An innovative UPLC-MS/MS method for the quantitation and pharmacokinetics of eupafolin in rat plasma.

In this experiment, a rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technology was established and validated for the quantitation and pharmacokinetic analysis of eupafolin in rat plasma, utilizing licochalcone B as internal standard (IS). After liquid-liquid extraction of the analyte samples by ethyl acetate, chromatographic separation was achieved using a UPLC HSS T3 column under gradient elution conditions, with the mobile phase consisting of acetonitrile and water (with 0.1 % formic acid). Eupafolin was quantified by multiple reaction monitoring (MRM) in electrospray positive-ion mode (ESI+), employing the mass transition m/z 315.2 â†’ 300.3 for eupafolin and m/z 285.4 â†’ 270.3 for IS. Eupafolin demonstrated excellent linear relationship (r > 0.99) over the concentration range of 1.25-1250 ng/mL, with the lower limit of quantification (LLOQ) of the UPLC-MS/MS assay determined as 1.25 ng/mL. Method validation followed the bioanalytical method validation criteria outlined by the FDA. The accuracy of eupafolin ranged from 86.7 % to 111.2 %, and the precision was less than 12 %. The matrix effect was observed at 92.8 %-98.6 %, while the recoveries exceeded 83.2 %. The established UPLC-MS/MS assay was successfully employed for the pharmacokinetic evaluation of eupafolin in rats. The half-lives (t1/2z) were determined to be 1.4 ± 0.4 h and 2.5 ± 1.4 h for intravenous and oral administration, respectively. Notably, the bioavailability of eupafolin was relatively low (8.3 %). The optimized UPLC-MS/MS technology showed highly sensitive, selective, and effective, rendering it suitable for the pharmacokinetics of eupafolin in preclinical practice.

Isoliquiritigenin: a potential drug candidate for the management of erectile dysfunction.

OBJECTIVE: This study aimed to assess the erectogenic properties of isoliquiritigenin taking sildenafil (SDF) as the standard. METHODS: The binding affinity of isoliquiritigenin (ISL) with the erectile marker proteins (endothelial nitric oxide synthase [eNOS] and enzyme phosphodiesterase type 5 [PDE5]) was investigated using Autodock Vina, which was validated using molecular dynamics simulation. Furthermore, the effect of ISL on the eNOS and PDE5 messenger ribonucleic acid (mRNA) expression and the sexual behavior of mice was investigated, along with the assessment of the pharmacokinetics of ISL. KEY FINDINGS: The results revealed that the binding affinity of ISL-eNOS/PDE5 and SDF-eNOS/PDE5 was in the range of -7.5 to -8.6 kcal/mol. The ISL-eNOS/PDE5 complexes remained stable throughout the 100 ns simulation period. Root mean square deviation, Rg, SASA, hydrogen, and hydrophobic interactions were similar between ISL-eNOS/PDE5 and SDF-eNOS/PDE5. Analysis of mRNA expressions in paroxetine (PRX)-induced ED mice showed that the co-administration of PRX with ISL reduced PDE5 and increased eNOS mRNA expression, similar to the co-administered group (PRX+SDF). The sexual behavior study revealed that the results of PRX+ISL were better than those of the PRX+SDF group. Pharmacokinetic evaluation further demonstrated that ISL possesses drug-like properties. CONCLUSIONS: The results showed that ISL is equally potent as SDF in terms of binding affinity, specific pharmacological properties, and modulating sexual behavior.

Pharmacokinetic study of multicomponent in Hong-Hua-Xiao-Yao tablet.

Hong-Hua-Xiao-Yao tablet (HHXYT) is attracting attention increasingly because of its use in treatment of mammary gland hyperplasia (MGH) and menopausal syndrome. However, its pharmacokinetics remains unclear. This study developed a sensitive and rapid method for simultaneous determination of 10 compounds of HHXYT in rat plasma by liquid chromatography-tandem mass spectrometry and to compare the pharmacokinetics of these compounds in MGH rats and sham operated rats. The linearity, accuracy, precision, stability and matrix effect were within acceptable ranges. This established method was successfully applied to a pharmacokinetics study of 10 compounds in sham operated and MGH rats. According to the results, the bioavailability of glycyrrhetinic acid was highest in MGH rats and sham operated rats. The mean residence times of glycyrrhetinic acid and glycyrrhetinic acid 3-O-glucuronide were higher than those of the other compounds while the mean residence time and half-life of liquiritin, isoliquiritin and paeoniflorin were lower. Some pharmacokinetic parameters of ormononetin, liquiritigenin, isoliquiritigenin, liquiritin, isoliquiritin, paeoniflorin, protocatechuic acid and senkyunolide I were significantly different between MGH rats and sham operated rats. This study elucidated the dynamic changes of multiple components in rats after oral administration of HHXYT systematically and comprehensively, which provided guidance for clinical application.

Cardamonin-loaded liposomal formulation for improving percutaneous penetration and follicular delivery for androgenetic alopecia.

Androgenic alopecia (AGA) has a considerable impact on the physical and mental health of patients. Nano preparations have apparent advantages and high feasibility in the treatment of AGA. Cardamonin (CAR) has a wide range of pharmacological activities, but it has the problems of poor solubility in water and low bioavailability. There are few, if any, researches on the use of nano-loaded CAR to improve topical skin delivery of AGA. In this study, a CAR-loaded liposomal formulation (CAR@Lip and CAR@Lip Gel) was developed and characterized. The prepared CAR@Lip exhibited a uniform and rounded vesicle in size. CAR@Lip and CAR@Lip Gel can significantly improve the cumulative release of CAR. Additionally, CAR@Lip can obviously promote the proliferation and migration of human dermal papilla cells (hDPCs). Cell uptake revealed that the uptake of CAR@Lip significantly increased compared with the free drug. Furthermore, both CAR@Lip and CAR@Lip Gel groups could markedly improve the transdermal performance of CAR, and increase the topical content of the drug in the hair follicle compared with CAR. The ratchet effect of hair follicles could improve the skin penetration depth of nanoformulations. Notably, Anti-AGA tests in the mice showed that CAR@Lip and CAR@Lip Gel groups could promote hair growth, and accelerate the transition of hair follicles to the growth stage. The anti-androgen effect was revealed by regulating the expression of IGF-1, VEGF, KGF, and TGF-ß, participating in SHH/Gli and Wnt/ß-catenin pathways. Importantly, the nanoformulations had no obvious skin irritation. Thus, our study showed that CAR-loaded liposomal formulation has potential application in the treatment of AGA.

Molecular mechanisms underlying chemopreventive potential of butein: Current trends and future perspectives.

Despite extensive efforts, cancer is still often considered as an incurable disease and initiation of novel drug development programs is crucial to improve the prognosis and clinical outcome of patients. One of the major approaches in designing the novel cancer drugs has historically comprised studies of natural agents with diverse anticancer properties. As only a marginal part of natural compounds has been investigated, this approach still represents an attractive source of new potential antitumor molecules. In this review article, different anticancer effects of plant-derived chalcone, butein, are discussed, including its growth inhibitory action, proapoptotic, antiangiogenic and antimetastatic activities in a variety of cancer cells. The molecular mechanisms underlying these effects are presented in detail, revealing interactions of butein with multiple cellular targets (Bcl-2/Bax, caspases, STAT3, cyclins, NF-κB, COX-2, MMP-9, VEGF/R etc.) and regulation of a wide range of intracellular signal transduction pathways. These data altogether allow a good basis for initiating further in vivo studies as well as clinical trials. Along with the efforts to overcome low bioavailability issues generally characteristic to plant metabolites, butein can be considered as a potential lead compound for safe and more efficient cancer drugs in the future.

Synthesis, Structure, Carbohydrate Enzyme Inhibition, Antioxidant Activity, In Silico Drug-Receptor Interactions and Drug-Like Profiling of the 5-Styryl-2-Aminochalcone Hybrids.

The 2-amino-5-(3/4-fluorostyryl)acetophenones were prepared and reacted with benzaldehyde derivatives to afford the corresponding 5-styryl-2-aminochalcone hybrids. The trans geometry of the styryl and α,ß-unsaturated carbonyl arms, and the presence of NH…O intramolecular hydrogen bond were validated using 1H-NMR and X-ray data. The 2-amino-5-styrylacetophenones and their 5-styryl-2-aminochalcone derivatives were screened in vitro for their capability to inhibit α-glucosidase and/or α-amylase activities. Their antioxidant properties were evaluated in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays. Kinetic studies of the most active derivatives from each series against α-glucosidase and/or α-amylase activities have been performed supported by molecular docking studies to determine plausible protein-ligand interactions on a molecular level. The key aspects of the pharmacokinetics of these compounds, i.e., absorption, distribution, metabolism, and excretion have also been simulated at theoretical level. The most active compounds from each series, namely, 2a and 3e, were evaluated for cytotoxicity against the normal monkey kidney cells (Vero cells) and the adenocarcinomic human epithelial (A549) cell line to establish their safety profile at least in vitro.

Thiazole-Chalcone Hybrids as Prospective Antitubercular and Antiproliferative Agents: Design, Synthesis, Biological, Molecular Docking Studies and In Silico ADME Evaluation.

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole-chalcone hybrids (1-20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC50 = 11 ± 1 µM) with an IC50 value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.

Antibacterial and antibiotic modifying activity, ADMET study and molecular docking of synthetic chalcone (E)-1-(2-hydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)prop-2-en-1-one in strains of Staphylococcus aureus carrying NorA and MepA efflux pumps.

A large number of infections are caused by multi-resistant bacteria worldwide, adding up to a figure of around 700,000 deaths per year. Because of that many strategies are being developed in order to combat the resistance of microorganisms to drugs, in recent times, chalcones have been studied for this purpose. Chalcones are known as α, ß-unsaturated ketones, characterized by having the presence of two aromatic rings that are joined by a three-carbon chain, they are a class of compounds considered an exceptional model due to chemical simplicity and a wide variety of biological activities, which include anticancer, anti-inflammatory, antioxidants, antimicrobials, anti-tuberculosis, anti-HIV, antimalarial, anti-allergic, antifungal, antibacterial, and antileishmanial. The objective of this work was evaluate the antibacterial and antibiotic modifying activity of chalcone (E)-1-(2-hydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)prop-2-en-1-one against the bacteria Staphylococcus aureus carrying a NorA and MepA efflux pump. The results showed that chalcone was able to synergistically modulate the action of Norfloxacin and Ethidium Bromide against the bacteria Staphylococcus aureus 1199B and K2068, respectively. The theoretical physicochemical and pharmacokinetic properties of chalcone showed that the chalcone did not present a severe risk of toxicity such as genetic mutation or cardiotoxicity, constituting a good pharmacological active ingredient.

MS-based metabolite analysis of two licorice chalcones in mice plasma, bile, feces, and urine after oral administration.

Isoliquiritigenin (ILG) and isoliquiritin (ILQ), two kinds of major flavonoids in licorice, are biological active substances with antioxidant, anti-inflammatory, and tumor-suppressive effects. However, their in vivo metabolites, possible material basis of this two licorice chalcones for the treatment of diseases, have not been studied completely. To determine the metabolism of ILG and ILQ, after oral administration of 100 mg/kg/day of these compounds for consecutive 8 days, the metabolites of these two licorice chalcones in mice plasma, urine, feces, and bile were determined using liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry in this study. The structures of those metabolites were tentatively identified according to their fragment pathways, accurate masses, characteristic product ions, metabolism law, and reference standards-matching. As a result, a total of 25 and 29 metabolites of ILG and ILQ were identified, respectively. Seven main metabolic pathways, oxidation and reduction, deglycosylation and glycosylation, dehydroxylation and hydroxylation, demethoxylation and methoxylation, acetylation, glucuronidation, and sulfation, were summarized to tentatively explain how the metabolites were biologically transformed. These results provide the important information on the metabolism of ILG and ILQ, which may be helpful for the further research of their pharmacological mechanism.

Development of an Orally Bioavailable Isoliquiritigenin Self-Nanoemulsifying Drug Delivery System to Effectively Treat Ovalbumin-Induced Asthma.

PURPOSE: Isoliquiritigenin (ILQ), an important component of Anti-Asthma Herbal Medicine Intervention (ASHMI), had shown potent anti-asthma effect in vitro in our previous study. However, poor solubility and low bioavailability hindered in vivo application to treat asthma. This study was to develop a novel ILQ loaded self-nanoemulsifying drug delivery system (ILQ-SMEDDS) with enhanced bioavailability. METHODS: The optimized SMEDDS formulation was composed of ethyl oleate (oil phase), Tween 80 (surfactant) and PEG400 (co-surfactant) at a mass ratio of 3:6:1. The physiochemical properties of ILQ-SMEDDS, including drug content, globule size, zeta potential, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, were characterized. And the in vitro release profile, in situ intestinal absorption, in vivo pharmacokinetic parameters and the anti-asthma effect of ILQ suspension and ILQ-SMEDDS were evaluated. RESULTS: The ILQ-SMEDDS had an average globule size of 20.63 ± 1.95 nm with a polydispersity index (PDI) of 0.11 ± 0.03, and its zeta potential was -12.64 ± 2.12 mV. The cumulative release rate of ILQ from ILQ-SMEDDS to the simulated gastrointestinal tract was significantly higher than that of free ILQ suspension. And area under curve with ILQ-SMEDDS was found to be 3.95 times higher than that of ILQ suspension indicating improved bioavailability by SMEDDS. Although ILQ-SMEDDS showed a slight less effective inhibitory effect on eotaxin-1 in human lung fibroblast (HFL-1) cells than free ILQ, in an ovalbumin-induced asthma model, ILQ-SMEDDS exhibited more efficacy than ILQ suspension in improving asthma-associated inflammation, including eosinophil production, ovalbumin-specific immunoglobulin E (OVA-sIgE), interleukin 4 (IL 4), interleukin 5 (IL 5) and interferon-γ (IFN-γ). Even the low dose of ILQ-SMEDDS group (10 mg/kg) showed better anti-asthma effect than that of the ILQ suspension group (20 mg/kg). CONCLUSION: Compared with ILQ suspension, ILQ-SMEDDS showed significantly improved bioavailability and anti-asthma effect, revealing its potential as a favorable pharmaceutical agent for treating asthma.

Marein ameliorates diabetic nephropathy by inhibiting renal sodium glucose transporter 2 and activating the AMPK signaling pathway in db/db mice and high glucose-treated HK-2 cells.

Marein, an active component of the Coreopsis tinctoria Nutt. plant, is known to improve diabetic nephropathy (DN). However, its anti-diabetic functions in DN and potential mechanisms remain unclear. The aim of this study was to elucidate the effects and mechanisms of Marein in diabetic db/db mice with DN, and in high glucose-treated HK-2 cells. In vivo, treating diabetic db/db mice with Marein for 12 consecutive weeks restored diabetes-induced hyperglycemia and dyslipidemia, and ameliorated renal function deterioration, glomerulosclerosis, and renal ectopic lipid deposition. Marein exerted renoprotective effects by directly inhibiting renal tubule sodium glucose transporter 2 (SGLT2) expression, and then activating the AMP-activated protein kinase (AMPK)/acetyl CoA carboxylase (ACC)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) pathway in db/db mice. Meanwhile, Marein ameliorated fibrosis and inflammation by suppressing the pro-inflammatory factors interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), and expression of the extracellular matrix proteins, fibronectin (FN) and collagen 1 (COL1) in diabetic mice. In vitro, MDCK monolayer cells were established to explore the characteristics of Marein transmembrane transport. Marein was found to be absorbed across the membrane at a medium level that involved active transport and this was mediated by SGLTs. In HK-2 cells, Marein decreased uptake of the fluorescent glucose analog, 2-NBDG, by 22 % by inhibiting SGLT2 expression. In high glucose-treated HK-2 cells, Marein decreased SGLT2 expression and increased phosphorylated (p)-AMPK/p-ACC to improve high glucose-induced cellular dysfunction. Furthermore, Marein treatment decreased SGLT2 expression in SGLT2-overexpressing HK-2 cells. In addition, molecular docking and dynamics analysis revealed that SGLT2 was a direct target of Marein. Collectively, our results demonstrated that Marein ameliorates DN by inhibiting renal SGLT2 and activating p-AMPK, suggesting Marein can potentially prevent DN by suppressing renal SGLT2 expression directly.

Synthesis and biological evaluation of 2'-Aminochalcone: A multi-target approach to find drug candidates to treat Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative process that compromises cognitive functions. The physiopathology of AD is multifactorial and is mainly supported by the cholinergic and amyloid hypotheses, which allows the identification the fundamental role of some markers, such as the enzymes acetylcholinesterase (AChE) and ß-secretase (BACE-1), and the ß-amyloid peptide (Aß). In this work, we prepared a series of chalcones and 2'-aminochalcones, which were tested against AChE and BACE-1 enzymes and on the aggregation of Aß. All compounds inhibited AChE activity with different potencies. We have found that the majority of chalcones having the amino group are able to inhibit BACE-1, which was not observed for chalcones without this group. The most active compound is the one derived from 2,3-dichlorobenzaldeyde, having an IC50 value of 2.71 µM. A molecular docking study supported this result, showing a good interaction of the amino group with aspartic acid residues of the catalytic diade of BACE-1. Thioflavin-T fluorescence emission is reduced in 30 - 40%, when Aß42 is incubated in the presence of some chalcones under aggregation conditions. In vitro cytotoxicity and in silico prediction of pharmacokinetic properties were also conducted in this study.

In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (Mpro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that out of 23 natural flavonoids and 25 synthetic indole chalcones, 30 compounds are capable of Mpro deactivation as well as potentially lowering the efficiency of Mpro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.

Discovery of novel isoliquiritigenin analogue ISL-17 as a potential anti-gastric cancer agent.

Isoliquiritigenin (ISL), a natural product isolated from licorice root, exhibits anti-gastric cancer effects. However, applications of ISL are still limited in clinical practice due to its poor bioavailability. To discovery of more effective anti-gastric cancer agents based on ISL, aldol condensation reaction was applied to synthesize the ISL analogues. MTS assay was used to evaluate the inhibitory activities of ISL analogues against SGC-7901, BGC-823 and GES-1 cells in vitro. Cell cycle distribution, apoptosis and reactive oxygen species (ROS) generation were detected by flow cytometry. Western blot assay was used to analyze the expression levels of related proteins. The drug-likeness and pharmacokinetic properties were predicted with Osiris property explorer and PreADMET server. As a result, 18 new ISL analogues (ISL-1 to ISL-18) were synthesized. Among these analogues, ISL-17 showed the strongest inhibitory activities against SGC-7901 and BGC-823 cells, and could induce G2/M cell cycle arrest and apoptosis in these two cell lines. Treatment with ISL-17 resulted in increased ROS production and elevated autophagy levels in SGC-7901 cells. The PI3K/AKT/mTOR signaling pathway was down-regulated after treatment with ISL-17 in SGC-7901 cells. The results of drug-likeness and pharmacokinetic prediction indicated that all the ISL analogues complied with Lipinski's rule of five and Veber rule and had a favorable ADME character. Overall, our results attest that ISL-17 holds promise as a candidate agent against gastric cancer.

Synthesis and evaluation of butein derivatives for in vitro and in vivo inflammatory response suppression in lymphedema.

Herein, we demonstrate that butein (1) can prevent swelling in a murine lymphedema model by suppressing tumor necrosis factor α (TNF-α) production. Butein derivatives were synthesized and evaluated to identify compounds with in vitro anti-inflammatory activity. Among them, 20 µM of compounds 7j, 7m, and 14a showed 50% suppression of TNF-α production in mouse peritoneal macrophages after lipopolysaccharide stimulation. Compound 14a, exhibited the strongest potency with an in vitro IC50 of 14.6 µM and suppressed limb volume by 70% in a murine lymphedema model. The prodrug strategy enabled a six-fold increase in kinetic solubility of compound 1 and five-fold higher levels of active metabolite in the blood for compound 14a via oral administration in the pharmacokinetics study. We suggest that the compound 14a could be developed as a potential therapeutic agent targeting anti-inflammatory activity to alleviate lymphedema progression.

Simultaneous characterization of multiple Psoraleae Fructus bioactive compounds in rat plasma by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry for application in sex-related differences in pharmacokinetics.

A method for the simultaneous quantification of 13 bioactive compounds (psoralen, isopsoralen, isobavachin, bakuchalcone, neobabaisoflavone, bavachin, corylin, psoralidin, isobavachalcone, bavachinin, corylifol A, bavachalcone, and bakuchiol) by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry has been developed and validated in rat plasma. Osthol was used as an internal standard and plasma samples were pretreated with one-step liquid-liquid extraction. These analytes were separated using a gradient mobile phase system of water and acetonitrile at a flow rate of 0.2 mL/min on a reverse-phase C18 column and analyzed in the selected multiple reactions monitoring mode. All calibration curves were linear (r > 0.9952) over the tested ranges. The intra- and interday accuracy and precisions of these analytes at three different concentration levels were within the acceptable limits of <15% at all concentrations. The mean recoveries of these analytes at three concentrations were more than 60.2% and the matrix effects were in the range of 85-115%. Stability studies proved that the analytes were stable under the tested conditions. The developed method was applied to evaluating the pharmacokinetic study of 13 bioactive compounds after oral administration of Psoraleae Fructus in rat of different genders. Some active compounds in Psoraleae Fructus had sex-related pharmacokinetics.

Estimation of an Appropriate Human Dose of Boesenbergia pandurata Extracts Based on Allometric Scaling Data of Panduratin A in Mice, Rats, and Dogs.

It can be difficult to identify health/functional foods that exert therapeutic benefits for alleviating gingivitis and periodontitis. Recently, extracts of Boesenbergia pandurata (Roxb.), which is a tropical plant, have shown promising inhibitory activity against lipopolysaccharide-induced periodontitis. As a result, a clinical trial is being planned to assess utility of B. pandurata (Roxb.) extracts for promoting oral health; this study was designed to determine an appropriate human dose of the extracts for the trial. Pharmacokinetic studies of panduratin A, which is an active substance in fingerroot, were carried out in mice, rats, and dogs after oral administration of the extracts. The clearance data for each species were used to estimate clearance in humans through allometric scaling based on the maximum lifespan potential, and a daily dose providing sufficient anti-periodontitis activity was estimated for use in the clinical trial. The findings indicated that allometric scaling is a reasonable approach that is relatively free of safety issues and can be used to determine doses of substances for incorporation into health/functional foods appropriate for humans.

Design, synthesis, docking and biological evaluation of chalcones as promising antidiabetic agents.

Diabetes mellitus (DM) is a serious chronic metabolic disorder which occurs due to dysfunction of insulin and therapeutic approaches are poor. It is an under estimation that 387 million people currently suffering globally with diabetic and more than 592 million people may be affected by 2030. It makes an urgent necessity to discover novel drugs to control amplified diabetic populations. In this study, amino chalcones (3a-j) were synthesized and hydroxy chalcones (3g-j) were isolated from natural source such as Sophora interrupta, Clerodendrum phlomidis and Andrographis macrobotrys. Structural elucidation was carried out using Mass, 1H and 13C NMR Spectra. In vivo studies were carried out with alloxan induced diabetic rats (100 mg/kg) which reveals compounds 3c, 3a and 3h have significant antidiabetic efficacy with decreased blood glucose levels in the diabetic rats while compared with control rats. Besides, docking studies with aldose reductase, dipeptidyl peptidase, PPAR and glucosidase were monitored which accomplishes that the compounds 3c, 3i, 3a and 3d have eloquent binding affinity (kcal/mol) with aldose reductase, besides the chalcones 3c, 3b, 3d, 3e and 3i were also showed inhibition with DPP-IV, PPAR-α and α-glucosidase. Also, these compounds explicated distinct interactions i.e., π-π, π-cationic, polar, electrostatic and hydrophobic bonds were observed with key residues of binding pockets. Bioavailability is disclosed with Lipinski rule of five and the design pharmacokinetic as well as pharmacodynamic properties are reliable. Therefore, chalcones were implied as antidiabetic leads for in further studies and could be worthwhile for the development of new classes of effective antidiabetic agents.

Ultrasound-assisted synthesis of novel chalcone, heterochalcone and bis-chalcone derivatives and the evaluation of their antioxidant properties and as acetylcholinesterase inhibitors.

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20-89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.

Simultaneous Determination and Pharmacokinetic Characterization of Glycyrrhizin, Isoliquiritigenin, Liquiritigenin, and Liquiritin in Rat Plasma Following Oral Administration of Glycyrrhizae Radix Extract.

Glycyrrhizae Radix is widely used as herbal medicine and is effective against inflammation, various cancers, and digestive disorders. We aimed to develop a sensitive and simultaneous analytical method for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin, the four marker components of Glycyrrhizae Radix extract (GRE), in rat plasma using liquid chromatography-tandem mass spectrometry and to apply this analytical method to pharmacokinetic studies. Retention times for glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were 7.8 min, 4.1 min, 3.1 min, and 2.0 min, respectively, suggesting that the four analytes were well separated without any interfering peaks around the peak elution time. The lower limit of quantitation was 2 ng/mL for glycyrrhizin and 0.2 ng/mL for isoliquiritigenin, liquiritigenin, and liquiritin; the inter- and intra-day accuracy, precision, and stability were less than 15%. Plasma concentrations of glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were quantified for 24 h after a single oral administration of 1 g/kg GRE to four rats. Among the four components, plasma concentration of glycyrrhizin was the highest and exhibited a long half-life (23.1 ± 15.5 h). Interestingly, plasma concentrations of isoliquiritigenin and liquiritigenin were restored to the initial concentration at 4-10 h after the GRE administration, as evidenced by liquiritin biotransformation into isoliquiritigenin and liquiritigenin, catalyzed by fecal lysate and gut wall enzymes. In conclusion, our analytical method developed for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin could be successfully applied to investigate their pharmacokinetic properties in rats and would be useful for conducting further studies on the efficacy, toxicity, and biopharmaceutics of GREs and their marker components.