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Carbonyl compounds are widely explored in medicinal inorganic chemistry and have drawn attention due to their signaling functions in homeostasis. Carbon-monoxide-releasing molecules (CORMs) were developed with the purpose of keeping the CO inactive until its release in the intracellular environment, considering its biological relevance. However, for therapeutic applications, the mechanisms of photorelease and which electronic and structural variations influence its rates must be fully understood. In this work, four ligands containing a pyridine, a secondary amine, and a phenolic group with different substituents were used to prepare new Mn(I) carbonyl compounds. Structural and physicochemical characterization of these complexes was carried out and confirmed the proposed structures. X-ray diffractometry structures obtained for the four organometallic compounds revealed that the substituents in the phenolic ring promote only negligible distortions in their geometry. Furthermore, UV-Vis and IR kinetics showed the direct dependence of the electron-withdrawing or donating ability of the substituent group, indicating an influence of the phenol ring on the CO release mechanism. These differences in properties were also supported by theoretical studies at the DFT, TD-DFT, and bonding situation analyses (EDA-NOCV). Two methods were used to determine the CO release constants (kCO,old and kCO,new), where Mn-HbpaBr (1) had the greatest kCO by both methods (Kco,old = 2.36 × 10-3 s-1 and kCO,new = 2.37 × 10-3 s-1). Carbon monoxide release was also evaluated using the myoglobin assay, indicating the release of 1.248 to 1.827 carbon monoxides upon light irradiation.
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Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type neolignans (DBNs) and two benzofuran-type neolignans (BNs) were synthesized and evaluated against amastigote forms of two Trypanosoma cruzi strains. The in vitro cytotoxicity and hemolytic activity of the most active compounds were also evaluated and their relationships with T. cruzi tubulin DBNs were investigated by an in silico approach. Four DBNs demonstrated activity against the T. cruzi Tulahuen lac-Z strain (IC50 from 7.96 to 21.12 µM), and DBN 1 exhibited the highest activity against the amastigote forms of the T. cruzi Y strain (IC50 3.26 µM). Compounds 1-4 showed CC50 values higher than antitrypanosomal activities, except for DBN 3. All DBNs with antitrypanosomal activity demonstrated CH50 higher than 100 µM. The in silico results indicated that DBNs 1, 2, and 4 are capable of destabilizing the dynamics of the tubulin-microtubule from the vinca site. These compounds displayed promising in vitro activity against T. cruzi, especially compound 1, and can be considered molecular prototypes for the development of new antiparasitic drugs.
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closo-Carboranes are structures that have been studied for many decades due to their vast applicability in medicine, catalysis, and energy storage. In order to go deeper into the physics behind the interactions of oppositely charged ions, which have potential applications in electrical energy storage and conversion devices, the present work aims to shed light on the physical nature of the interactions involving (R-CB11H11-, R = H, F, CH3, CF3) and Mq+ = Li+, Na+, Mg2+, Zn2+ ions. The bonding situations are evaluated in light of both canonical Kohn-Sham energy decomposition, EDA-NOCV, and local energy decomposition, LED, analyses. Electron and hole transports are also evaluated through charge transfer integrals. The findings reveal that such complexes present not only more significant electrostatic, but also non-negligible orbital contributions. Both energy decomposition analyses EDA-NOCV and DLPNO-LED confirm that the strength of ionic pair interactions (R-CB11H11- â Mq+) is much more dependent on the nature of the cation employed than on the substituent R used. The results also reveal that charge transfers are not significant in such interacting systems.
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Gold and silver subnanoclusters with few atoms are prominent candidates for catalysis-related applications, primarily because of the large fraction of lower-coordinated atoms exposed and ready to interact with external chemical species. However, an in-depth energetic analysis is necessary to characterize the relevant terms within the molecular adsorption process that can frame the interactions within the Sabatier principle. Herein, we investigate the interaction between Agn and Aun subnanoclusters (clu, n = 2-7) and N2 , NO, CO, and O2 molecules, using scalar-relativistic density functional theory calculations within van der Waals D3 corrections. The onefold top site is preferred for all chemisorption cases, with a predominance of linear (≈180°) and bent (≈120°) molecular geometries. A larger magnitude of adsorption energy is correlated with smaller distances between molecules and clusters and with the weakening of the adsorbates bond strength represented by the increase of the equilibrium distances and decrease of molecular stretching frequencies. From the energetic decomposition, the interaction energy term was established as an excellent descriptor to classify subnanoclusters in the adsorption/desorption process concomitant with the Sabatier principle. The limiting cases: (i) weak molecular adsorption on the subnanoclusters, which may compromise the reaction activation, where an interaction energy magnitude close to 0 eV is observed (e.g., physisorption in N2 /Ag6 ); and (ii) strong molecular interactions with the subnanoclusters, given the interaction energy magnitude is larger than at least one of the individual fragment binding energies (e.g., strong chemisorption in CO/Au4 and NO/Au4 ), conferring a decrease in the desorption rate and an increase in the possible poisoning rate. However, the intermediate cases are promising by involving interaction energy magnitudes between zero and fragment binding energies. Following the molecular closed-shell (open-shell) electronic configuration, we find a predominant electrostatic (covalent) nature of the physical interactions for N2 â¯clu and CO â¯clu (O2 â¯clu and NOâ¯clu), except in the physisorption case (N2 /Ag6 ) where dispersive interaction is dominant. Our results clarify questions about the molecular adsorption on subnanoclusters as a relevant mechanistic step present in nanocatalytic reactions.
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The complexity of Cu13, Ag13, and Au13 coinage-metal clusters was investigated through their energy contributions via a density functional theory study, considering improvements in the PBE functional, such as van der Waals (vdW) corrections, spin-orbit coupling (SOC), Hubbard term (+U), and their combinations. Investigating two-dimensional (planar 2D) and three-dimensional (distorted 3D, CUB - cuboctahedral, and ICO - icosahedral) configurations, we found that vdW corrections are dominant in modulating the stability swapping between 2D and ICO (3D) for Ag13 (Au13), whereas for Cu13 its role is increasing the relative stability between 2D (least stable) and 3D (most stable), setting ICO as the reference. Among the energy portions that constitute the relative total energy, the dimensionality difference correlates with the magnitude of the relative dispersion energy (large for 2D/ICO and small for 3D/ICO) as the causal factor responsible for an eventual stability swapping. For instance, empirical vdW corrections may favor Ag13 as ICO, while semi empirical ones tend to swap the stability by favoring 2D. The same tendency is observed for Au13, except when SOC is included, which enlarges the stability of 3D over 2D. Energy decomposition analysis combined with the natural orbitals for the chemical valence approach confirmed the correlations between the dimensionality difference and the magnitude of the relative dispersion energies. Our structural analysis protocol was able to capture the local distortion effects (or even their absence) through the quantification of the Hausdorff chirality measure. Here, ICO, CUB, and 2D are achiral configurations for all coinage-metal clusters, whereas Cu13 as 3D presents a slight chirality when vdW correction based on many body dispersion is used, at the same time Ag13 as 3D turned out to be chiral for all calculation protocols as evidence of the role of the chemical composition.
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This work aimed to synthesize poly (D, L-lactic-co-glycolic acid) (PLGA) microparticles containing hinokinin (HNK) and to evaluate their cytotoxic activity against tumoral SiHa cells and non-tumoral HaCaT cells. Hinokinin was incorporated into PLGA (PLGA-HNK) with an encapsulation efficiency of 84.18 ± 2.32%. PLGA and PLGA-HNK were characterized by SEM microscopy and showed spherical morphology with an average size of â¼3.33. Encapsulation efficiency was determined by a calibration curve using UV-vis spectroscopy. PLGA-HNK more active inhibiting proliferation of SiHa cells (IC50 = 14.68 µM) than free HNK (IC50 = 225.5 µM). In relation to HaCaT cells, PLGA-HNK showed no significant difference compared to the negative control. These results led to an increase in HNK bioavailability and thereby, biological activity. In silico prediction analysis suggests that HNK is cytotoxic against SiHa cells with E6 and MDM2 inhibition as possible main mechanism of action.
Assuntos
Antineoplásicos , Nanopartículas , 4-Butirolactona/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzodioxóis , Ácido Láctico/química , Lignanas , Nanopartículas/química , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
The coinage-metal clusters possess a natural complexity in their theoretical treatment that may be accompanied by inherent shortcomings in the methodological approach. Herein, we performed a scalar-relativistic density functional theory study, considering Perdew, Burke, and Ernzerhof (PBE) with (empirical and semi empirical) van der Waals (vdW), spin-orbit coupling (SOC), +U (Hubbard term), and their combinations, to treat the Cu 13 , Ag 13 , and Au 13 clusters in different structural motifs. The energetic scenario is given by the confirmation of the 3D lowest energy configurations for Cu 13 and Ag 13 within all approaches, while for Au 13 there is a 2D/3D competition, depending on the applied correction. The 2D geometry is 0.43 eV more stable with plain PBE than the 3D one, the SOC, +U, and/or vdW inclusion decreases the overestimated stability of the planar configurations, where the most surprising result is found by the D3 and D3BJ vdW corrections, for which the 3D configuration is 0.29 and 0.11 eV, respectively, more stable than the 2D geometry (with even higher values when SOC and/or +U are added). The D3 dispersion correction represents 7.9% (4.4%) of the total binding energy for the 3D (2D) configuration, (not) being enough to change the sd hybridization and the position of the occupied d -states. Our predictions are in agreement with experimental results and in line with the best results obtained for bulk systems, as well as with hybrid functionals within D3 corrections. The properties description undergoes small corrections with the different approaches, where general trends are maintained, that is, the average bond length is smaller (larger) for lower (higher)-coordinated structures, since a same number of electrons are shared by a smaller (larger) number of bonds, consequently, the bonds are stronger (weaker) and shorter (longer) and the sd hybridization index is larger (smaller). Thus, Au has a distinct behavior in relation to its lighter congeners, with a complex potential energy surface, where in addition to the relevant relativistic effects, correlation and dispersion effects must also be considered.
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Lignan dinitrohinokinin displays important biological activities, which led to the preparation of its poly-ε-caprolactone nanoparticles. Kinetics analysis revealed initially slow drug release followed by a prolonged, moderate release 6 h later due to DNHK diffusion through the polymeric matrix. Molecular dynamics simulations show that DNHK molecules that interact stronger with other DNHK molecules near the PCL/DNHK surface are more difficult to dissociate from the nanoparticle. The smaller diameter nanocapsules with negative surface charge conferred good colloidal stability. The formulations showed a size distribution with monodisperse systems formation. In vivo evaluation of schistosomicidal activity against Schistosoma mansoni showed that DNHK, when incorporated into nanoparticles, caused egg number reduction of 4.2% and 28.1% at 40 mg/kg and 94.2% and 84.4% at 400 mg/kg in the liver and the spleen, respectively. The PCL nanoparticles were stable in aqueous dispersion and could be optimized to be used as a promising lignan release agent.
Assuntos
Lignanas , Nanopartículas , Esquistossomicidas , Portadores de Fármacos , Lignanas/farmacologia , PoliésteresRESUMO
Unraveling the different contributing terms to an efficient anion encapsulation is a relevant issue for further understanding of the underlying factors governing the formation of endohedral species. Herein, we explore the favorable encapsulation of hydride and halide anions in the [Ag8(X){S2P(OPr)2}6]+ (X- = H, 1, F, 2, Cl, 3, Br, 4, and, I, 5) series on the basis of relativistic DFT-D level of theory. The resulting Ag8-X interaction is sizable, which decreases along the series: -232.2 (1) > -192.1 (2) > -165.5 (3) > -158.0 (4) > -144.2 kcal mol-1 (5), denoting a more favorable inclusion of hydride and fluoride anions within the silver cage. Such interaction is mainly stabilized by the high contribution from electrostatic type interactions (80.9 av%), with a lesser contribution from charge-transfer (17.4 av%) and London type interactions (1.7 av%). Moreover, the ionic character of the electrostatic contributions decreases from 90.7% for hydride to 68.6% for the iodide counterpart, in line with the decrease in hardness according to the Pearson's acid-base concept (HSAB) owing to the major role of higher electrostatic interaction terms related to the softer (Lewis) bases. Lastly, the [Ag8{S2P(OPr)2}6]2+ cluster is able to adapt its geometry in order to maximize the interaction towards respective monoatomic anion, exhibiting structural flexibility. Such insights shed light on the physical reasoning necessary for a better understanding of the different stabilizing and destabilizing contributions related to metal-based cavities towards favorable incorporation of different monoatomic anions.
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Brazilian green and red propolis stand out as commercial products for different medical applications. In this article, we report the antimicrobial activities of the hydroalcoholic extracts of green (EGP) and red (ERP) propolis, as well as guttiferone E plus xanthochymol (8) and oblongifolinâ B (9) from red propolis, against multidrug-resistant bacteria (MDRB). We undertook the minimal inhibitory (MIC) and bactericidal (MBC) concentrations, inhibition of biofilm formation (MICB50 ), catalase, coagulase, DNase, lipase, and hemolysin assays, along with molecular docking simulations. ERP was more effective by displaying MIC and MBC values <100â µg mL-1 . Compoundsâ 8 andâ 9 displayed the lowest MIC values (0.98 to 31.25â µg mL-1 ) against all tested Gram-positive MDRB. They also inhibited the biofilm formation of S. aureus (ATCC 43300 and clinical isolate) and S. epidermidis (ATCC 14990 and clinical isolate), with MICB50 values between 1.56 and 6.25â µg mL-1 . The molecular docking results indicated thatâ 8 andâ 9 might interact with the catalase's amino acids. Compounds 8 and 9 have great antimicrobial potential.