Total synthesis/semi-synthesis of natural isopentenyl flavonoids with inhibitory activity on NLRP3 inflammasome.

Inflammation is the body's defense response to stimuli. When the homeostatic balance is disturbed, disease may result. Flavonoids have clear anti-inflammatory effects and the isopentenyl group significantly enhances the pharmacological activity of flavonoids. Therefore, isopentenyl flavonoids have the potential to serve as lead compounds for the development of anti-inflammatory drugs. Throughout this research, eight natural compounds were synthesized, including 5,7-dihydroxy-4'-methoxy-8-prenylflavonoid (1), 4'-O-Methylatalantoflavone (2), Kushenol W (3) and Racemoflavone (5), which were totally synthesized for the first time. Additionally, three flavonols: Licoflavonol (6), 3,5,7,3',4'-pentahydroxy-6-prenylflavonol (7) and Macarangin (8), can be one-step synthesized by direct C-isopentenylation. In the process, an economical and efficient C-isopentenylation method was also simultaneously explored that could facilitate the efficient synthesis of natural products. These compounds were evaluated for their potential anti-inflammatory activities via the NLRP3 signaling pathway. Notably, Macarangin (8) manifested the most potent inhibitory effect. The SAR (Structure-Activity Relationships) also showed the introduction of the isopentenyl group was determined to enhance these effects, whereas simple flavonoid frameworks or cyclization of isopentenyl groups all diminished anti-inflammatory activity.

Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry.

The flavonoid family is a set of well-known bioactive natural molecules, with a wide range of potential therapeutic applications. Despite the promising results obtained in preliminary in vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, the scaffold-hopping approach is a promising strategy for the structural optimization of natural leads to discover more potent analogues. In this scenario, this Perspective provides a critical analysis on how the replacement of the chromon-4-one flavonoid core with other bioisosteric nitrogen/sulphur heterocycles might affect the chemical, pharmaceutical and biological properties of the resulting new chemical entities. The investigated derivatives were classified on the basis of their biological activity and potential therapeutic indications. For each session, the target(s), the specific mechanism of action, if available, and the key pharmacophoric moieties were highlighted, as revealed by X-ray crystal structures and in silico structure-based studies. Biological activity data, in vitro/vivo studies, were examined: a particular focus was given on the improvements observed with the new heterocyclic analogues compared to the natural flavonoids. This overview of the scaffold-hopping advantages in flavonoid compounds is of great interest to the medicinal chemistry community to better exploit the vast potential of these natural molecules and to identify new bioactive molecules.

Discovery of novel chrysin derivatives as potential Anti-Psoriasis agents.

Psoriasis is a chronic inflammatory disease and is difficult to cure. In this work, a series of novel chrysin derivatives have been designed and prepared while evaluating anti-inflammatory activities in vitro and in vivo. In vitro, RAW264.7 cells were used to detect the inflammatory activities at first, and compounds 4h, 4k, and 4o significantly decreased the levels of NO, TNF-α, and IL-6. In particular, compound 4o showed superior anti-inflammatory activities than other compounds. Moreover, compound 4o decreased the level of IL-17A in LPS-induced HaCaT cells in vitro. The effect and mechanism of anti-inflammatory activities on psoriasis were determined by imiquimod (IMQ)-induced psoriasis-like mice in vivo. Compound 4o deduced the level of IL-6, IL-17A, IL-22, IL-23, and TNF-α, and showed potent anti-psoriasis activity. Further mechanism study suggested that compound 4o could improve the skin inflammation of psoriasis by inhibiting the NF-κB and STAT3 signaling pathways.

Antimicrobial Properties of Flavonoid Derivatives with Bromine, Chlorine, and Nitro Group Obtained by Chemical Synthesis and Biotransformation Studies.

The search for new substances of natural origin, such as flavonoids, is necessary in the fight against the growing number of diseases and bacterial resistance to antibiotics. In our research, we wanted to check the influence of flavonoids with chlorine or bromine atoms and a nitro group on pathogenic and probiotic bacteria. We synthesized flavonoids using Claisen-Schmidt condensation and its modifications, and through biotransformation via entomopathogenic filamentous fungi, we obtained their glycoside derivatives. Biotransformation yielded two new flavonoid glycosides: 8-amino-6-chloroflavone 4'-O-ß-D-(4″-O-methyl)-glucopyranoside and 6-bromo-8-nitroflavone 4'-O-ß-D-(4″-O-methyl)-glucopyranoside. Subsequently, we checked the antimicrobial properties of the aforementioned aglycon flavonoid compounds against pathogenic and probiotic bacteria and yeast. Our studies revealed that flavones have superior inhibitory effects compared to chalcones and flavanones. Notably, 6-chloro-8-nitroflavone showed potent inhibitory activity against pathogenic bacteria. Conversely, flavanones 6-chloro-8-nitroflavanone and 6-bromo-8-nitroflavanone stimulated the growth of probiotic bacteria (Lactobacillus acidophilus and Pediococcus pentosaceus). Our research has shown that the presence of chlorine, bromine, and nitro groups has a significant effect on their antimicrobial properties.

Developments in the stereoselective synthesis of benzopyran, benzopyrone and flavonoid based natural product analogues using C-glycosides as an intrinsic chiral synthon.

Stereoselective synthesis is essential for propelling mainstream academia toward a relentless pursuit of novel and cutting-edge strategies for constructing molecules with unparalleled precision. Naturally derived benzopyrans, benzopyrones, and flavonoids are an essentially prominent group of oxa-heterocycles, highly significant targets in medicinal chemistry owing to their extensive abundance in biologically active natural products and pharmaceuticals. The molecular complexity and stereoselectivity induced by heterocycles embedded with C-glycosides have attracted considerable interest and emerged as a fascinating area of research for synthetic organic chemists. This present article emphasizes the existing growths in the strategies involving the diastereoselective synthesis of C-glycosylated benzopyrans, benzopyrones, and flavonoids using naturally acquired glycones as chiral synthons.

Synthesis, characterisation, and in vitro antiparasitic activity of new flavanoidal tetrazinan-6'-ones and their binding study with calf thymus DNA using molecular modelling and spectroscopic techniques.

With the developing resistance to traditional antiparasitic medications, the purpose of this study was to efficiently develop a series of six noble flavanoidal tetrazinane-6'-one derivatives by a one-pot reaction pathway. FT-IR, 1HNMR, 13CNMR, and Mass spectra were employed for the structural elucidation of the synthesized compounds (7-12). Clinostomum complanatum, a parasite infection model that has been well-established, demonstrated that all the synthesized compounds are potent antiparasitic agents. DNA is the main target for various medicinal compounds. As a result, thestudy of how small molecules attach to DNA has received a lot of attention. In the present study, we have performed various biophysical techniques to determine the mode of binding of synthesized compounds (7-12) with calf thymus DNA (ct-DNA). It was observed from the UV-visible absorbance and fluorescence spectra that all synthesized compounds (7-12) form complexes with the ct-DNA. The value of binding constant (Kb) was obtained to be in the range of 4.36---24.50 × 103 M - 1 at 298 K. Competitive displacement assay with ethidium bromide (EB), CD spectral analysis, viscosity measurements, and in silico molecular docking confirmed that ligands (7-12) incorporate with ct-DNA through groove binding only. Molecular docking studies were performed for all synthesized compounds with the calf thymus DNA and it was found that all the newly synthesized compounds strongly bind with the chain B of DNA in the minor groove with the value of binding energy in the range of -8.54 to -9.04 kcal per mole and several hydrogen bonding interactions.

Structure optimizing of flavonoids against both MRSA and VRE.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) cause more than 100,000 deaths each year, which need efficient and non-resistant antibacterial agents. SAR analysis of 162 flavonoids from the plant in this paper suggested that lipophilic group at C-3 was crucial, and then 63 novel flavonoid derivatives were designed and total synthesized. Among them, the most promising K15 displayed potent bactericidal activity against clinically isolated MRSA and VRE (MICs = 0.25-1.00 µg/mL) with low toxicity and high membrane selectivity. Moreover, mechanism insights revealed that K15 avoided resistance by disrupting biofilm and targeting the membrane, while vancomycin caused 256 times resistance against MRSA, and ampicillin caused 16 times resistance against VRE by the same 20 generations inducing. K15 eliminated residual bacteria in mice skin MRSA-infected model (>99 %) and abdominal VRE-infected model (>92 %), which was superior to vancomycin and ampicillin.

Fisetin-loaded pluronic-based nanogel: Radiation synthesis for alleviating neurocognitive impairments in a rat model of alzheimer's disease via modulation of the apoptotic cascade.

Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive impairment and memory loss. In this study, AD was experimentally induced in rats using aluminum chloride (AlCl3) and D-galactose (D-gal). Fisetin (Fis), a natural compound with antioxidant and anti-inflammatory properties, has potential for neurodegeneration management, but its low bioavailability limits clinical applications. To address this, we synthesized and characterized Pluronic-2-Acrylamido-2-methylpropane sulfonic acid (PLUR-PAMPS) nanogels using gamma radiation and successfully loaded Fis onto them (Fis-PLUR-PAMPS). The optimal formulation exhibited minimal particle size, a highly acceptable polydispersity index, and the highest zeta-potential, enhancing stability and solubilization efficiency. Our goal was to improve Fis's bioavailability and assess its efficacy against AlCl3/D-gal-induced AD. Male albino Wistar rats were pre-treated orally with Fis (40 mg/kg) or Fis-PLUR-PAMPS for seven days, followed by a seven-day intraperitoneal injection of AlCl3 and D-gal. Behavioral assessments, histopathological analysis, and biochemical evaluation of markers related to AD pathology were conducted. Results demonstrated that Fis-PLUR-PAMPS effectively mitigated cognitive impairments and neurodegenerative signs induced by AlCl3/D-gal. These findings suggest that Fis-PLUR-PAMPS nanogels enhance Fis's bioavailability and therapeutic efficacy, offering a promising approach for AD management.

Structure-based screening, optimization and biological evaluation of novel chrysin-based derivatives as selective PPARγ modulators for the treatment of T2DM and hepatic steatosis.

In consideration of several serious side effects induced by the classical AF-2 involved "lock" mechanism, recently disclosed PPARγ-Ser273 phosphorylation mode of action has become an alternative and mainstream mechanism for currently PPARγ-based drug discovery and development with an improved therapeutic index. In this study, by virtue of structure-based virtual high throughput screening (SB-VHTS), structurally chemical optimization by targeting the inhibition of the PPARγ-Ser273 phosphorylation as well as in vitro biological evaluation, which led to the final identification of a chrysin-based potential hit (YGT-31) as a novel selective PPARγ modulator with potent binding affinity and partial agonism. Further in vivo evaluation demonstrated that YGT-31 possessed potent glucose-lowering and relieved hepatic steatosis effects without involving the TZD-associated side effects. Mechanistically, YGT-31 presented such desired therapeutic index, mainly because it effectively inhibited the CDK5-mediated PPARγ-Ser273 phosphorylation, selectively elevated the level of insulin sensitivity-related Glut4 and adiponectin but decreased the expression of insulin-resistance-associated genes PTP1B and SOCS3 as well as inflammation-linked genes IL-6, IL-1ß and TNFα. Finally, the molecular docking study was also conducted to uncover an interesting hydrogen-bonding network of YGT-31 with PPARγ-Ser273 phosphorylation-related key residues Ser342 and Glu343, which not only gave a clear verification for our targeting modification but also provided a proof of concept for the abovementioned molecular mechanism.

Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability.

Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.

Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation.

With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1-4) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and ß-amyloid (Aß) aggregation inhibition in vitro were evaluated. The results showed that 1-4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu2+ ions), antioxidation, self-induced, Cu2+-induced, and AChE-induced Aß aggregation inhibition activities, and suitable blood-brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10-8 M magnitude) and BuChE (10-7 M magnitude) and showed the best inhibition on AChE-induced Aß aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.

Predicción de la energía de unión y efecto antiinflamatorio de flavonoides sobre el receptor de glucocorticoides mediante simulaciones de dinámica molecular y el método linear de energía de interacción / Prediction of ligand binding energy and anti-inflammatory effect of flavonoids in the glucocorticoid receptor by molecular dynamics simulations and linear interaction energy method

Flavonoids are compounds composed of a three-ring structurewith various substitutions formed in plants, from aromatic aminoacids phenylalanine and tyrosine, to participate in the light-dependphase of photosynthesis catalyzing electron transport. Their antiinflammatoryproperties are of special interest as adverse reactions inhumans appear to be rare. For this reason the aim of this work is totry to explain the binding mode of flavonoids and to estimate thebinding energy of the compounds to glucocorticoids receptor usingthe LIE method. Fifteen flavonoids were used to correlate calculatedbinding energy with experimental values. The squared correlationcoefficient achieved is significant (R2 = 0.74 and p = 0.000) and gooddescription of the binding mode was obtained. Three hydrogenbinding zones were identified corresponding to aminoacids Arg81-Gln40, Thr205-Gln111 and Leu33-Asn34. The interaction with the firstzone was found related with lower values of energy of binding withstatistically significance of 95%(AU)

Los flavonoides son compuestos formados por tres anillos convarias sustituciones sintetizados en vegetales de los aminoácidosaromáticos fenilalanina y tirosina para participar en la fase luzdependientede la fotosíntesis transportando electrones. Sus propiedadesantiinflamatorias son de especial interés debido a que lasreacciones adversas que estos producen en humanos son raras. Poresta razón, el objetivo del presente trabajo es explicar el modo deunión de estas moléculas y estimar la energía de unión al receptorde glucocorticoides utilizando el método LIE. Se utilizaron 15 flavonoidespara correlacionar sus energías de unión estimadas con lasexperimentales. El coeficiente de correlación alcanzado fue significativo(R2 = 0,74 y p = 0,000) y se obtuvo una buena descripción delmodelo. Se encontraron tres zonas de unión por puente de hidrógenocorrespondiendo a los aminoácidos Arg81-Gln40, Thr205-Gln111and Leu33-Asn34. La primera zona se pudo correlacionar con menoresvalores de energía con una confianza del 95%(AU)

Flavonoides y enfermedad inflamatoria intestinal / Flavonoides and Infl ammatory bowel disease

Estudios epidemiológicos han puesto en evidencia el papel que tienen los alimentos de origen vegetal en la prevenciónde numerosas enfermedades. Los antioxidantes naturales presentes en estos alimentos, entre los que destacanlos fl avonoides, pueden ser responsables de esta actividad. Los fl avonoides son compuestos de bajo peso molecularque se encuentran ampliamente distribuidos en el reino vegetal. Pueden mejorar los estados de diarrea aguda ycrónica a través de la inhibición de la secreción y motilidad intestinal y también ser muy útiles en la reducción deldaño infl amatorio crónico en el intestino, protegiéndolo del estrés oxidativo y preservando la función de la mucosa.Por ello, se proponen como agentes terapéuticos en el tratamiento de la Enfermedad Infl amatoria Intestinal, en laque factores diversos promueven una reacción inmunológica exacerbada que conduce a una infl amación crónicadel intestino

Epidemiological studies have revealed the important role that foodstuffs of vegetable origin have to play in the prevention ;;of numerous illnesses. The natural antioxidants present in such foodstuffs, among which the fl avonoids are widely ;;present, may be responsible for such an activity. Flavonoids are compounds that are low in molecular weight and widely ;;distributed throughout the vegetable kingdom. They may be of great utility in states of accute or chronic diarrhoea ;;through the inhibition of intestinal secretion and motility, and may also be benefi cial in the reduction of chronic infl ammatory ;;damage in the intestine, by affording protection against oxidative stress and by preserving mucosal function. ;;For this reason, the use of these agents is recommended in the treatment of infl ammatory bowel disease, in which ;;various factors are involved in extreme immunological reactions, which lead to chronic intestinal infl ammation

Eficácia dos flavonóides na dislipidemia / Efficacy of Flavonoids in Dyslipidemias

Os flavonóides têm se tornado cada vez mais evidentes devido aos efeitos benéficos à saúde, sendo destacada a sua função nas dislipidemias. São oxidantes polifenólicos encontrados nos alimentos, principalmente nas verduras, frutas, grãos, sementes como o cacau, castanhas, condimentos e ervas e também em bebidas como vinho e chá. Inibem a oxidação do LDL, diminuindo a aterogenicidade e conseqüentemente, o risco de doença coronariana, além de sua ação antioxidante. Este trabalho, elaborado a partir de uma revisão bibliográfica, visa avaliar a eficácia dos flavonóides nas dislipidemias, verificando se é possível diminuir os níveis de concentrações lipídicas plasmáticas e atuar como antioxidante evitando assim a aterogenicidade, aterosclerose. O consumo de flavonóides demonstrou uma diminuição dos triglicerídeos no plasma, da concentração do colesterol total, dos níveis de LDL e aumento ou inalteração do HDL. O mecanismo de ação pode ser explicado por meio da regulação dos receptores de LDL, do aumento do turnover da apolipoproteína B do LDL e da estabilização da membrana tecidual, uma vez que houve uma diminuição da fluidez lipídica dessa membrana. Estudos recentes demonstraram que os flavonóides inibem a atividade da enzima squalene epoxidase, essencial na síntese do colesterol. Concluiu-se que os flavonóides presentes da dieta podem estar envolvidos na prevenção da aterosclerose, mas ainda existem algumas controvérsias, sendo necessários mais estudos para que todo o mecanismo de ação seja esclarecido e sua eficácia comprovada