Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world's population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2'-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Silver and copper nanoparticles were produced by chemical reduction of their respective nitrates by ascorbic acid in the presence of chitosan using microwave heating. Particle size was shown to increase by increasing the concentration of nitrate and reducing the chitosan concentration. Surface zeta potentials were positive for all nanoparticles produced and these varied from 27.8 to 33.8 mV. Antibacterial activities of Ag, Cu, mixtures of Ag and Cu, and Ag/Cu bimetallic nanoparticles were tested using Bacillus subtilis and Escherichia coli. Of the two, B. subtilis proved more susceptible under all conditions investigated. Silver nanoparticles displayed higher activity than copper nanoparticles and mixtures of nanoparticles of the same mean particle size. However when compared on an equal concentration basis Cu nanoparticles proved more lethal to the bacteria due to a higher surface area. The highest antibacterial activity was obtained with bimetallic Ag/Cu nanoparticles with minimum inhibitory concentrations (MIC) of 0.054 and 0.076 mg/L against B. subtilis and E. coli, respectively.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Phytochemical studies on the stem bark of Garcinia nervosa has resulted in the discovery of one new pyranoxanthone derivative, garner xanthone (1) and five other compounds, 1,5-dihydroxyxanthone (2), 6-deoxyisojacareubin (3), 12b-hydroxy-des-D-garcigerrin A (4) stigmasterol (5), and β-sitosterol (6). The structures of these compounds were elucidated with the aid of spectroscopic techniques, such as NMR and MS. The crude extracts of the plant were assessed for their antimicrobial activity.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
An intelligent prediction system has been developed to discriminate drug-like and non drug-like molecules pattern. The system is constructed by using the application of advanced version of standard multilayer perceptron (MLP) neural network called Hybrid Multilayer Perceptron (HMLP) neural network and trained using Modified Recursive Prediction Error (MRPE) training algorithm. In this work, a well understood and easy excess Rule of Five + Veber filter properties are selected as the topological descriptor. The main idea behind the selection of this simple descriptor is to assure that the system could be used widely, beneficial and more advantageous regardless at all user level within a drug discovery organization.
Matched MeSH terms: Drug Evaluation, Preclinical/methods*
The aim of this study was to prepare a lipid-based self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of a poorly water-soluble compound, buparvaquone (BPQ).
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Momordica charantia (MC; bitter gourd) is a traditional herb commonly used for its antidiabetic, antioxidant, contraceptive and antibacterial properties. It is also used for the rapid healing of wounds.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The aim of the study was to isolate digestive enzymes inhibitors from Mimosa pudica through a bioassay-guided fractionation approach. Repeated silica gel and sephadex LH 20 column chromatographies of bioactive fractions afforded stigmasterol, quercetin and avicularin as digestive enzymes inhibitors whose IC50 values as compared to acarbose (351.02 ± 1.46 μg mL-1) were found to be as 91.08 ± 1.54, 75.16 ± 0.92 and 481.7 ± 0.703 μg mL-1, respectively. In conclusion, M. pudica could be a good and safe source of digestive enzymes inhibitors for the management of diabetes in future.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28) were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary in the range between 2.64 ± 0.05 and 460.14 ± 3.25 μM. The IC50 values were being compared to the standard acarbose (IC50=856.45 ± 5.60 μM) and it was found that compounds 6-9, 12, 13, 16, 18, 20, 22-28 were found to be more active than acarbose, while other compounds showed no activity. Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50=2.64 ± 0.05 μM), which has trihydroxy substitution at C-2', C-4', and C-5' on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC50=856.45 ± 5.60 μM). Compound 23 (IC50=34.64 ± 0.35 μM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2' to C-4' (6) and C-3' (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Ensemble docking can be a successful virtual screening technique that addresses the innate conformational heterogeneity of macromolecular drug targets. Yet, lacking a method to identify a subset of conformational states that effectively segregates active and inactive small molecules, ensemble docking may result in the recommendation of a large number of false positives. Here, three knowledge-based methods that construct structural ensembles for virtual screening are presented. Each method selects ensembles by optimizing an objective function calculated using the receiver operating characteristic (ROC) curve: either the area under the ROC curve (AUC) or a ROC enrichment factor (EF). As the number of receptor conformations, N, becomes large, the methods differ in their asymptotic scaling. Given a set of small molecules with known activities and a collection of target conformations, the most resource intense method is guaranteed to find the optimal ensemble but scales as O(2(N)). A recursive approximation to the optimal solution scales as O(N(2)), and a more severe approximation leads to a faster method that scales linearly, O(N). The techniques are generally applicable to any system, and we demonstrate their effectiveness on the androgen nuclear hormone receptor (AR), cyclin-dependent kinase 2 (CDK2), and the peroxisome proliferator-activated receptor δ (PPAR-δ) drug targets. Conformations that consisted of a crystal structure and molecular dynamics simulation cluster centroids were used to form AR and CDK2 ensembles. Multiple available crystal structures were used to form PPAR-δ ensembles. For each target, we show that the three methods perform similarly to one another on both the training and test sets.
Matched MeSH terms: Drug Evaluation, Preclinical/methods*
Benefits of whole grains as dietary supplements and active ingredients in health products have been promoted. Despite being neglected as an agricultural byproduct of polished rice, pigmented rice bran has emerged as a promising source of natural anti-aging compounds. Indeed, the extract of red rice bran Hom Dang cultivar contained rich phenolic acids and flavonoids. It displayed high antioxidant activities in vitro and in vivo assays. Using yeast model, extract and bioactive compounds, quercetin and protocatechuic acid found in the rice bran pericarp, effectively reduced levels of intracellular reactive oxygen species (ROS), restored plasma membrane damages and prolonged life-span of pre-treated wild-yeast cells. Importantly, these molecules modulated life span-extension through a mechanism of ROS reduction that resembles to that operated under the highly conserved Tor1- and Sir2-dependent signaling pathways, with the human homologs TORC1 and SIRT1, respectively. The key longevity factors Sch9 and Rim15 kinases, Msn2/4 regulators and a novel transcription factor Asg1, the antioxidant enzymes superoxide dismutases and glutathione peroxidases played important role in mediating longevity. Yeast clearly provides an instrumental platform for rapid screening of compounds with anti-aging efficacies and advances knowledge in the molecular study of ageing.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Goniothalamus scortechinii, Andrographis paniculata and Aralidium pinnatifidum were selected for the study based on their ethnomedicinal values. They were screened for anti-malarial activity towards Plasmodium falciparum in vitro using the lactate dehydrogenase (LDH) assay. The crude extract of G. scortechinii exhibited the most potent schizonticidal activity compared to the other extracts. It is effective against both the chloroquine resistant isolate, Gombak A and the sensitive strain, D10 of Plasmodium falciparum. Furthermore a better IC(50) value was obtained against the resistant strain, (9 microg/ml) compared to the sensitive strain, 40 microg/ml. When the crude extract was fractionated into 3 fractions, the chloroform fraction yielded the best activity, exhibiting equipotency against both strains of parasite used; IC(50) of 23.53 microg/ml against Gombak A and 21.06 microg/ml against D10.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright 'Franz-type' diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Current research is based on the identification of novel inhibitors of α-amylase enzyme. For that purpose, new hybrid molecules of hydrazinyl thiazole substituted chromones 5-27 were synthesized by multi-step reaction and fully characterized by various spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemistry of the iminic bond was confirmed by NOESY analysis of a representative molecule. All compounds 5-27 along with their intervening intermediates 1-4, were screened for in vitro α-amylase inhibitory, DPPH and ABTS radical scavenging activities. All compounds showed good inhibition potential in the range of IC50 = 2.186-3.405 µM as compared to standard acarbose having IC50 value of 1.9 ± 0.07 µM. It is worth mentioning that compounds were also demonstrated good DPPH (IC50 = 0.09-2.233 µM) and ABTS (IC50 = 0.584-3.738 µM) radical scavenging activities as compared to standard ascorbic acid having IC50 = 0.33 ± 0.18 µM for DPPH and IC50 = 0.53 ± 0.3 µM for ABTS radical scavenging activities. In addition to that cytotoxicity of the compounds were checked on NIH-3T3 mouse fibroblast cell line and found to be non-toxic. In silico studies were performed to rationalize the binding mode of compounds (ligands) with the active site of α-amylase enzyme.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The present study aims to investigate the effect of cocoa extract on serum glucose levels and lipid profiles in streptozotocin-diabetic rats. Cocoa extract (contained 285.6 mg total polyphenol per gram extract) was prepared from fermented and roasted (140 degrees C, 20 min) beans by extracting using 80% ethanol in the ratio of 1-10. The extract of three dosages (1, 2, and 3%) was fed to normal and diabetic rats for a period of 4 weeks. In hyperglycaemic group, cocoa extract (1 and 3%) diets were found to significantly lower (p<0.05) the serum glucose levels compared to the control. Furthermore, supplementation of 1 and 3% cocoa extract had significantly reduced (p<0.05) the level of total cholesterol in diabetic rats. In addition, 1, 2, and 3% cocoa extract diets had significantly lowered (p<0.05) the total triglycerides. Interestingly, this study found that serum HDL-cholesterol had increased significantly (p<0.05) in diabetic rats fed with 2% cocoa extract, while the LDL-cholesterol had decreased significantly (p<0.05) in the 1% treated group. These results indicate that cocoa extract may possess potential hypoglycaemic and hypocholestrolemic effects on serum glucose levels and lipid profiles, respectively. The results also found that the effect of cocoa extract was dose-dependent.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Dengue virus infects millions of people worldwide and there is no vaccine or anti-dengue therapeutic available. Screening large numbers of medicinal plants for anti-dengue activities is an alternative strategy in order to find the potent therapeutic compounds. Therefore, this study was designed to identify anti-dengue activities in nineteen medicinal plant extracts that are used in traditional medicine. Local medicinal plants Vernonia cinerea, Hemigraphis reptans, Hedyotis auricularia, Laurentia longiflora, Tridax procumbers and Senna angustifolia were used in this study. The highest inhibitory activates against dengue NS2B-NS3pro was observed in ethanolic extract of S. angustifolia leaves, methanolic extract of V. cinerea leaves and ethanol extract of T. procumbens stems. These findings were further verified by in vitro viral inhibition assay. Methanolic extract of V. cinerea leaves, ethanol extract of T. procumbens stems and at less extent ethanolic extract of S. angustifolia leaves were able to maintain the normal morphology of DENV2-infected Vero cells without causing much cytopathic effects (CPE). The percentage of viral inhibition of V. cinerea and T. procumbens extracts were significantly higher than S. angustifolia extract as measured by plaque formation assay and RT-qPCR. In conclusion, The outcome of this study showed that the methanolic extract of V. cinerea leaves and ethanol extract of T. procumbens stems possessed high inhibitory activates against dengue virus that worth more investigation.
Matched MeSH terms: Drug Evaluation, Preclinical/methods*
Chalcones are a group of compounds widely distributed in plant kingdom. The aim of this study was to assess the neurite outgrowth stimulatory activity of selected chalcones, namely helichrysetin, xanthohumol and flavokawin-C. Using adherent rat pheochromocytoma (PC12 Adh) cells, the chalcones were subjected to neurite outgrowth assay and the extracellular nerve growth factor (NGF) levels were determined. Xanthohumol (10 μg/mL) displayed the highest (p
Matched MeSH terms: Drug Evaluation, Preclinical/methods
A new xenicane diterpenoid, 15-deoxy-isoxeniolide-A (1) along with four known compounds 9-deoxy-isoxeniolide-A (2), isoxeniolide-A (3), xeniolide-A (4) and coraxeniolide-B (5) were isolated from the Bornean soft coral Xenia sp. The structures of these metabolites were elucidated on the basis of spectral analysis, NMR and HRESIMS. Compound 5 showed cytotoxic activity against ATL cell line, S1T.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Four new bicyclogermacrenes, capgermacrenes D (1) E (2) F (3) and G (4) were isolated from a population of Bornean soft coral Capnella imbricata. The structures of these metabolites were elucidated based on their nuclear magnetic resonance and high-resolution electrospray ionisation mass spectrometry spectral data. These compounds showed bacteriastatic and bacteriacidal activities against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
A novel synthetic compound from the 2-benzoyl-6-benzylidenecyclohexanone analogue, namely 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC), showed pronounced nitric oxide inhibition in IFN-γ/LPS-induced RAW 264.7 cells. Based on this previous finding, our present study aimed to investigate the antinociceptive effects of BBHC via chemical and thermal stimuli in vivo. The investigation of the antinociceptive activity of BBHC (0.1, 0.3, 1.0 and 3.0 mg/kg, i.p.) was initiated with 3 preliminary screening tests, then BBHC was subjected to investigate its possible involvement with excitatory neurotransmitters and opioid receptors. The potential acute toxicity of BBHC administration was also studied. Administration of BBHC significantly inhibited acetic acid-induced abdominal constrictions, formalin-induced paw licking activity and developed notable increment in the latency time. BBHC's ability to suppress capsaicin- and glutamate-induced paw licking activities, as well as to antagonise the effect of naloxone, had indicated the possible involvement of its antinociception with TRPV1, glutamate and opioid receptors, respectively. The antinociceptive activities of BBHC was not related to any sedative action and no evidence of acute toxic effect was detected. The present study showed that BBHC possessed significant peripheral and central antinociceptive activities via chemical- and thermal-induced nociceptive murine models without any locomotor alteration and acute toxicity.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.
Matched MeSH terms: Drug Evaluation, Preclinical/methods