Design and synthesis of epigallocatechin (EGC) analogs selective to inhibit α-amylase over α-glucosidases via the incorporation of caffeine acid and its derivatives.

Natural products are a promising and underappreciated reservoir for the preferred chemical scaffolds in the search of antidiabetic drugs. In this study twenty-one EGC-based derivatives selective to inhibit human pancreatic α-amylase (HPA), the enzyme at the top of the starch digestion pyramid, have been designed and synthesized in terms of the lead myricetin-caffeic acid conjugate 1 reported ever. We focus on methylation of caffeic acid, length of a liker, a double bond contained in the linker on the inhibition activity and selectivity of EGC-based conjugates. As a result, methylation of caffeic acid and the length of a linker affect significantly the activity and selectivity of EGC-based conjugates, but the effect of a double in caffeic acid is limited. Conjugate 2a-1 having a six-carbon-atom linker fused to EGC and caffeic acid demonstrates the most ponent inhibitory activity to HPA and its selectivity towards HPA over α-glucosidase by far superior to that construct 1. Molecular docking studies reveal that conjugate 2a-1 accommodates well to the active site of HPA with four hydrogen bonds in the form of the preorganization of two moieties EGC and caffeic acid via π-stacking interaction. Collectively, conjugating caffeic acid and EGC with an appropriate linker possibly provides a new strategy for finding the specific HPA inhibitors in the discovery of anti-diabetes mellitus drugs.

Choline Chloride-urea Deep Eutectic Mixture Water for the Synthesis of an Amphiphilic Compound of Glyceryl Monocaffeate.

The Lipase-catalyzed synthesis of glyceryl monocaffeate (GMC) in choline chloride-urea of natural deep eutectic solvent (NADES) media is reported to provide amphiphilic character to caffeic acid (CA). The modification of CA into GMC could potentially increase its solubility and widen the application of CA's biological activities in water and oil-based systems. The high conversion was achieved when the reaction was carried out with the addition of more than 20 %v/v water, at a high molar ratio of glycerol and 40°C. It was found that the lipase-catalyzed transesterification of ethyl caffeate (EC) and glycerol in choline chloride-urea of DES media obeyed ping-pong bi-bi mechanism with Vmax = 10.9 mmol.min-1, KmEC = 126.5 mmol and KmGly = 1842.7 mmol.

Synthesis of trans- methyl ferulate bearing an oxadiazole ether as potential activators for controlling plant virus.

A series of new ferulic acid derivatives bearing an oxadiazole ether was synthesized by introducing a structure of oxadiazole into trans-ferulic acid via an ether linkage. The synthesized target compounds were evaluated in vivo for their anti-TMV (tobacco mosaic virus) activity, which indicated that some synthesized compounds displayed strong activity for controlling TMV. For protective activity, compounds 6f and 6h had the most activities of 65% and 69.8% at 500 mg L-1, respectively. Compounds 6a, 6b, 6e, 6f and 6h showed > 60% curative activities at 500 mg L-1. Preliminary proteomics analysis showed that compound 6h could regulate the phenylpropanoid biosynthesis pathway and chloroplast function. These results indicated that synthesized novel ferulic acid derivatives could be used for controlling TMV.

Synthesis of Caffeoyl-Prolyl-Histidyl-Xaa Derivatives and Evaluation of Their Activities and Stability upon Long-Term Storage.

Antioxidants play a critical role in the treatment of degenerative diseases and delaying the aging of dermal tissue. Caffeic acid (CA) is a representative example of the antioxidants found in plants. However, CA is unsuitable for long-term storage because of its poor stability under ambient conditions. Caffeoyl-Pro-His-NH2 (CA-Pro-His-NH2, CA-PH) exhibits the highest antioxidant activity, free radical scavenging and lipid peroxidation inhibition activity among the histidine-containing CA-conjugated dipeptides reported to date. The addition of short peptides to CA, such as Pro-His, is assumed to synergistically enhance its antioxidative activity. In this study, several caffeoyl-prolyl-histidyl-Xaa-NH2 derivatives were synthesized and their antioxidative activities evaluated. CA-Pro-His-Asn-NH2 showed enhanced antioxidative activity and higher structural stability than CA-PH, even after long-term storage. CA-Pro-His-Asn-NH2 was stable for 3 months, its stability being evaluated by observing the changes in its NMR spectra. Moreover, the solid-phase synthetic strategy used to prepare these CA-Pro-His-Xaa-NH2 derivatives was optimized for large-scale production. We envision that CA-Pro-His-Xaa-NH2 derivatives can be used as potent dermal therapeutic agents and useful cosmetic ingredients.

Caffeic Acid Phenethyl Ester-Incorporated Radio-Sensitive Nanoparticles of Phenylboronic Acid Pinacol Ester-Conjugated Hyaluronic Acid for Application in Radioprotection.

We synthesized phenylboronic acid pinacol ester (PBPE)-conjugated hyaluronic acid (HA) via thiobis(ethylamine) (TbEA) linkage (abbreviated as HAsPBPE conjugates) to fabricate the radiosensitive delivery of caffeic acid phenetyl ester (CAPE) and for application in radioprotection. PBPE was primarily conjugated with TbEA and then PBPE-TbEA conjugates were conjugated again with hyaluronic acid using carbodiimide chemistry. CAPE-incorporated nanoparticles of HAsPBPE were fabricated by the nanoprecipitation method and then the organic solvent was removed by dialysis. CAPE-incorporated HAsPBPE nanoparticles have a small particle size of about 80 or 100 nm and they have a spherical shape. When CAPE-incorporated HAsPBPE nanoparticles were irradiated, nanoparticles became swelled or disintegrated and their morphologies were changed. Furthermore, the CAPE release rate from HAsPBPE nanoparticles were increased according to the radiation dose, indicating that CAPE-incorporated HAsPBPE nanoparticles have radio-sensitivity. CAPE and CAPE-incorporated HAsPBPE nanoparticles appropriately prevented radiation-induced cell death and suppressed intracellular accumulation of reactive oxygen species (ROS). CAPE and CAPE-incorporated HAsPBPE nanoparticles efficiently improved survivability of mice from radiation-induced death and reduced apoptotic cell death. We suggest that HAsPBPE nanoparticles are promising candidates for the radio-sensitive delivery of CAPE.

A Simple and Efficient Method for Synthesis and Extraction of Ethyl Ferulate from γ-Oryzanol.

Ethyl ferulate (EF) is a ferulic acid (FA) derivative with high commercial value. It is not found naturally and is mostly synthesized from FA via esterification with ethanol. The present work aimed to synthesize the EF from γ-oryzanol, a natural antioxidant from rice bran oil via acid-catalyzed transethylation at refluxing temperature of ethanol. The reaction was optimized by central composite design (CCD) under response surface methodology. Based on the CCD, the optimum condition for the synthesis of EF from 0.50 g of γ-oryzanol was as follows: γ-oryzanol to ethanol ratio of 0.50:2 (g/mL), 12.30% (v/v) H2SO4, and a reaction time of 9.37 h; these conditions correspond to a maximum EF yield of 87.11%. Moreover, the optimized transethylation condition was further validated using 12.50 g of γ-oryzanol. At the end of the reaction time, distilled water was added as antisolvent to selectively crystallize the co-products, phytosterol and unreacted γ-oryzanol, by adjusting the ethanol concentration to 49.95% (v/v). The recovery yield of 83.60% with a purity of 98% of EF was achieved. In addition, the DPPH and ABTS assays showed similar antioxidant activities between the prepared and commercial EF.

Chemoenzymatic semisynthesis of caffeic acid ß-phenethyl ester, an antioxidative component in propolis, from raw coffee bean extract.

Caffeic acid ß-phenethyl ester (CAPE), an antioxidative bioactive catechol isolated from propolis, was semisynthesized from chlorogenic acid and related compounds in an extract of raw (unroasted) Robusta coffee (Coffea canephora) beans in 5 steps and a total yield of 31%. Oxidative degradation of the intermediates and target molecule was prevented by alkaline hydrolysis of the chlorogenic acids in the presence of sodium dithionite (Na2S2O4) and deprotection of the catecholic diacetate precursor by Candida antarctica lipase B-mediated transesterification as the final step.

Molecular docking and synthesis of caffeic acid analogous and its anti-inflammatory, analgesic and ulcerogenic studies.

A series of caffeic acid (CA) derivatives 7a-j were synthesized via etherification and coupling action and their chemical structures were elucidated spectroscopically. Motivated by the various biological activities displayed by CA derivatives such as anti-inflammatory, antiviral, anticancer and antioxidant and also based on its extensively consumption in the human diet. In the present work, the newly synthesized compounds 7a-j were evaluated for anti-inflammatory and analgesic action and most of them exerted comparable activity to the reference compound celecoxib. Further, ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drug. Among the title series 7a-j, compounds 7f and 7g with electron withdrawing bromo and chloro group respectively, at the para position of the phenoxy ring was showed good activity compared to all other compounds. Interestingly, the COX-I/COX-II activity ratio of potent compounds 7f and7g showed an almost equal inhibitory effect on both isoenzymes. Further, molecular docking studies have been performed for the potent compounds which showed statistically significant result.

Synthesis of novel caffeic acid derivatives and their protective effect against hydrogen peroxide induced oxidative stress via Nrf2 pathway.

AIM: This study was aimed to synthesize novel caffeic acid derivatives and evaluate their potential applications for the treatment of oxidative stress associated disease. MAIN METHODS: Caffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid and fully characterized by melting point test, FT-IR, MS, NMR, UV-vis and n-octanol-water distribution assay. Their free radical scavenging ability was evaluated using DPPH assay and cytotoxicity against A549 cells were determined by MTT assay. The protective effect of these derivatives against hydrogen peroxide (H2O2) induced oxidative injury was assessed in A549 cells from cell viability, production of reactive oxygen species (ROS) and malondialdehyde (MDA), alternation of antioxidase activities, and expressions of Nrf2 and its target genes. KEY FINDINGS: Six novel caffeic acid sulfonamide derivatives were obtained. The derivatives showed better liphophilicity than the parent caffeic acid. CASMZ, CAST and CASQ exhibited similar DPPH scavenging capability as caffeic acid, while the protection of hydroxyl groups on the benzene ring with acetyl groups caused decrease in radical scavenging activity. No inhibitory effect on the proliferation of A549 cells were observed up to a concentration of 50 µM. Pre-treatment of cells with these derivatives strongly inhibited H2O2 induced decrease of cell viability, reduced the production of ROS and MDA, promoted antioxidase activities, and further upregulated the expression of Nrf2 and its target genes. SIGNIFICANCE: Caffeic acid sulfonamide derivatives were synthesized with simple reactions under mild conditions. They might protect cells from H2O2-induced oxidative injury via Nrf2 pathway.

FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Protects against Oxidative Stress-Mediated Neuronal Cell Apoptosis and Scopolamine-Induced Cognitive Impairment by Activating Nrf2/HO-1 Signaling.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4-O-glucoside (FA-97) is synthesized. We validate that FA-97 attenuates H2O2-induced apoptosis in SH-SY5Y and PC12 cells and suppresses H2O2-induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments in vivo via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD.

Thermoresponsive Catechol Based-Polyelectrolyte Complex Coatings for Controlled Release of Bortezomib.

To overcome the high relapse rate of multiple myeloma (MM), a drug delivery coating for functionalization of bone substitution materials (BSM) is reported based on adhesive, catechol-containing and stimuli-responsive polyelectrolyte complexes (PECs). This system is designed to deliver the MM drug bortezomib (BZM) directly to the anatomical site of action. To establish a gradual BZM release, the naturally occurring caffeic acid (CA) is coupled oxidatively to form poly(caffeic acid) (PCA), which is used as a polyanion for complexation. The catechol functionalities within the PCA are particularly suitable to form esters with the boronic acid group of the BZM, which are then cleaved in the body fluid to administer the drug. To achieve a more thorough control of the release, the thermoresponsive poly(N-isoproplyacrylamide-co-dimethylaminoethylmethacrylate) (P(NIPAM-co-DMAEMA)) was used as a polycation. Using turbidity measurements, it was proven that the lower critical solution temperature (LCST) character of this polymer was transferred to the PECs. Further special temperature dependent attenuated total reflection infrared spectroscopy (ATR-FTIR) showed that coatings formed by PEC immobilization exhibit a similar thermoresponsive performance. By loading the coatings with BZM and studying the release in a model system, via UV/Vis it was observed, that both aims, the retardation and the stimuli control of the release, were achieved.

Caffeic acid phenethyl ester (CAPE)-derivatives act as selective inhibitors of acetylcholinesterase.

Unexpected inhibitory effects against eeAChE could be found for a newly synthesized class of caffeic acid phenethyl ester (CAPE) derivatives. Thus, phenethyl-(E)-3-(3,5-dimethoxy-4-phenethoxyphenyl)-acrylate (Ki = 1.97 ±â€¯0.38 µM, Ki´â€¯= 2.44 ±â€¯0.07 µM) and 4-(2-(((E)-3-(3,4-bis(benzyloxy)phenyl)acryloyl)oxy)ethyl)-1,2-phenylene (2E,2'E)-bis(3-(3,4-bis(benzyloxy)phenyl)acrylate) (Ki = 0.72 ±â€¯0.31 µM, Ki´â€¯= 1.80 ±â€¯0.21 µM) showed very good inhibition of eeAChE, while being non cytotoxic for malignant human cancer cells and non-malignant mouse fibroblasts. Also, they are weak inhibitors for BChE (from equine serum).

Synthesis and characterization of CAPE derivatives as xanthine oxidase inhibitors with radical scavenging properties.

Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.

New Caffeic Acid Derivatives as Antimicrobial Agents: Design, Synthesis, Evaluation and Docking.

BACKGROUND: Phenolic acids (caffeic-, ferulic and p-coumaric acid) are widely distributed in the plant kingdom and exhibit broad spectrum of biological activities, including antimicrobial activity. OBJECTIVE: The goal of this paper is the synthesis of some caffeic acid derivatives selected based on computer-aided predictions and evaluate their in vitro antimicrobial properties against Gram positive and Gram negative bacteria and also a series of fungi. METHODS: In silico prediction of biological activity was used to identify the most promising structures for synthesis and biological testing, and the putative mechanisms of their antimicrobial action. The designed compounds were synthesized using classical organic synthesis methods. The antimicrobial activity was studied using microdilution method. RESULTS: Twelve tested compounds have shown good antibacterial activity. Five out of twelve tested compounds appeared to be more active than the reference drugs ampicillin and streptomycin. Despite that all compounds exhibited good activity against all bacteria tested, the sensitivity of bacteria towards compounds in general was different. The evaluation of antifungal activity revealed that all compounds were more active than ketoconazole, while seven compounds (2, 3, 4, 5, 7, 8 and 12) appeared to be more active than bifonazole. Docking results indicate that gyrase inhibition is the putative mechanism of antibacterial action while the inhibition of 14α-demethylase may be responsible for antifungal action. Prediction of cytotoxicity by PROTOX showed that compounds are not toxic (LD50 1000-2000 mg/kg). CONCLUSION: Thirteen compounds, from which six are new ones, were synthesized, and twelve compounds were tested for antimicrobial activity. The studied compounds appeared to be promising potent and non-toxic antimicrobials, which could be considered as leads for new pharmaceutical agents.

Synthesis, antioxidant and Aß anti-aggregation properties of new ferulic, caffeic and lipoic acid derivatives obtained by the Ugi four-component reaction.

We report herein the synthesis antioxidant and Aß anti-aggregation capacity of (E)-N-benzyl-N-[2-(benzylamino)-2-oxoethyl]-3-(aryl)acrylamides and related (R)-N-benzyl-N-(2-(benzylamino)-2-oxoethyl)-5-(1,2-dithiolan-3-yl)pentanamides 1-12. These compounds have been obtained, via Ugi four-component reaction, from modest to good yields. Their antioxidant analysis, using the DPPH and ORAC assays, allowed us to identify compounds 8 and 9, as potent antioxidant agents, showing also strong Aß1-40 self-aggregation inhibition, two biological properties of interest in pathologies linked to the oxidative stress, such as Alzheimer's disease.

Preservation of Cichoric Acid Antioxidant Properties Loaded in Heat Treated Lactoferrin Nanoparticles.

In the current research, a new cichoric acid (CA) encapsulation system was investigated. The optimal condition for the formation of lactoferrin-cichoric acid nanoparticles (LF-CA NPs) was determined by controlling the solution pH, the thermal treatment conditions, and the concentration of CA. Fluorescence indicated that the electrostatic force and the hydrophobic force were the main forces in the formation of LF-CA NPs. LF-CA NPs prepared under different conditions were spherical in shape with smaller particle sizes and good zeta potential demonstrating good colloidal stability. Especially, the prepared particle size of the LF-CA NPs at pH 7 and 95 °C was about 67.20 ± 1.86 nm. The circular dichroism (CD) and the Fourier transform infrared spectroscopy (FTIR) results showed that the combination of LF (lactoferrin) and CA affected the secondary structure of the LF. The differential scanning calorimetry (DSC) results indicated that the addition of CA increased the thermal stability of LF. In vitro antioxidant experiments confirmed the antioxidant capacity of LF-CA NPs was better than CA. CA was successfully encapsulated into LF NPs with high encapsulated efficiency (97.87⁻99.87%) by high performance liquid chromatography (HPLC). These results showed that LF could be used as the wall material of CA with excellent nature.

Synthesis and Antioxidant Activity of Caffeic Acid Derivatives.

A series of caffeic acid derivatives were synthesized via a modified Wittig reaction which is a very important tool in organic chemistry for the construction of unsaturated carbon⁻carbon bonds. All reactions were performed in water medium at 90 °C. The aqueous Wittig reaction worked best when one unprotected hydroxyl group was present in the phenyl ring. The olefinations in the aqueous conditions were also conducted with good yields in the presence of two unprotected hydroxyl groups. When the number of the hydroxyl groups was increased to three, the reaction yields were worse, and the derivatives 12, 13, and 18 were obtained with 74%, 37%, and 70% yields, respectively. Nevertheless, the Wittig reaction using water as the essential medium is an elegant one-pot synthesis and a greener method, which can be a safe alternative for implementation in organic chemistry. The obtained compounds were tested for their antioxidant activity, and 12, 13, and 18 showed the highest activities. Moreover, all synthesized compounds displayed no cytotoxicity, and can therefore be used in the pharmaceutical or cosmetic industry.

Design, synthesis, and anti-inflammatory activity of caffeoyl salicylate analogs as NO production inhibitors.

Chlorogenic acid (CGA) has been reported to exhibit potent anti-inflammatory activity. However, the development of anti-inflammatory agent based on CGA has not been investigated. In this paper, a series of caffeoyl salicylate compounds derived from CGA were designed, synthesized, and evaluated by LPS-induced nitric oxide synthase inhibition and QRT-PCR technique. Most compounds showed modest activity to inhibit production of nitric oxide (NO) in RAW 264.7 cells induced by lipopolysaccharides (LPS). Among these compounds, QRT-PCR and western blotting results indicated that compounds 6b, 6c, 6f, 6g and D104 that possess 5-member ring or 6-member ring caused a significant inhibition against expression of the iNOS2 in LPS-induced macrophages. In addition, cytotoxic assay displayed most derivatives have good safety in vitro. This new promising scaffold could be further exploited for the development of anti-inflammatory agent in the future.

ß-Lactoglobulin Peptide Fragments Conjugated with Caffeic Acid Displaying Dual Activities for Tyrosinase Inhibition and Antioxidant Effect.

The regulation of tyrosinase activity and reactive oxygen species is of great importance for the prevention of dermatological disorders in the fields of medicine and cosmetics. Herein, we report a strategy based on solid-phase peptide chemistry for the synthesis of ß-lactoglobulin peptide fragment/caffeic acid (CA) conjugates (CA-Peps) with dual activities of tyrosinase inhibition and antioxidation. The purity of the prepared conjugates, CA-MHIR, CA-HIRL, and CA-HIR, significantly increased to 99%, as acetonide-protected CA was employed in solid-phase coupling reactions on Rink amide resins. The tyrosinase inhibitory activities of all CA-Pep derivatives were higher than the activity of kojic acid, and CA-MHIR exhibited the highest tyrosinase inhibition activity (IC50 = 47.9 µM). Moreover, CA-Pep derivatives displayed significantly enhanced antioxidant activities in the peroxidation of linoleic acid as compared to the pristine peptide fragments. All CA-Pep derivatives showed no cytotoxicity against B16-F1 melanoma cells.

Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury.

Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.