.g., Ctn [15-34]) with multiple biological functionalities that mimic the native peptide. Another structural characteristic of crotalidicin and congeners is a unique repetitive stretch of amino acid sequences in tandem embedded in their primary structures. One of the encrypted vipericidn peptides (Ctn [1-9]) was synthesized, and the analog covalently conjugated with rhodamine B (RhoB-Ctn [1-9]) displayed considerable antimicrobial activity and selective cytotoxicity. Methods to evaluate antimicrobial peptides' toxicity include lysis of red blood cells (hemolysis) in vitro and cytotoxicity of healthy cultured cells (e.g., fibroblasts). Here, as a non-conventional model of toxicity, the bovine oocytes were exposed to two standardized concentrations of RhoB-Ctn [1-9], and embryo viability and development at its first stage of cleavage (division of cells) and blastocyst formation were evaluated. Oocytes treated with peptide at 10 and 40 µM induced cleavage rates of 44.94% and 51.53%, resulting in the formation of blastocysts of 7.07% and 11.73%, respectively. Light sheet microscopy and in silico prediction analysis indicated that RhoB-Ctn [1-9] peptide interacts with zona pellucida and internalizes into bovine oocytes and developing embryos. The ADMET prediction estimated good bioavailability of RhoB-Ctn [1-9]. In conclusion, the peptide appeared harmless to bovine oocytes and, remarkably, activated the parthenogenesis in vitro.
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We report the DNA-binding properties of three porphyrins with peripheral thienyl substituents (TThPor, PdTThPor and PtTThPor). The binding capacity of each porphyrin with DNA was determined by UV-Vis and steady-state fluorescence emission spectroscopy combined with molecular docking calculations. The results suggest that the interaction of these compounds probably occurs via secondary interactions via external grooves (minor grooves) around the DNA macromolecule. Moreover, porphyrins containing peripheral Pd(II) or Pt(II) complexes (PdTThPor and PtTThPor) were able to promote photo-damage in the DNA.
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Porfirinas , Porfirinas/química , Simulación del Acoplamiento Molecular , Espectrometría de Fluorescencia , ADN/químicaRESUMEN
Chalcone and thiosemicarbazone have attracted attention due to their easy synthetic procedure and high success in the development of antiviral and antitumor, however, there are few biological data on the evaluation of chalcone-thiosemicarbazone hybrids and their complexation with metal ions. In this sense, the present work reports the synthesis and characterization of the hybrid (Z)-2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)hydrazine-1-carbothioamide (CTCl) and its Zn(II)-complex (CTCl-Zn). The compounds were cell-based evaluated in terms of cytotoxicity against human T-cell lymphotropic virus type 1 (HTLV-1) infected leukemia cells (MT-2) and the experimental data were correlated with molecular docking calculations. The ligand and Zn(II)-complex were easily synthesized with a good yield - 57% and 79%, respectively. The dynamic of E/Z isomers with respect to the imine bond configuration of CTCl was evidenced by 1H NMR experiments in DMSOd6, while the X-ray diffraction of CTCl-Zn showed that Zn(II) ion is tetracoordinated to two ligands in a bidentate mode and the metal ion lies on an intermediate geometry between the see-saw and trigonal pyramid. The ligand and complex exhibited low toxicity and the Zn(II)-complex is more cytotoxic than the ligand, with the corresponding IC50 value of 30.01 and 47.06 µM. Both compounds had a pro-apoptotic effect without the release of reactive oxygen species (ROS) and they can interact with DNA via minor grooves driven by van der Waals forces.
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Antineoplásicos , Chalcona , Chalconas , Virus Linfotrópico T Tipo 1 Humano , Tiosemicarbazonas , Humanos , Tiosemicarbazonas/química , Ligandos , Simulación del Acoplamiento Molecular , Virus Linfotrópico T Tipo 2 Humano , Zinc/química , Antineoplásicos/químicaRESUMEN
Rhinoviruses (RVs) are the major cause of common cold, a respiratory disease that generally takes a mild course. However, occasionally, RV infection can lead to serious complications in patients debilitated by other ailments, e.g., asthma. Colds are a huge socioeconomic burden as neither vaccines nor other treatments are available. The many existing drug candidates either stabilize the capsid or inhibit the viral RNA polymerase, the viral proteinases, or the functions of other non-structural viral proteins; however, none has been approved by the FDA. Focusing on the genomic RNA as a possible target for antivirals, we asked whether stabilizing RNA secondary structures might inhibit the viral replication cycle. These secondary structures include G-quadruplexes (GQs), which are guanine-rich sequence stretches forming planar guanine tetrads via Hoogsteen base pairing with two or more of them stacking on top of each other; a number of small molecular drug candidates increase the energy required for their unfolding. The propensity of G-quadruplex formation can be predicted with bioinformatics tools and is expressed as a GQ score. Synthetic RNA oligonucleotides derived from the RV-A2 genome with sequences corresponding to the highest and lowest GQ scores indeed exhibited characteristics of GQs. In vivo, the GQ-stabilizing compounds, pyridostatin and PhenDC3, interfered with viral uncoating in Na+ but not in K+-containing phosphate buffers. The thermostability studies and ultrastructural imaging of protein-free viral RNA cores suggest that Na+ keeps the encapsulated genome more open, allowing PDS and PhenDC3 to diffuse into the quasi-crystalline RNA and promote the formation and/or stabilization of GQs; the resulting conformational changes impair RNA unraveling and release from the virion. Preliminary reports have been published.
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G-Cuádruplex , Rhinovirus , Humanos , Rhinovirus/genética , Oligonucleótidos , ARN Viral/genética , Emparejamiento BaseRESUMEN
The trans-A2B-corrole series was prepared starting with 5-(pentafluorophenyl)dipyrromethene, which was then reacted with respective aryl-substituted aldehyde by Gryko synthesis. It was further characterized by HRMS and electrochemical methods. In addition, we investigated experimental photophysical properties (absorption, emission by steady-state and time-resolved fluorescence) in several solvents and TDDFT calculations, aggregation, photostability and reactive oxygen species generation (ROS), which are relevant when selecting photosensitizers used in photodynamic therapy and many other photo-applications. In addition, we also evaluated the biomolecule-binding properties with CT-DNA and HSA by spectroscopy, viscometry and molecular docking calculations assays.
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Fotoquimioterapia , Porfirinas , Simulación del Acoplamiento Molecular , Porfirinas/química , FotobiologíaRESUMEN
Antibiotic resistance associated with pulmonary infection agents has become a public health problem, being considered one of the main priorities for immediate resolution. Thus, to increase the therapeutic options in the fight against resistant microorganisms, the synthesis of molecules from pre-existing drugs has shown to be a promising alternative. In this sense, the present work reports the synthesis, characterization, and biological evaluation (against fungal and bacterial agents that cause lung infections) of potential metallodrugs based on sulfamethoxazole complexed with AuI, AgI, HgII, CdII, NiII, and CuII. The minimal inhibitory concentration (MIC) value was used to evaluate the antifungal and antibacterial properties of the compounds. In addition, it was also evaluated the antibiofilm capacity in Pseudomonas aeruginosa, through the quantification of its biomass and visualization using atomic force microscopy. For each case, molecular docking calculations were carried out to suggest the possible biological target of the assayed inorganic complexes. Our results indicated that the novel inorganic complexes are better antibacterial and antifungal than the commercial antibiotic sulfamethoxazole, highlighting the AgI-complex, which was able to inhibit the growth of microorganisms that cause lung diseases with concentrations in the 2-8 µg mL-1 range, probably at targeting dihydropteroate synthetase - a key enzyme involved in the folate synthesis. Furthermore, sulfamethoxazole complexes were able to inhibit the formation of bacterial biofilms at significantly lower concentrations than free sulfamethoxazole, probably mainly targeting the active site of LysR-type transcriptional regulator (PqsR). Overall, the present study reports preliminary results that demonstrate the derivatization of sulfamethoxazole with transition metal cations to obtain potential metallodrugs with applications as antimicrobial and antifungal against pulmonary infections, being an alternative for drug-resistant strains.
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Antifúngicos , Sulfametoxazol , Sulfametoxazol/farmacología , Antifúngicos/farmacología , Simulación del Acoplamiento Molecular , Antibacterianos/química , Biopelículas , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosaRESUMEN
With the increasing development of metallopharmaceuticals, coordination compounds become viable alternatives for therapeutic uses. Despite the importance of platinum derivatives in this area, first-row transition metals complexes are welcome due to their characteristics. Vanadium is a promising metal in this context, as it has a range of compounds with different biological applications, including anticancer therapeutic effects. In this effort, the study of interactions between coordination compounds with deoxyribonucleic acid and with human serum albumin is fundamental. In this way, ten iminic ligands were synthesized by condensing p-substituted aromatic benzohydrazides (OH, CH3, H, NO2, and NH2) with salicylaldehyde (L1As-L5As) or pyridoxal hydrochloride (L1P-L5P). These ligands have characteristics that allow the tridentate coordination of vanadium cations, leading to the formation of ten vanadium(V) complexes (C1As-C5As and C1P-C5P) with different structural features, all characterized by single-crystal X-ray diffraction, UV-Vis and infrared spectroscopies, and cyclic voltammetry. In addition, the complexes were tested for their interactions with calf thymus deoxyribonucleic acid and human serum albumin by spectroscopic assays and molecular docking calculations. These new results can contribute to further research and provide different ways to design new vanadium complexes with biological applications.
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Complejos de Coordinación , Vanadio , Humanos , Vanadio/química , Simulación del Acoplamiento Molecular , Ligandos , Albúmina Sérica Humana/química , ADN/química , Tomografía Computarizada por Rayos X , Complejos de Coordinación/farmacología , Complejos de Coordinación/químicaRESUMEN
Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated. We designed a series of (E)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles based on the reported antiparasitic and anticancer activities of structurally related compounds. The synthesis of such compounds led to the development of a new, fast, and efficient strategy for the construction of a 1,2,4-oxadiazole ring on a silica-supported system under microwave irradiation. One hit compound (23) was identified during the in vitro evaluation against drug-sensitive and drug-resistant chronic myeloid leukemia cell lines (EC50 values ranging from 5.5 to 13.2 µM), Trypanosoma cruzi amastigotes (EC50 = 2.9 µM) and Leishmania amazonensis promastigotes (EC50 = 12.2 µM) and amastigotes (EC50 = 13.5 µM). In silico studies indicate a correlation between the in vitro activity and the interaction with tubulin at the colchicine binding site. Furthermore, ADMET in silico predictions indicate that the compounds possess a high druggability potential due to their physicochemical, pharmacokinetic, and toxicity profiles, and for hit 23, it was identified by multiple spectroscopic approaches that this compound binds with human serum albumin (HSA) via a spontaneous ground-state association with a moderate affinity driven by entropically and enthalpically energies into subdomain IIA (site I) without significantly perturbing the secondary content of the protein.
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Despite the fast development of vaccines, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still circulates through variants of concern (VoC) and escape the humoral immune response. SARS-CoV-2 has provoked over 200,000 deaths/months since its emergence and only a few antiviral drugs showed clinical benefit up to this moment. Thus, chemical structures endowed with anti-SARS-CoV-2 activity are important for continuous antiviral development and natural products represent a fruitful source of substances with biological activity. In the present study, agathisflavone (AGT), a biflavonoid from Anacardium occidentale was investigated as a candidate anti-SARS-CoV-2 compound. In silico and enzymatic analysis indicated that AGT may target mainly the viral main protease (Mpro) and not the papain-like protease (PLpro) in a non-competitive way. Cell-based assays in type II pneumocytes cell lineage (Calu-3) showed that SARS-CoV-2 is more susceptible to AGT than to apigenin (APG, monomer of AGT), in a dose-dependent manner, with an EC50 of 4.23 ± 0.21 µM and CC50 of 61.3 ± 0.1 µM and with a capacity to inhibit the level of pro-inflammatory mediator tumor necrosis factor-alpha (TNF-α). These results configure AGT as an interesting chemical scaffold for the development of novel semisynthetic antivirals against SARS-CoV-2.
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Biflavonoides , Tratamiento Farmacológico de COVID-19 , Humanos , SARS-CoV-2 , Proteasas 3C de Coronavirus , Biflavonoides/farmacología , Péptido Hidrolasas , Antivirales/química , Inhibidores de Proteasas/químicaRESUMEN
The chymotrypsin-like cysteine protease (3CLpro, also known as main protease-Mpro) and papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been used as the main targets for screening potential synthetic inhibitors for posterior in vitro evaluation of the most promising compounds. In this sense, the present work reports for the first time the evaluation of the interaction between Mpro/PLpro with a series of 17 porphyrin analogues-corrole (C1), meso-aryl-corrole (C2), and 15 fluorinated-meso-aryl-corrole derivatives (C3-C17) via molecular docking calculations. The impact of fluorine atoms on meso-aryl-corrole structure was also evaluated in terms of binding affinity and physical-chemical properties by two-dimensional quantitative structure-activity relationship (2D-QSAR). The presence of phenyl moieties increased the binding capacity of corrole for both proteases and depending on the position of fluorine atoms might impact positively or negatively the binding capacity. For Mpro the para-fluorine atoms might decrease drastically the binding capacity, while for PLpro there was a certain increase in the binding affinity of fluorinated-corroles with the increase of fluorine atoms into meso-aryl-corrole structure mainly from tri-fluorinated insertions. The 2D-QSAR models indicated two separated regions of higher and lower affinity for Mpro:C1-C17 based on dual electronic parameters (σI and σR), as well as one model was obtained with a correlation between the docking score value of Mpro:C2-C17 and the corresponding 13C nuclear magnetic resonance (NMR) chemical shifts of the sp2 carbon atoms (δC-1 and δC-2) of C2-C17. Overall, the fluorinated-meso-aryl-corrole derivatives showed favorable in silico parameters as potential synthetic compounds for future in vitro assays on the inhibition of SARS-CoV-2 replication.
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Tratamiento Farmacológico de COVID-19 , Porfirinas , Antivirales/farmacología , Carbono , Quimotripsina , Proteasas 3C de Coronavirus , Flúor , Humanos , Simulación del Acoplamiento Molecular , Papaína , Péptido Hidrolasas , Porfirinas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad Cuantitativa , SARS-CoV-2RESUMEN
The interaction between human serum albumin (HSA) and the non-charged synthetic photosensitizer 5,10,15,20-tetra(pyridine-4-yl)porphyrin (4-TPyP) was evaluated by in vitro assays under physiological conditions using spectroscopic techniques (UV-vis, circular dichroism, steady-state, time-resolved, synchronous, and 3D-fluorescence) combined with in silico calculations by molecular docking. The UV-vis and steady-state fluorescence parameters indicated a ground-state association between HSA and 4-TPyP and the absence of any dynamic fluorescence quenching was confirmed by the same average fluorescence lifetime for HSA without (4.76 ± 0.11 ns) and with 4-TPyP (4.79 ± 0.14 ns). Therefore, the Stern-Volmer quenching (KSV) constant reflects the binding affinity, indicating a moderate interaction (104 M-1) being spontaneous (ΔG°= -25.0 kJ/mol at 296 K), enthalpically (ΔH° = -9.31 ± 1.34 kJ/mol), and entropically (ΔS° = 52.9 ± 4.4 J/molK) driven. Binding causes only a very weak perturbation on the secondary structure of albumin. There is just one main binding site in HSA for 4-TPyP (n ≈ 1.0), probably into the subdomain IIA (site I), where the Trp-214 residue can be found. The microenvironment around this fluorophore seems not to be perturbed even with 4-TPyP interacting via hydrogen bonding and van der Waals forces with the amino acid residues in the subdomain IIA.
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Porfirinas , Sitios de Unión , Dicroismo Circular , Humanos , Simulación del Acoplamiento Molecular , Porfirinas/metabolismo , Unión Proteica , Piridinas , Albúmina Sérica/química , Albúmina Sérica Humana/química , Espectrometría de Fluorescencia , TermodinámicaRESUMEN
Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF-α levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 3'-5' exonuclease (ExoN).
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Tratamiento Farmacológico de COVID-19 , Flavonas , Isoflavonas , Flavonas/farmacología , Flavonoides/farmacología , Flavonoles/farmacología , Humanos , Isoflavonas/farmacología , Quempferoles , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas , Quercetina/farmacología , SARS-CoV-2RESUMEN
Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is used as a reference compound. However, resistant strains are commonly observed. Herein, we investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04, ARA-05, and AM-57, on HSV-1 in vitro replication. We show that the 50% effective concentration (EC50) values of the compounds ARA-04, ARA-05, and AM-57 were 1.00 ± 0.10, 1.00 ± 0.05, and 0.70 ± 0.10 µM, respectively. These compounds presented high 50% cytotoxic concentration (CC50) values, which resulted in a selective index (SI) of 1000, 1000, and 857.1 for ARA-04, ARA-05, and AM-57, respectively. To gain insight into which step of the HSV-1 replication cycle these molecules would impair, we performed adsorption and penetration inhibition assays and time-of-addition experiments. Our results indicated that ARA-04 and ARA-05 affected viral adsorption, while AM-57 interfered with the virus replication during its α- and γ-phases and decreased ICP27 content during initial and late events of HSV-1 replication. In addition, we also observed that AM-57 caused a strong decrease in viral gD content, which was reinforced by in silico calculations that suggested AM-57 interacts preferentially with the viral complex between a general transcription factor and virion protein (TFIIBc-VP16). In contrast, ARA-04 and ARA-05 interact preferentially in the proteins responsible for the viral adsorption process (nectin-1 and glycoprotein). Thus, our results suggest that the 1H-pyrazolo[3,4-b]pyridine derivatives inhibit the HSV-1 replicative cycle with a novel mechanism of action, and its scaffold can be used as a template for the synthesis of promising new molecules with antiviral effects, including to reinforce the presented data herein for a limited number of molecules.
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Herpes Simple , Infecciones por Herpesviridae , Herpesvirus Humano 1 , Aciclovir/farmacología , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Chlorocebus aethiops , Herpes Simple/tratamiento farmacológico , Infecciones por Herpesviridae/tratamiento farmacológico , Herpesvirus Humano 1/fisiología , Pirazoles , Piridinas/farmacología , Piridinas/uso terapéutico , Células Vero , Replicación ViralRESUMEN
Helical complexes composed of organic ligand strands and metallic centers, called helicates, present interactions with biomacromolecules, such as deoxyribonucleic acid, as one of their main biological applications in bioinorganic chemistry. Despite the potential antineoplastic and antibacterial results of the interactions between helicates and biomacromolecules, there is still a gap of research in the literature, primarily in terms of solubility in aqueous media. In this study, we present the synthesis, structural analysis, and interaction with biomacromolecules of two water-soluble cobalt(II) double-stranded helicates: [CoII2L22][CoII(NCS)4]â9H2O (C1) and [CoII2L42]Cl2â11H2O (C2). These complexes are obtained from iminic ligands (L2 and L4) derived from pyridoxal, a vitamin B6 aldehyde derivative. Through spectroscopic assays, these helical complexes were shown to have weak and moderate binding capacities with calf-thymus deoxyribonucleic acid and human serum albumin, respectively. The theoretical assays suggest that C1 and C2 interact with the minor groove of deoxyribonucleic acid and have different main binding sites with human serum albumin. Furthermore, Van der Waals and hydrogen bonds were shown to be the main intermolecular forces for these C1-C2:biomacromolecules interactions.
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Cobalto , Piridoxal , Cobalto/química , ADN/química , Humanos , Ligandos , Albúmina Sérica Humana , Agua/químicaRESUMEN
SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.