Thermal Degradation of Linalool-Chemotype Cinnamomum osmophloeum Leaf Essential Oil and Its Stabilization by Microencapsulation with β-Cyclodextrin

The thermal degradation of linalool-chemotype Cinnamomum osmophloeum leaf essential oil and the stability effect of microencapsulation of leaf essential oil with β-cyclodextrin were studied. After thermal degradation of linalool-chemotype leaf essential oil, degraded compounds including β-myrcene, cis-ocimene and trans-ocimene, were formed through the dehydroxylation of linalool; and ene cyclization also occurs to linalool and its dehydroxylated products to form the compounds such as limonene, terpinolene and α-terpinene. The optimal microencapsulation conditions of leaf essential oil microcapsules were at a leaf essential oil to the β-cyclodextrin ratio of 15:85 and with a solvent ratio (ethanol to water) of 1:5. The maximum yield of leaf essential oil microencapsulated with β-cyclodextrin was 96.5%. According to results from the accelerated dry-heat aging test, β-cyclodextrin was fairly stable at 105 °C, and microencapsulation with β-cyclodextrin can efficiently slow down the emission of linalool-chemotype C. osmophloeum leaf essential oil.     

α-Functionally Substituted α,β-Unsaturated Aldehydes as Fine Chemicals Reagents: Synthesis and Application

α-Functionalized α,β-unsaturated aldehydes is an important class of compounds, which are widely used in fine organic synthesis, biology, medicine and pharmacology, chemical industry, and agriculture. Some of the 2-substituted 2-alkenals are found to be the key metabolites in plant and animal cells. Therefore, the development of efficient methods for their synthesis attracts the attention of organic chemists. This review focusses on the recent advances in the synthesis of 2-functionally substituted 2-alkenals. The approaches to the preparation of α-alkyl α,β-unsaturated aldehydes are not included in this review.     

Molecular Dynamic Simulation Analysis on the Inclusion Complexation of Plumbagin with β-Cyclodextrin Derivatives in Aqueous Solution

Stable encapsulation of medically active compounds can lead to longer storage life and facilitate the slow-release mechanism. In this work, the dynamic and molecular interactions between plumbagin molecule with β-cyclodextrin (BCD) and its two derivatives, which are dimethyl-β-cyclodextrin (MBCD), and 2-O-monohydroxypropyl-β-cyclodextrin (HPBCD) were investigated. Molecular dynamics simulations (MD) with GLYCAM-06 and AMBER force fields were used to simulate the inclusion complex systems under storage temperature (4 °C) in an aqueous solution. The simulation results suggested that HPBCD is the best encapsulation agent to produce stable host–guest binding with plumbagin. Moreover, the observation of the plumbagin dynamic inside the binding cavity revealed that it tends to orient the methyl group toward the wider rim of HPBCD. Therefore, HPBCD is a decent candidate for the preservation of plumbagin with a promising longer storage life and presents the opportunity to facilitate the slow-release mechanism.     

The Biological Fate of Pharmaceutical Excipient β-Cyclodextrin: Pharmacokinetics,Tissue Distribution,Excretion, and Metabolism of β-Cyclodextrin in Rats

β-cyclodextrin has a unique annular hollow ultrastructure that allows encapsulation of various poorly water-soluble drugs in the resulting cavity, thereby increasing drug stability. As a bioactive molecule, the metabolism of β-cyclodextrin is mainly completed by the flora in the colon, which can interact with API. In this study, understanding the in vivo fate of β-cyclodextrin, a LC-MS/MS method was developed to facilitate simultaneous quantitative analysis of pharmaceutical excipient β-cyclodextrin and API dextromethorphan hydrobromide. The established method had been effectively used to study the pharmacokinetics, tissue distribution, excretion, and metabolism of β-cyclodextrin after oral administration in rats. Results showed that β-cyclodextrin was almost wholly removed from rat plasma within 36 h, and high concentrations of β-cyclodextrin distributed hastily to organs with increased blood flow velocities such as the spleen, liver, and kidney after administration. The excretion of intact β-cyclodextrin to urine and feces was lower than the administration dose. It can be speculated that β-cyclodextrin metabolized to maltodextrin, which was further metabolized, absorbed, and eventually discharged in the form of CO₂ and H₂O. Results proved that β-cyclodextrin, with relative low accumulation in the body, had good safety. The results will assist further study of the design and safety evaluation of adjuvant β-cyclodextrin and promote its clinical development.     

Manufacturing and Assessing the New Orally Disintegrating Tablets,Containing Nimodipine-hydroxypropyl-β-cyclodextrin and Nimodipine-methyl-β-cyclodextrin Inclusion Complexes

The aim of the present study was to manufacture new orally disintegrating tablets containing nimodipine–hydroxypropyl-β-cyclodextrin and nimodipine–methyl-β-cyclodextrin inclusion complexes. For obtaining a better quality of the manufactured tablets, three methods of the preparation of inclusion complexes, in a 1:1 molar ratio, were used comparatively; namely, a solid-state kneading method and two liquid state coprecipitation and lyophilization techniques. The physical and chemical properties of the obtained inclusion complexes, as well as their physical mixtures, were investigated using Fourier transformed infrared spectroscopy, scanning electron microscopy, X-ray diffraction analyses, and differential scanning calorimetry. The results showed that the lyophilization method can be successfully used for a better complexation. Finally, the formulation and precompression studies for tablets for oral dispersion, containing Nim–HP-β-CD and Nim–Me-β-CD inclusion complexes, were successfully assessed.     

Insulin Complexation with Cyclodextrins—A Molecular Modeling Approach

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5–7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule.     

Losartan Interactions with 2-Hydroxypropyl-β-CD

Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD). First, its complexation is shown through Differential Scanning Calorimetry as lyophilization provided distinct thermal properties in comparison to the mixture. The complexation is further proved by utilizing the chemical shift changes in the complexation and T1 values. Furthermore, the reversible favorable complexation was shown by MD calculations. Such physical chemical properties provide evidence that this formulation must be further explored through biological experiments.     

Encapsulation of α-Pinene in Delivery Systems Based on Liposomes and Cyclodextrins

The essential oil component α-pinene has multiple biological activities. However, its application is limited owing to its volatility, low aqueous solubility, and chemical instability. For the aim of improving its physicochemical properties, α-pinene was encapsulated in conventional liposomes (CLs) and drug-in-cyclodextrin-in-liposomes (DCLs). Hydroxypropyl-β-cyclodextrin/α-pinene (HP-β-CD/α-pinene) inclusion complexes were prepared in aqueous solution, and the optimal solubilization of α-pinene occurred at HP-β-CD:α-pinene molar ratio of 7.5:1. The ethanol-injection method was applied to produce different formulations using saturated (Phospholipon 90H) or unsaturated (Lipoid S100) phospholipids in combination with cholesterol. The size, the phospholipid and cholesterol incorporation rates, the encapsulation efficiency (EE), and the loading rate (LR) of α-pinene were determined, and the storage stability of liposomes was assessed. The results showed that α-pinene was efficiently entrapped in CLs and DCLs with high EE values. Moreover, Lipoid S100 CLs displayed the highest LR (22.9 ± 2.2%) of α-pinene compared to the other formulations. Both carrier systems HP-β-CD/α-pinene inclusion complex and Lipoid S100 CLs presented a gradual release of α-pinene. Furthermore, the DPPH radical scavenging activity of α-pinene was maintained upon encapsulation in Lipoid S100 CLs. Finally, it was found that all formulations were stable after three months of storage at 4 °C.     

Comprehensive Characterisation of the Ketoprofen-β-Cyclodextrin Inclusion Complex Using X-ray Techniques and NMR Spectroscopy

Racemic ketoprofen (KP) and β-cyclodextrin (β-CD) powder samples from co-precipitation (1), evaporation (2), and heating-under-reflux (3) were analysed using X-ray techniques and nuclear magnetic resonance (NMR) spectroscopy. On the basis of NMR studies carried out in an aqueous solution, it was found that in the samples obtained by methods 1 and 2, there were large excesses of β-CD in relation to KP, 10 and 75 times, respectively, while the sample obtained by method 3 contained equimolar amounts of β-CD and KP. NMR results indicated that KP/β-CD inclusion complexes were formed and the estimated binding constants were approximately 2400 M⁻¹, showing that KP is quite strongly associated with β-CD. On the other hand, the X-ray single-crystal technique in the solid state revealed that the (S)-KP/β-CD inclusion complex with a stoichiometry of 2:2 was obtained as a result of heating-under-reflux, for which the crystal and molecular structure were examined. Among the methods used for the preparation of the KP/β-CD complex, only method 3 is suitable.     

Carrier-Free Immobilization of α-Galactosidase as Nano-Biocatalysts for Synthesizing Prebiotic α-Galacto-Oligosaccharides

α-Galacto-oligosaccharides (α-GOSs) have great functions as prebiotics and therapeutics. This work established the method of batch synthesis of α-GOSs by immobilized α-galactosidase for the first time, laying a foundation for industrial applications in the future. The α-galactosidase from Aspergillus niger L63 was immobilized as cross-linked enzyme aggregates (CLEAs) nano-biocatalyst through enzyme precipitating and cross-linking steps without using carriers. Among the tested agents, the ammonium sulfate showed high precipitation efficacy and induced regular structures of α-galactosidase CLEAs (Aga-CLEAs) that had been analyzed by scanning electron microscopy and Fourier-transform infrared spectroscopy. Through optimization by response surface methodology, the ammonium sulfate-induced Aga-CLEAs achieved a high activity recovery of around 90% at 0.55 U/mL of enzymes and 36.43 mM glutaraldehyde with cross-linking for 1.71 h. Aga-CLEAs showed increased thermal stability and organic solvent tolerance. The storage ability was also improved since it maintained 74.5% activity after storing at 4 °C for three months, significantly higher than that of the free enzyme (21.6%). Moreover, Aga-CLEAs exhibited excellent reusability in the α-GOSs synthesis from galactose, retaining above 66% of enzyme activity after 10 batch reactions, with product yields all above 30%.     

Molecular Dynamics Simulation Studies on the Aggregation of Amyloid-β Peptides and Their Disaggregation by Ultrasonic Wave and Infrared Laser Irradiation

Alzheimer’s disease is understood to be caused by amyloid fibrils and oligomers formed by aggregated amyloid-β (Aβ) peptides. This review article presents molecular dynamics (MD) simulation studies of Aβ peptides and Aβ fragments on their aggregation, aggregation inhibition, amyloid fibril conformations in equilibrium, and disruption of the amyloid fibril by ultrasonic wave and infrared laser irradiation. In the aggregation of Aβ, a β-hairpin structure promotes the formation of intermolecular β-sheet structures. Aβ peptides tend to exist at hydrophilic/hydrophobic interfaces and form more β-hairpin structures than in bulk water. These facts are the reasons why the aggregation is accelerated at the interface. We also explain how polyphenols, which are attracting attention as aggregation inhibitors of Aβ peptides, interact with Aβ. An MD simulation study of the Aβ amyloid fibrils in equilibrium is also presented: the Aβ amyloid fibril has a different structure at one end from that at the other end. The amyloid fibrils can be destroyed by ultrasonic wave and infrared laser irradiation. The molecular mechanisms of these amyloid fibril disruptions are also explained, particularly focusing on the function of water molecules. Finally, we discuss the prospects for developing treatments for Alzheimer’s disease using MD simulations.     

β-Cyclodextrin-Polyacrylamide Hydrogel for Removal of Organic Micropollutants from Water

Water pollution by various toxic substances remains a serious environmental problem, especially the occurrence of organic micropollutants including endocrine disruptors, pharmaceutical pollutants and naphthol pollutants. Adsorption process has been an effective method for pollutant removal in wastewater treatment. However, the thermal regeneration process for the most widely used activated carbon is costly and energy-consuming. Therefore, there has been an increasing need to develop alternative low-cost and effective adsorption materials for pollutant removal. Herein, β-cyclodextrin (β-CD), a cheap and versatile material, was modified with methacrylate groups by reacting with methacryloyl chloride, giving an average degree of substitution of 3 per β-CD molecule. β-CD-methacrylate, which could function as a crosslinker, was then copolymerized with acrylamide monomer via free-radical copolymerization to form β-CD-polyacrylamide (β-CD-PAAm) hydrogel. Interestingly, in the structure of the β-CD-PAAm hydrogel, β-CD is not only a functional unit binding pollutant molecules through inclusion complexation, but also a structural unit crosslinking PAAm leading to the formation of the hydrogel 3D networks. Morphological studies showed that β-CD-PAAm gel had larger pore size than the control PAAm gel, which was synthesized using conventional crosslinker instead of β-CD-methacrylate. This was consistent with the higher swelling ratio of β-CD-PAAm gel than that of PAAm gel (29.4 vs. 12.7). In the kinetic adsorption studies, phenolphthalein, a model dye, and bisphenol A, propranolol hydrochloride, and 2-naphthol were used as model pollutants from different classes. The adsorption data for β-CD-PAAm gel fitted well into the pseudo-second-order model. In addition, the thermodynamic studies revealed that β-CD-PAAm gel was able to effectively adsorb the different dye and pollutants at various concentrations, while the control PAAm gel had very low adsorption, confirming that the pollutant removal was due to the inclusion complexation between β-CD units and pollutant molecules. The adsorption isotherms of the different dye and pollutants by the β-CD-PAAm gel fitted well into the Langmuir model. Furthermore, the β-CD-PAAm gel could be easily recycled by soaking in methanol and reused without compromising its performance for five consecutive adsorption/desorption cycles. Therefore, the β-CD-PAAm gel, which combines the advantage of an easy-to-handle hydrogel platform and the effectiveness of adsorption by β-CD units, could be a promising pollutant removal system for wastewater treatment applications.     

One-Step Extraction of Olive Phenols from Aqueous Solution Using β-Cyclodextrin in the Solid State,a Simple Eco-Friendly Method Providing Photochemical Stability to the Extracts

The extraction of phenolic compounds from olive mill wastes is important, not only to avoid environmental damages, but also because of the intrinsic value of those biophenols, well-known for their high antioxidant potential and health benefits. This study focuses on tyrosol (Tyr) and hydroxytyrosol (HT), two of the main phenolic compounds found in olive mill wastes. A new, simple, and eco-friendly extraction process for the removal of phenolic compounds from aqueous solutions using native β-cyclodextrin (β-CD) in the solid state has been developed. Several β-CD/biophenol molar ratios and biophenol concentrations were investigated, in order to maintain β-CD mostly in the solid state while optimizing the extraction yield and the loading capacity of the sorbent. The extraction efficiencies of Tyr and HT were up to 61%, with a total solid recovery higher than 90% using an initial concentration of 100 mM biophenol and 10 molar equivalents of β-CD. The photochemical stability of the complexes thus obtained was estimated from ∆E*ab curve vs. illumination time. The results obtained showed that the phenols encapsulated into solid β-CD are protected against photodegradation. The powder obtained could be directly developed as a safe-grade food supplement. This simple eco-friendly process could be used for extracting valuable biophenols from olive mill wastewater.     

Picking Out Logic Operations in a Naphthalene β-Diketone Derivative by Using Molecular Encapsulation,Controlled Protonation,and DNA Binding

On–off switching and molecular logic in fluorescent molecules are associated with what chemical inputs can do to the structure and dynamics of these molecules. Herein, we report the structure of a naphthalene derivative, the fashion of its binding to β-cyclodextrin and DNA, and the operation of logic possible using protons, cyclodextrin, and DNA as chemical inputs. The compound crystallizes out in a keto-amine form, with intramolecular N−H⋅⋅⋅O bonding. It shows stepwise formation of 1:1 and 1:2 inclusion complexes with β-cyclodextrin. The aminopentenone substituents are encapsulated by β-cyclodextrin, leaving out the naphthalene rings free. The binding constant of the β-cyclodextrin complex is 512 m⁻¹. The pK_a value of the guest molecule is not greatly affected by the complexation. Dual input logic operations, based on various chemical inputs, lead to the possibility of several molecular logic gates, namely NOR, XOR, NAND, and Buffer. Such chemical inputs on the naphthalene derivative are examples of how variable signal outputs based on binding can be derived, which, in turn, are dependent on the size and shape of the molecule.     

On the Interactions of Melatonin/β-Cyclodextrin Inclusion Complex: A Novel Approach Combining Efficient Semiempirical Extended Tight-Binding (xTB) Results with Ab Initio Methods

Melatonin (MT) is a molecule of paramount importance in all living organisms, due to its presence in many biological activities, such as circadian (sleep–wake cycle) and seasonal rhythms (reproduction, fattening, molting, etc.). Unfortunately, it suffers from poor solubility and, to be used as a drug, an appropriate transport vehicle has to be developed, in order to optimize its release in the human tissues. As a possible drug-delivery system, β-cyclodextrin (βCD) represents a promising scaffold which can encapsulate the melatonin, releasing when needed. In this work, we present a computational study supported by experimental IR spectra on inclusion MT/βCD complexes. The aim is to provide a robust, accurate and, at the same time, low-cost methodology to investigate these inclusion complexes both with static and dynamic simulations, in order to study the main actors that drive the interactions of melatonin with β-cyclodextrin and, therefore, to understand its release mechanism.     

The Fumarprotocetraric Acid Inhibits Tau Covalently,Avoiding Cytotoxicity of Aggregates in Cells

Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s addition appears as a feasible type of interaction involving an α, β unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish β sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael’s acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species.     

The Bifurcated σ-Hole···σ-Hole Stacking Interactions

The bifurcated σ-hole···σ-hole stacking interactions between organosulfur molecules, which are key components of organic optical and electronic materials, were investigated by using a combined method of the Cambridge Structural Database search and quantum chemical calculation. Due to the geometric constraints, the binding energy of one bifurcated σ-hole···σ-hole stacking interaction is in general smaller than the sum of the binding energies of two free monofurcated σ-hole···σ-hole stacking interactions. The bifurcated σ-hole···σ-hole stacking interactions are still of the dispersion-dominated noncovalent interactions. However, in contrast to the linear monofurcated σ-hole···σ-hole stacking interaction, the contribution of the electrostatic energy to the total attractive interaction energy increases significantly and the dispersion component of the total attractive interaction energy decreases significantly for the bifurcated σ-hole···σ-hole stacking interaction. Another important finding of this study is that the low-cost spin-component scaled zeroth-order symmetry-adapted perturbation theory performs perfectly in the study of the bifurcated σ-hole···σ-hole stacking interactions. This work will provide valuable information for the design and synthesis of novel organic optical and electronic materials.     

Green Synthesis of Indeno[1,2-b]quinoxalines Using β-Cyclodextrin as Catalyst

An efficient, mild, and green method was developed for the synthesis of indeno[1,2-b]quinoxaline derivatives via o-phenylenediamine (OPD) and 2-indanone derivatives utilizing β-cyclodextrin (β-CD) as the supramolecular catalyst. The reaction can be carried out in water and in a solid state at room temperature. β-CD can also catalyze the reaction of indan-1,2-dione with OPD with a high degree of efficiency. Compared to the reported methods, this procedure is milder, simpler, and less toxic, making it an eco-friendly alternative. In addition, the β-CD can be recovered and reused without the loss of activity.     

β-Carotene Inhibits Expression of Matrix Metalloproteinase-10 and Invasion in Helicobacter pylori-Infected Gastric Epithelial Cells

Matrix metalloproteinases (MMPs), key molecules of cancer invasion and metastasis, degrade the extracellular matrix and cell–cell adhesion molecules. MMP-10 plays a crucial role in Helicobacter pylori-induced cell-invasion. The mitogen-activated protein kinase (MAPK) signaling pathway, which activates activator protein-1 (AP-1), is known to mediate MMP expression. Infection with H. pylori, a Gram-negative bacterium, is associated with gastric cancer development. A toxic factor induced by H. pylori infection is reactive oxygen species (ROS), which activate MAPK signaling in gastric epithelial cells. Peroxisome proliferator-activated receptor γ (PPAR-γ) mediates the expression of antioxidant enzymes including catalase. β-Carotene, a red-orange pigment, exerts antioxidant and anti-inflammatory properties. We aimed to investigate whether β-carotene inhibits H. pylori-induced MMP expression and cell invasion in gastric epithelial AGS (gastric adenocarcinoma) cells. We found that H. pylori induced MMP-10 expression and increased cell invasion via the activation of MAPKs and AP-1 in gastric epithelial cells. Specific inhibitors of MAPKs suppressed H. pylori-induced MMP-10 expression, suggesting that H. pylori induces MMP-10 expression through MAPKs. β-Carotene inhibited the H. pylori-induced activation of MAPKs and AP-1, expression of MMP-10, and cell invasion. Additionally, it promoted the expression of PPAR-γ and catalase, which reduced ROS levels in H. pylori-infected cells. In conclusion, β-carotene exerts an inhibitory effect on MAPK-mediated MMP-10 expression and cell invasion by increasing PPAR-γ-mediated catalase expression and reducing ROS levels in H. pylori-infected gastric epithelial cells.     

Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.