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BACKGROUND: Malaria is a major global health concern, particularly in tropical and subtropical countries. With growing resistance to first-line treatment with artemisinin, there is an urgent need to discover novel antimalarial drugs. Mesua ferrea Linn., a plant used in traditional medicine for various purposes, has previously been investigated by our research group for its cytotoxic properties. The objective of this study was to explore the compounds isolated from M. ferrea with regards to their potential antiplasmodial activity, their interaction with Plasmodium falciparum lactate dehydrogenase (PfLDH), a crucial enzyme for parasite survival, and their pharmacokinetic and toxicity profiles. METHODS: The isolated compounds were assessed for in vitro antiplasmodial activity against a multidrug-resistant strain of P. falciparum K1 using a parasite lactate dehydrogenase (pLDH) assay. In vitro cytotoxicity against Vero cells was determined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The interactions between the isolated compounds and the target enzyme PfLDH were investigated using molecular docking. Additionally, pharmacokinetic and toxicity properties were estimated using online web tools SwissADME and ProTox-II, respectively. RESULTS: Among the seven compounds isolated from M. ferrea roots, rheediachromenoxanthone (5), which belongs to the pyranoxanthone class, demonstrated good in vitro antiplasmodial activity, with the IC50 being 19.93 µM. Additionally, there was no toxicity towards Vero cells (CC50 = 112.34 µM) and a selectivity index (SI) of 5.64. Molecular docking analysis revealed that compound (5) exhibited a strong binding affinity of - 8.6 kcal/mol towards PfLDH and was stabilized by forming hydrogen bonds with key amino acid residues, including ASP53, TYR85, and GLU122. Pharmacokinetic predictions indicated that compound (5) possessed favorable drug-like properties and desired pharmacokinetic characteristics. These include high absorption in the gastrointestinal tract, classification as a non-substrate of permeability glycoprotein (P-gp), non-inhibition of CYP2C19, ease of synthesis, a high predicted LD50 value of 4,000 mg/kg, and importantly, non-hepatotoxic, non-carcinogenic, and non-cytotoxic effects. CONCLUSIONS: This study demonstrated that compounds isolated from M. ferrea exhibit activity against P. falciparum. Rheediachromenoxanthone has significant potential as a scaffold for the development of potent antimalarial drugs.
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Antimaláricos , Simulação de Acoplamento Molecular , Extratos Vegetais , Raízes de Plantas , Plasmodium falciparum , Xantonas , Antimaláricos/farmacologia , Antimaláricos/farmacocinética , Antimaláricos/química , Antimaláricos/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Xantonas/farmacologia , Xantonas/química , Xantonas/farmacocinética , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Chlorocebus aethiops , Células VeroRESUMO
Cycloartenyl ferulate is a derivative of γ-oryzanol with varied biological activity, including diabetes mellitus treatment. This research focused on improving the cycloartenyl ferulate accumulation in germinated rice by gamma irradiation under saline conditions. Moreover, the inhibitory potential of cycloartenyl ferulate against carbohydrate hydrolysis enzymes (α-glucosidase and α-amylase) was investigated through in vitro and in silico techniques. The results revealed that cycloartenyl ferulate increased in germinated rice under saline conditions upon gamma irradiation. A suitable condition for stimulating the highest cycloartenyl ferulate concentration (852.20±20.59 µg/g) in germinated rice was obtained from the gamma dose at 100 Gy and under 40 mM salt concentration. The inhibitory potential of cycloartenyl ferulate against α-glucosidase (31.31±1.43%) was higher than against α-amylase (12.72±1.11%). The inhibition mode of cycloartenyl ferulate against α-glucosidase was demonstrated as a mixed-type inhibition. A fluorescence study confirmed that the cycloartenyl ferulate interacted with the α-glucosidase's active site. A docking study revealed that cycloartenyl ferulate bound to seven amino acids of α-glucosidase with a binding energy of -8.8 kcal/mol and a higher binding potential than α-amylase (-8.2 kcal/mol). The results suggested that the gamma irradiation technique under saline conditions is suitable for stimulating γ-oryzanol, especially cycloartenyl ferulate. Furthermore, cycloartenyl ferulate demonstrated its potential as a candidate compound for blood glucose management in diabetes mellitus treatment.
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BACKGROUND: The emergence of antimalarial drug resistance encourages the search for new antimalarial agents. Mammea siamensis belongs to the Calophyllaceae family, which is a medicinal plant that is used in traditional Thai preparations. The hexane and dichloromethane extracts of this plant were found to have potent antimalarial activity. Therefore, this study aimed to isolate active compounds from M. siamensis flowers and evaluate their antimalarial potential and their interactions with Plasmodium falciparum lactate dehydrogenase (PfLDH). METHODS: The compounds from M. siamensis flowers were isolated by chromatographic techniques and evaluated for their antimalarial activity against chloroquine (CQ)-resistant P. falciparum (K1) strains using a parasite lactate dehydrogenase (pLDH) assay. Interactions between the isolated compounds and the PfLDH enzyme were investigated using a molecular docking method. RESULTS: The isolation produced the following thirteen compounds: two terpenoids, lupeol (1) and a mixture of ß-sitosterol and stigmasterol (5); two mammea coumarins, mammea A/AA cyclo D (6) and mammea A/AA cyclo F (7); and nine xanthones, 4,5-dihydroxy-3-methoxyxanthone (2), 4-hydroxyxanthone (3), 1,7-dihydroxyxanthone (4), 1,6-dihydroxyxanthone (8), 1-hydroxy-5,6,7-trimethoxyxanthone (9), 3,4,5-trihydroxyxanthone (10), 5-hydroxy-1-methoxyxanthone (11), 2-hydroxyxanthone (12), and 1,5-dihydroxy-6-methoxyxanthone (13). Compound 9 exhibited the most potent antimalarial activity with an IC50 value of 9.57 µM, followed by 10, 1, 2 and 13 with IC50 values of 15.48, 18.78, 20.96 and 22.27 µM, respectively. The molecular docking results indicated that 9, which exhibited the most potent activity, also had the best binding affinity to the PfLDH enzyme in terms of its low binding energy (-7.35 kcal/mol) and formed interactions with ARG109, ASN140, and ARG171. CONCLUSION: These findings revealed that isolated compounds from M. siamensis flowers exhibited antimalarial activity. The result suggests that 1-hydroxy-5,6,7-trimethoxyxanthone is a possible lead structure as a potent inhibitor of the PfLDH enzyme.
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Antimaláricos , Flores , Mammea , Extratos Vegetais , Antimaláricos/farmacologia , Flores/química , Mammea/química , Simulação de Acoplamento Molecular , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologiaRESUMO
BACKGROUND: This study investigated the inhibitory efficiency of phenolic compounds content methyl vanillate, syringic acid and vanillic acid against α-glucosidase and α-amylase. The phenolic compound contents of 10 Thai colored rice cultivars were also determined, and the relationship between the inhibitory efficiency of colored rice extract with methyl vanillate, syringic acid and vanillic acid was evaluated. RESULTS: The results revealed that the inhibition efficiency of methyl vanillate, syringic acid and vanillic acid was higher against α-glucosidase than against α-amylase. Inhibitory activity of vanillic acid against α-glucosidase and α-amylase was highest, with IC50 of 0.100 ± 0.01 and 0.130 ± 0.02 mmol L-1 , respectively. Docking study showed strong binding by three hydrogen bonds and four hydrogen bonds between vanillic acid with the amino acid in the binding site of α-glucosidase and α-amylase, respectively. Inhibition modes of these phenolic compounds were defined as a mixed type inhibition against α-glucosidase. Highest phenolic compound contents of methyl vanillate, syringic acid and vanillic acid were obtained from methanol extracts of all rice cultivars. The methanol extracts of all colored rice cultivars such as Khao Leum Pua also showed the highest inhibition potential against α-glucosidase and α-amylase. The results indicated that these phenolic compound contents were closely related to the inhibition potential of colored rice extracts against α-glucosidase and α-amylase. CONCLUSION: Our results suggest that rice, especially colored rice cultivars, has the source of phenolic compounds. Moreover, the phenolic compounds had the greatest source of natural inhibitor against α-glucosidase and α-amylase. © 2022 Society of Chemical Industry.
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Oryza , alfa-Glucosidases , Aminoácidos , Antioxidantes/farmacologia , Ácido Gálico/análogos & derivados , Inibidores de Glicosídeo Hidrolases/farmacologia , Metanol , Oryza/metabolismo , Fenóis/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Tailândia , Ácido Vanílico/análogos & derivados , Ácido Vanílico/farmacologia , alfa-Amilases , alfa-Glucosidases/metabolismoRESUMO
Three previously undescribed isoflavones, derrisrobustones A-C, and a previously undescribed natural isoflavone, derrisrobustone D, along with eight known isoflavones, were isolated from the twig extract of Derris robusta (DC.) Benth. All structures were identified by extensive spectroscopic analysis. Derrisrobustones A-C were obtained as scalemic mixtures and were resolved by chiral HPLC. The (1â³R, 2â³R) absolute configuration of (+)-derrisrobustone B was established by single-crystal X-ray crystallography using Cu Kα radiation. The absolute configurations of derrisrobustones A and C were determined by analysis of experimental and calculated ECD data. All compounds were evaluated for their α-glucosidase inhibitory activity. Of these, derrubone displayed the best α-glucosidase inhibitory activity with an IC50 value of 64.2 µM.
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Derris , Isoflavonas , Derris/química , Derris/metabolismo , Isoflavonas/química , Isoflavonas/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , alfa-Glucosidases/metabolismoRESUMO
The mixed ligand synthetic approach offers an alternative to engineering a specific character in metal-organic framework (MOFs) materials. Herein, we synthesized and characterized a well-known prototype zirconium-based-MOF, so-called UiO-66, and its mixed ligand derivatives UiO-66-xATA, where x is mole fraction (0.5, 0.75, and 1.0) and ATA is 2-animoterephthalate. The study investigates whether the dye adsorption capacity can be tuned/enhanced by the ATA ligand substitution into the framework. We found that, at room temperature, UiO-66-0.75ATA shows the highest adsorption capacity toward various dye solutions, including methylene blue (MB), indigo carmine (IC), and congo red (CR). The optimum adsorption conditions in all four materials were in a common trend where their adsorption capacities can be increased with decreasing pH and adsorbent dose, increasing IC concentration, contact time, and temperature. Pseudo-second order kinetics model fits best with their adsorption data, where UiO-66-ATA has the fastest adsorption rate. Langmuir and Freundlich isotherms were found best to describe adsorption behavior in ATA-containing UiO-66 and UiO-66, respectively, where adsorption processes were found to be physisorption. Confirming by thermodynamic studies, the adsorption in all four materials occurred spontaneously, driven by entropy. Computational studies showed ligand to metal charge transfer where the distribution of electron densities was varied with the amount of functionalized ligand. Adsorption mechanism is proposed as a synergistic interplay between electrostatic interaction and hydrogen bonding. The findings in this work broaden the potential strategy to fine-tune the dye adsorption capacity in MOF materials.
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BACKGROUND: At present, the emergence and spread of antimalarial drug resistance has become a significant problem worldwide. There has been a challenge in searching for natural products for the development of novel antimalarial drugs. Therefore, this study aims to evaluate compounds from Dioscorea bulbifera responsible for antimalarial properties and investigate potential interactions of the compounds with Plasmodium falciparum lactate dehydrogenase (PfLDH), an essential glycolytic enzyme in the parasite's life cycle. METHODS: An in vitro study of antimalarial activity against chloroquine (CQ)-resistant Plasmodium falciparum (K1 strain) and CQ-sensitive P. falciparum (3D7 strain) was performed using the 3H-hypoxanthine uptake inhibition method. The cytotoxic effects of the pure compounds were tested against Vero cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The interactions of the compounds with the PfLDH active site were additionally investigated using a molecular docking method. RESULTS: Quercetin (6) exhibited the highest antimalarial activity against the P. falciparum K1 and 3D7 strains, with IC50 values of 28.47 and 50.99 µM, respectively. 2,4,3',5'-Tetrahydroxybibenzyl (9), 3,5-dimethoxyquercetin (4) and quercetin-3-O-ß-D-galactopyranoside (14) also possessed antimalarial effects against these two strains of P. falciparum. Most pure compounds were nontoxic against Vero cells at a concentration of 80 µg/ml, except for compound 9, which had a cytotoxic effect with a CC50 value of 16.71 µM. The molecular docking results indicated that 9 exhibited the best binding affinity to the PfLDH enzyme in terms of low binding energy (- 8.91 kcal/mol) and formed strong hydrogen bond interactions with GLY29, GLY32, THR97, GLY99, PHE100, THR101 and ASN140, amino acids as active sites. In addition, 6 also possessed remarkable binding affinity (- 8.53 kcal/mol) to PfLDH by interacting with GLY29, ILE31, ASP53, ILE54, THR97 and THR101. CONCLUSION: Quercetin is a major active compound responsible for the antimalarial activity of D. bulbifera and is an inhibitor of PfLDH. These findings provide more evidence to support the traditional use of D. bulbifera for malaria treatment. Structural models of its interactions at the PfLDH active site are plausibly useful for the future design of antimalarial agents.
Assuntos
Antimaláricos , Dioscorea/química , Extratos Vegetais , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Quercetina/química , Quercetina/metabolismo , Quercetina/farmacologia , Quercetina/toxicidade , Células VeroRESUMO
SO3H-carbocatalysts with nitrogen functionalities were prepared using the carbonization of polybenzoxazine derived from four different amines (aniline, ethylenediamine, triethylenetetramine, and tetraethylenepentamine) and then sulfonation. The obtained SO3H-carbocatalysts underwent catalytic testing for furfural oxidation with H2O2 to produce succinic acid. The effects of nitrogen functionalities were reported for the first time. The results showed that all carbon samples exhibited a microporous characteristic with comparable textural properties and contained various nitrogen functionalities (N-6, N-5, N-Q, and N-X). After sulfonation, the SO3H-carbocatalyst prepared from tetraethylenepentamine-based polybenzoxazine had the highest amount of sulfonic acid groups (1.45 mmol g-1) and a high nitrogen content (4.23%), providing a maximum succinic acid yield of 93.0% within a rapid reaction time of 60 min under the optimized conditions. This was higher than from Amberlyst-type catalysts and SO3H-carbocatalyst without nitrogen functionalities and was ascribed to the synergistic activity of the sulfonic acid groups and nitrogen functionalities. The XPS spectra and computational study confirmed that such nitrogen functionalities, especially N-5, are capable of forming hydrogen bonding with furfural, facilitating the formation of an intermediate compound and thereby enhancing the catalytic efficiency. However, after four cycles, the succinic acid yield decreased to 40% due to leaching of the sulfonic acid groups.
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Conformations and spectroscopic properties of laccaic acid A (lacA) were studied by means of the experimental and theoretical approaches. The minimum energy conformers of lacA in the gas phase and in implicit water obtained from the B3LYP/6-311G(d,p) calculations displayed the same orientation of the COOH and OH groups on the anthraquinone-based component. The intramolecular hydrogen bonds (H-bonds) formed between the COOH, C=O and OH groups are very strong. In contrast, the orientations of the Ph(OH)CH(2)CH(2)NHCOCH(3) substituent moiety on the anthraquinone-based component in the gas phase and in implicit water are completely different. The substituent prefers to bind with the anthraquinone-based component in the gas phase while it moves away from the anthraquinone-based component in implicit water. The calculated IR spectra of the two lowest-lying energy conformers of lacA in the gas phase fit to the experimental FTIR spectrum. The full assignments of the vibrational modes with the correlated vibrational wavenumbers of those conformers were proposed here, for the first time. The intramolecular H-bond formations in lacA can cause the shift of the vibrational wavenumber for the COOH, C=O, OH and NH groups as compared to the normal vibrations of these groups. The NMR spectra showed that the stabilities of the two lowest-lying energy conformers of lacA in the gas phase are comparable and this is consistent with their computational energies. The UV-Vis spectra of the lowest-lying energy conformers of lacA in implicit water were compared with the experimental UV-Vis spectrum. The calculations suggested that the electronic transition in the visible region involves with the singlet πâπ(*) excitation which the electron density transfers to a COOH group on the anthraquinone ring.
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Compostos Azo/química , Corantes/química , Corantes de Alimentos/química , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Água/químicaRESUMO
Two combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, namely HF/MM and B3LYP/MM, have been performed to investigate the local hydration structure and dynamics of carbonate (CO(3)(2-)) in dilute aqueous solution. With respect to the QM/MM scheme, the QM region, which contains the CO(3)(2-) and its surrounding water molecules, was treated at HF and B3LYP levels of accuracy, respectively, using the DZV+ basis set, while the rest of the system is described by classical MM potentials. For both the HF/MM and B3LYP/MM simulations, it is observed that the hydrogen bonds between CO(3)(2-) oxygens and their nearest-neighbor waters are relatively strong, i.e., compared to water-water hydrogen bonds in the bulk, and that the first shell of each CO(3)(2-) oxygen atom somewhat overlaps with the others, which allows migration of water molecules among the coordinating sites to exist. In addition, it is observed that first-shell waters are either "loosely" or "tightly" bound to the respective CO(3)(2-) oxygen atoms, leading to large fluctuations in the number of first-shell waters, ranging from 1 to 6 (HF/MM) and 2 to 7 (B3LYP/MM), with the prevalent value of 3. Upon comparing the HF and B3LYP methods in describing this hydrated ion, the latter is found to overestimate the hydrogen-bond strength in the CO(3)(2-)-water complexes, resulting in a slightly more compact hydration structure at each of the CO(3)(2-) oxygens.
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Carbonatos/química , Simulação de Dinâmica Molecular , Teoria Quântica , Água/química , Ligação de Hidrogênio , SoluçõesRESUMO
Two combined QM/MM molecular dynamics (MD) simulations, namely, HF/MM and B3LYP/MM, in which the central CH(3)COO(-) and its surrounding water molecules were treated at HF and B3LYP levels of accuracy, respectively, using the DZV+ basis set, have been performed to investigate the characteristics of CH(3)COO(-)-water hydrogen bonds in dilute aqueous solution. Both HF/MM and B3LYP/MM simulations clearly indicate relatively strong hydrogen bonds between CH(3)COO(-) oxygens and their nearest-neighbor waters compared with those of water-water hydrogen bonds in the bulk. In addition, it is observed that first-shell waters are either "loosely" or "tightly" bound to their respective CH(3)COO(-) oxygen atoms, leading to large fluctuations in the coordination number, ranging from 2 to 5, with the prevalent value of 3. Among the HF and B3LYP methods for the description of the QM-treated region, the latter predicts slightly higher hydrogen-bond strength in the CH(3)COO(-)-water complex.
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Acetatos/química , Simulação de Dinâmica Molecular , Teoria Quântica , Água/química , Ligação de Hidrogênio , SoluçõesRESUMO
The effective Hamiltonian-molecular orbital and valence bond (EH-MOVB) method based on non-orthogonal block-localized fragment orbitals has been implemented into the program CHARMM for molecular dynamics simulations of chemical and enzymatic reactions, making use of semiempirical quantum mechanical models. Building upon ab initio MOVB theory, we make use of two parameters in the EH-MOVB method to fit the barrier height and the relative energy between the reactant and product state for a given chemical reaction to be in agreement with experiment or high-level ab initio or density functional results. Consequently, the EH-MOVB method provides a highly accurate and computationally efficient QM/MM model for dynamics simulation of chemical reactions in solution. The EH-MOVB method is illustrated by examination of the potential energy surface of the hydride transfer reaction from trimethylamine to a flavin cofactor model in the gas phase. In the present study, we employed the semiempirical AM1 model, which yields a reaction barrier that is more than 5 kcal/mol too high. We use a parameter calibration procedure for the EH-MOVB method similar to that employed to adjust the results of semiempirical and empirical models. Thus, the relative energy of these two diabatic states can be shifted to reproduce the experimental energy of reaction, and the barrier height is optimized to reproduce the desired (accurate) value by adding a constant to the off-diagonal matrix element. The present EH-MOVB method offers a viable approach to characterizing solvent and protein-reorganization effects in the realm of combined QM/MM simulations.
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Characteristics of HCOO(-)-water hydrogen bonds in dilute aqueous solution have been investigated by means of combined HF/MM and B3LYP/MM molecular dynamics simulations, in which the central HCOO(-) and its surrounding water molecules were treated at HF and B3LYP levels of accuracy, respectively, using DZV+ basis set. Both HF/MM and B3LYP/MM simulations supply information that the hydrogen bonds between HCOO(-) oxygens and first-shell waters are relatively strong, that is, compared to the water-water hydrogen bonds. Regarding to the HF/MM and B3LYP/MM trajectories, it is observed that first-shell waters are either "loosely" or "tightly" bound to their respective HCOO(-) oxygen atoms, showing large fluctuations in the hydration number, varying from 2 to 6 (HF/MM) and 1 to 5 (B3LYP/MM), with the prevalent value of 3. Comparing the HF and B3LYP methods for the description of QM treated region, the first one leads to slightly too weak and thus longer hydrogen bonds, while the latter predicts them stronger but with the wrong dynamical data.