3,4-Dimethoxycinnamic Acid

Antiplatelet and Anticoagulant Effects of Two New Phenylpropanoid Sucrose Esters and Other Secondary Metabolites from the Aerial Part of Canna edulis.[Pubmed:38454878]

Chem Biodivers. 2024 Mar 8:e202400302.

This study isolated pure compounds from Canna edulis aerial parts and assessed their antiplatelet and anticoagulant potential. Structural elucidation resulted in the identification of two new compounds: caneduloside A (1) and caneduloside B (2), and eleven known compounds: 6'-acetyl-3,6,2'-tri-p-coumaroyl sucrose (3), 6'-acetyl-3,6,2'-triferuloyl sucrose (4), tiliroside (5), afzelin (6), quercitrin (7), 2-hydroxycinnamaldehyde (8), cinnamic acid (9), 3,4-Dimethoxycinnamic Acid (10), dehydrovomifoliol (11), 4-hydroxy-3,5-dimethoxybenzaldehyde (12), and (S)-(-)-rosmarinic acid (13). Compounds 3, 4, 6-9, 13 were previously reported for antithrombotic properties. Hence, antithrombotic tests were conducted for 1, 2, 5, 10-12. All tested compounds demonstrated a dose-dependent antiaggregatory effect, and 10 and 12 were the most potent for both ADP and collagen activators. Additionally, 10 and 12 showed anticoagulant effects, with prolonged prothrombin time and activated partial thromboplastin time. The new compound 1 displayed antiplatelet and anticoagulant activity, while 2 mildly inhibited platelet aggregation. C. edulis is a potential source for developing antithrombotic agents.

Xanthine oxidase inhibition study of isolated secondary metabolites from Dolichandrone spathacea (Bignoniaceae): In vitro and in silico approach.[Pubmed:38439949]

Saudi Pharm J. 2024 Apr;32(4):101980.

Xanthine oxidase (XO) has been widely recognized as a pivotal enzyme in developing hyperuricemia, primarily contributing to the excessive production of uric acid during purine metabolism in the liver. One of the standard treatment approaches involves reducing uric acid levels by inhibiting XO activity. In this study, the leaf extract of Dolichandrone spathacea, traditionally used in folk medicine, was found to inhibit XO activity in the ethyl acetate and butanol fractions at a concentration of 100 microg/mL, their values were 78.57 +/- 3.85 % (IC(50) = 55.93 +/- 5.73 microg/ml) and 69.43 +/- 8.68 % (IC(50) = 70.17 +/- 7.98 microg/ml), respectively. The potential XO inhibitory components were isolated by bioactivity assays and the HR-ESI-MS and NMR spectra system. The main constituents of leaf extracts of Dolichandrone spathacea, six compounds, namely trans-4-methoxycinnamic acid (3), trans-3,4-Dimethoxycinnamic Acid (4), p-coumaric acid (5), martynoside (6), 6-O-(p-methoxy-E-cinnamoyl)-ajugol (7), and scolymoside (17), were identified as potent XO inhibitors with IC(50) values ranging from 19.34 +/- 1.63 muM to 64.50 +/- 0.94 muM. The enzyme kinetics indicated that compounds 3-5, 7, and 17 displayed competitive inhibition like allopurinol, while compound 6 displayed a mixed-type inhibition. Computational studies corroborated these experimental results, highlighting the interactions between potential metabolites and XO enzyme. The hydrogen bonds played crucial roles in the binding interaction, especially, scolymoside (17) forms a hydrogen bond with Mos3004, exhibited the lowest binding energy (-18.3286 kcal/mol) corresponding to the lowest IC(50) (19.34 +/- 1.63 muM). Furthermore, nine compounds were isolated for the first time from this plant. In conclusion, Dolichandrone spathacea and its constituents possess the potential to modulate the xanthine oxidase enzyme involved in metabolism.

Antioxidant and Hypolipidemic Activities of Cinnamic Acid Derivatives.[Pubmed:37764507]

Molecules. 2023 Sep 21;28(18):6732.

Oxidative stress and hyperlipidemia are important factors for the initiation and progression of various cell degenerative pathological conditions, including cardiovascular and neurological diseases. A series of cinnamic acid-derived acids, such as ferulic acid, sinapic acid, 3,4-Dimethoxycinnamic Acid, p-coumaric acid, and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid, were esterified or amidated with various moieties, bearing different biological activities, and evaluated. The antioxidant and radical scavenging abilities of the compounds via inhibition of rat hepatic microsomal membrane lipid peroxidation, as well as their interaction with the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH), were assessed. Further, their hypolipidemic activity in vivo was tested. The majority of the obtained compounds demonstrated considerable radical scavenging and antioxidant action, with a parallel decrease in Triton-induced hyperlipidemia in rats. The (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid derivative with morpholine and 4-methylpiperidine (compounds 4 and 13, respectively) significantly decreased triglycerides and total cholesterol in the plasma of hyperlipidemic rats, with an antioxidant capacity similar to that of the antioxidant Trolox. The compounds were designed to exhibit antioxidant and hypolipidemic pharmacological actions, and this succeeded for the majority of them. Thus, such agents may be of interest in conditions and diseases implicating oxidative stress and dyslipidemia.

Suppression of human lysozyme aggregation by a novel copper-based complex of 3,4-dimethoxycinnamic acid.[Pubmed:37578054]

J Biomol Struct Dyn. 2023 Aug 14:1-13.

In this work, a new Cu(II)-based complex as a chemotherapeutic drug agent, formulated as[Cu(DCA)(4)(H(2)O)(2)]⋅4H(2)O⋅4MeOH, (DCA = 3,4-Dimethoxycinnamic Acid), namely 1 was successfully synthesized utilizing DCA as a ligand to arrest fibrillation in Human lysozyme. The 1 was thoroughly characterized by single crystal X-ray diffraction (SC-XRD), spectroscopic (UV-Vis and FTIR) techniques, PXRD, and TGA analysis. Its crystal structure reveals a paddle wheel network around central copper metal ions. The Cu(II) metal ions exhibit a distorted square pyramidal configuration. The fluorescence titration studies showed moderate binding interaction of 1 with HuL with Ka of 6.3x10(5) M(-1) at pH-2, 25 degrees C due to its interaction withAsp53, Tyr63, Val110, and Ala111 as shown by docking and simulation studies. 1suppresses the HuL fibrillation in a concentration-dependent manner, as demonstrated by ThT assay. At 200 microM concentration, it leads to the formation of smaller species of the protein in comparison to the control sample, as suggested by Light Scattering studies. The species formed are less hydrophobic and retain their native alpha-helix structure compared to the control samples, which are hydrophobic and form beta-sheet rich amyloids as shown by ANS hydrophobicity assay and CD spectroscopy, respectively. Furthermore, morphological analysis of the species by AFM has demonstrated that, unlike mature amyloid fibrils in the control sample, HuL forms small-size aggregates in the presence of 1 under similar fibrillation conditions. It can be concluded that 1 effectively suppresses HuL fibrillation due to moderate binding to the protein.Communicated by Ramaswamy H. Sarma.

Ferulic, Sinapic, 3,4-Dimethoxycinnamic Acid and Indomethacin Derivatives with Antioxidant, Anti-Inflammatory and Hypolipidemic Functionality.[Pubmed:37507974]

Antioxidants (Basel). 2023 Jul 17;12(7):1436.

A series of thiomorpholine and cinnamyl alcohol derivatives, conjugated with cinnamic acid-containing moieties, such as ferulic acid, sinapic acid and 3,4-Dimethoxycinnamic Acid, were synthesized and tested for their antioxidant, anti-inflammatory and hypolipidemic properties. An indomethacin ester with 2,6-di-tert-butyl-4-(hydroxymethyl)phenol was also prepared for reasons of comparison. The majority of the compounds demonstrated considerable antioxidant capacity and radical scavenging activity, reaching up to levels similar to the well-known antioxidant trolox. Some of them had an increased anti-inflammatory effect on the reduction of carrageenan-induced rat paw edema (range 17-72% at 150 mumol/kg), having comparable activity to the NSAIDs (non-steroidal anti-inflammatory drugs) used as reference. They had moderate activity in soybean lipoxygenase inhibition. All the tested compounds exhibited a significant decrease in lipidemic indices in Triton-induced hyperlipidemia in rats, whilst the most active triglycerides and total cholesterol decreased by 72.5% and 76%, respectively, at 150 mumol/kg (i.p.), slightly better than that of simvastatin, a well-known hypocholesterolemic drug, but with negligible triglyceride-lowering effect. Since our designed compounds seem to exhibit multiple pharmacological activities, they may be of use in occasions involving inflammation, oxidative stress, lipidemic deregulation and degenerative conditions.

Behavioral, Electrophysiological, and Toxicological Responses of Plutella xylostella to Extracts from Angelica pubescens.[Pubmed:37504619]

Insects. 2023 Jul 6;14(7):613.

Plutella xylostella L. is a destructive pest affecting cruciferous vegetables, causing massive economic losses worldwide. Plant-based insecticides are considered promising insect control agents. The Angelica pubescens extract inhibited female oviposition, with an oviposition deterrence index (ODI) of 61.65% at 12.5 mg/mL. We aimed to identify the bioactive compounds in A. pubescens extract. The compounds from A. pubescens extract were analyzed using LC-MS techniques. The toxicity and behavioral responses of larvae and adults of P. xylostella to ten compounds were investigated. We found that the caryophyllene oxide and 3,4-Dimethoxycinnamic Acid inhibited female oviposition; the ODIs were 98.31% and 97.59% at 1.25 mg/mL, respectively. The A. pubescens extract, caryophyllene oxide, and 3,4-Dimethoxycinnamic Acid caused larval mortality, with LC(50) values of 21.31, 4.56, and 5.52 mg/mL, respectively. The EAG response of females was higher than that of males under A. pubescens extract conditions, while the EAG response of males was higher than that of females in caryophyllene oxide and 3,4-Dimethoxycinnamic Acid conditions. The A. pubescens extract and caryophyllene oxide showed repellent activity against both female and male adults, while the 3,4-Dimethoxycinnamic Acid did not elicit any notable behavioral responses from P. xylostella adults. A. pubescens extract and caryophyllene oxide are potential insecticides, oviposition deterrents, and behavioral regulators against P. xylostella, and they could be potential candidates for the development of biological insecticides to control P. xylostella.

Citrus Honey Ameliorates Liver Disease and Restores Gut Microbiota in Alcohol-Feeding Mice.[Pubmed:36904078]

Nutrients. 2023 Feb 21;15(5):1078.

Citrus honey (CH) is rich in nutrients that have a wide variety of biological functions, such as antibacterial, anti-inflammatory, and antioxidant activities, and which demonstrate therapeutic properties, such as anti-cancer and wound-healing abilities. However, the effects of CH on alcohol-related liver disease (ALD) and the intestinal microbiota remain unknown. This study aimed to determine the alleviating effects of CH on ALD and its regulatory effects on the gut microbiota in mice. In total, 26 metabolites were identified and quantified in CH, and the results suggested that the primary metabolites were abscisic acid, 3,4-Dimethoxycinnamic Acid, rutin, and two markers of CH, hesperetin and hesperidin. CH lowered the levels of aspartate aminotransferase, glutamate aminotransferase, and alcohol-induced hepatic edema. CH could promote the proliferation of Bacteroidetes while reducing the abundance of Firmicutes. Additionally, CH also showed some inhibitory effects on the growth of Campylobacterota and Turicibacter. CH enhanced the secretion of short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, butyric acid, and valeric acid. Given its alleviating functions in liver tissue damage and its regulatory effects on the gut microbiota and SCFAs, CH could be a promising candidate for the therapeutic treatment of ALD.

Hydroxycinnamic Acid Derivatives from Coffee Extracts Prevent Amyloid Transformation of Alpha-Synuclein.[Pubmed:36140356]

Biomedicines. 2022 Sep 12;10(9):2255.

Earlier we showed that derivatives of hydroxycinnamic acids prevent amyloid transformation of alpha-synuclein and prion protein. The aim of this work was to determine the content of 3-hydroxycinnamic acid derivatives in coffee extracts and to evaluate their activity in relation to alpha-synuclein amyloid aggregation. Hydroxycinnamic acid derivatives were identified in aqueous and ethanol extracts of coffee beans by quantitative mass spectrometric analysis. Only 3,4-Dimethoxycinnamic Acid (13-53 mug/mL) was detected in significant amounts in the coffee extracts, while ferulic acid was present in trace amounts. In addition, 3-methoxy-4-acetamidoxycinnamic acid (0.4-0.8 mug/mL) was detected in the roasted coffee extracts. The half-maximum inhibitory concentrations of alpha-synuclein fibrillization reaction in the presence of coffee extracts, as well as inhibitory constants, were determined using thioflavin T assay. The inhibitory effect of black and green coffee extracts on alpha-synuclein fibrillization is dose-dependent, and in a pairwise comparison, the constants of half-maximal inhibition of fibrillization for green coffee extracts are comparable to or greater than those for black coffee. Thus, coffee extracts prevent pathological transformation of alpha-synuclein in vitro, probably due to the presence of 3,4-Dimethoxycinnamic Acid in them. Consequently, coffee drinks and coffee extracts can be used for the prevention of synucleinopathies including Parkinson's disease.

Identification of Multi-Target Anti-AD Chemical Constituents From Traditional Chinese Medicine Formulae by Integrating Virtual Screening and In Vitro Validation.[Pubmed:34335272]

Front Pharmacol. 2021 Jul 16;12:709607.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens the health of the elderly. At present, no drugs have been proven to cure or delay the progression of the disease. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach provides an innovative and promising idea in search for new drugs against AD. In order to find potential multi-target anti-AD drugs from traditional Chinese medicine (TCM) formulae, a compound database derived from anti-AD Chinese herbal formulae was constructed and predicted by the anti-AD multi-target drug prediction platform established in our laboratory. By analyzing the results of virtual screening, 226 chemical constituents with 3 or more potential AD-related targets were collected, from which 16 compounds that were predicted to combat AD through various mechanisms were chosen for biological validation. Several cell models were established to validate the anti-AD effects of these compounds, including KCl, Abeta, okadaic acid (OA), SNP and H(2)O(2) induced SH-SY5Y cell model and LPS induced BV2 microglia model. The experimental results showed that 12 compounds including Nonivamide, Bavachromene and 3,4-Dimethoxycinnamic Acid could protect model cells from AD-related damages and showed potential anti-AD activity. Furthermore, the potential targets of Nonivamide were investigated by molecular docking study and analysis with CDOCKER revealed the possible binding mode of Nonivamide with its predicted targets. In summary, 12 potential multi-target anti-AD compounds have been found from anti-AD TCM formulae by comprehensive application of computational prediction, molecular docking method and biological validation, which laid a theoretical and experimental foundation for in-depth study, also providing important information and new research ideas for the discovery of anti-AD compounds from traditional Chinese medicine.

Phytochemical, Antiplasmodial, Cytotoxic and Antimicrobial Evaluation of a Southeast Brazilian Brown Propolis Produced by Apis mellifera Bees.[Pubmed:34227213]

Chem Biodivers. 2021 Sep;18(9):e2100288.

Seven phenolic compounds (ferulic acid, caffeic acid, 4-methoxycinnamic acid, 3,4-Dimethoxycinnamic Acid, 3-hydroxy-4-methoxybenzaldehyde, 3-methoxy-4-hydroxypropiophenone and 1-O,2-O-digalloyl-6-O-trans-p-coumaroyl-beta-D-glucopyranoside), a flavanonol (7-O-methylaromadendrin), two lignans (pinoresinol and matairesinol) and six diterpenic acids/alcohol (19-acetoxy-13-hydroxyabda-8(17),14-diene, totarol, 7-oxodehydroabietic acid, dehydroabietic acid, communic acid and isopimaric acid) were isolated from the hydroalcoholic extract of a Brazilian Brown Propolis and characterized by NMR spectral data analysis. The volatile fraction of brown propolis was characterized by CG-MS, composed mainly of monoterpenes and sesquiterpenes, being the major alpha-pinene (18.4 %) and beta-pinene (10.3 %). This propolis chemical profile indicates that Pinus spp., Eucalyptus spp. and Araucaria angustifolia might be its primary plants source. The brown propolis displayed significant activity against Plasmodium falciparum D6 and W2 strains with IC(50) of 5.3 and 9.7 mug/mL, respectively. The volatile fraction was also active with IC(50) of 22.5 and 41.8 mug/mL, respectively. Among the compounds, 1-O,2-O-digalloyl-6-O-trans-p-coumaroyl-beta-D-glucopyranoside showed IC(50) of 3.1 and 1.0 mug/mL against D6 and W2 strains, respectively, while communic acid showed an IC(50) of 4.0 mug/mL against W2 strain. Cytotoxicity was determined on four tumor cell lines (SK-MEL, KB, BT-549, and SK-OV-3) and two normal renal cell lines (LLC-PK1 and VERO). Matairesinol, 7-O-methylaromadendrin, and isopimaric acid showed an IC(50) range of 1.8-0.78 mug/mL, 7.3-100 mug/mL, and 17-18 mug/mL, respectively, against the tumor cell lines but they were not cytotoxic against normal cell lines. The crude extract of brown propolis displayed antimicrobial activity against C. neoformans, methicillin-resistant Staphylococcus aureus, and P. aeruginosa at 29.9 mug/mL, 178.9 mug/mL, and 160.7 mug/mL, respectively. The volatile fraction inhibited the growth of C. neoformans at 53.0 mug/mL. The compounds 3-hydroxy-4-methoxybenzaldehyde, 3-methoxy-4-hydroxypropiophenone and 7-oxodehydroabietic acid were active against C. neoformans, and caffeic and communic acids were active against methicillin-resistant Staphylococcus aureus.

Grouping, Spectrum-Effect Relationship and Antioxidant Compounds of Chinese Propolis from Different Regions Using Multivariate Analyses and Off-Line Anti-DPPH Assay.[Pubmed:32708723]

Molecules. 2020 Jul 16;25(14):3243.

49 samples of propolis from different regions in China were collected and analyzed for their chemical compositions, contents of total flavonoids (TFC), total phenolic acid (TPC) and antioxidant activity. High-performance liquid chromatography (HPLC) analysis identified 15 common components, including key marker compounds pinocembrin, 3-O-acetylpinobanksin, galangin, chrysin, benzyl p-coumarate, pinobanksin and caffeic acid phenethyl ester (CAPE). Cluster analysis (CA) and correlation coefficients (CC) analysis showed that these propolis could be divided into three distinct groups. Principal component analysis (PCA) and multiple linear regression analysis (MLRA) revealed that the contents of isoferulic acid, caffeic acid, CAPE, 3,4-Dimethoxycinnamic Acid, chrysin and apigenin are closely related to the antioxidant properties of propolis. In addition, eight peak areas decreased after reacting with 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radicals, indicating that these compounds have antioxidant activity. The results indicate that the grouping and spectrum-effect relationship of Chinese propolis are related to their chemical compositions, and several compounds may serve as a better marker for the antioxidant activity of Chinese propolis than TFC and TPC. The findings may help to develop better methods to evaluate the quality of propolis from different geographic origins.

Naturally occurring cinnamic acid derivatives prevent amyloid transformation of alpha-synuclein.[Pubmed:31945397]

Biochimie. 2020 Mar;170:128-139.

In search of the compounds that interfere with amyloid transformation of alpha-synuclein, 9 natural and synthetic cinnamic acid derivatives were studied. They are structurally similar to a half of curcumin, which has pronounced anti-aggregatory and anti-amyloid effects. We have shown that some of these derivatives prevent ovine prion protein amyloidization. Subsequently, thioflavin T binding assay showed that 3 out of 9 studied compounds effectively prevented amyloid transformation of alpha-synuclein with IC50 of 13, 50 and 251 muM. Molecular modeling approach revealed possible binding sites of the three selected ligands with alpha-synuclein fibrils, while monomeric alpha-synuclein does not bind to the ligands according to experimental results. This led us to believe that compounds may act by changing the structure of primary aggregates, preventing the formation of full-length fibrils. The inhibiting effect of the ligands on aggregation of alpha-synuclein was further confirmed by monitoring aggregation via turbidimetry, susceptibility to proteolytic cleavage, changes in beta-sheet content, and scanning ion-conductance microscopy. Studied derivatives were not cytotoxic, and, moreover, two studied compounds (ferulic and 3,4-Dimethoxycinnamic Acid) are found in plant sources and are natural metabolites present in human blood, so they can be promising candidate drugs for synucleinopathies, including Parkinson's disease.

Evaluation of cinnamic acid and six analogues against eggs and larvae of Haemonchus contortus.[Pubmed:31213238]

Vet Parasitol. 2019 Jun;270:25-30.

This study evaluated the in vitro anthelmintic (AH) activity of cinnamic acid and six analogues against eggs and larvae of Haemonchus contortus. Stock solutions of each compound (trans-cinnamic acid, p-coumaric acid, caffeic acid, trans-ferulic acid, trans-sinapic acid, 3,4-Dimethoxycinnamic Acid, and chlorogenic acid) were prepared in PBS:Tween-20 (1%) for use in the egg hatch test (EHT) and larval exsheathment inhibition test (LEIT) at different concentrations (25-400 mug/mL). The respective effective concentration 50% (EC(50)) values with 95% confidence intervals were estimated. Mixtures made of all cinnamic acid and its analogues as well as some selected individual compounds were also tested in the EHT. Only ferulic and chlorogenic acids showed AH activity in the EHT (EC(50): 245.2 mug/mL (1.26 mM) and 520.8 mug/mL (1.47 mM), respectively) (P < 0.05). A higher EC(50) (1628.10 mug/mL) of the mixture of cinnamic acid and its analogues was required to observe activity against eggs mostly blocking the larvae hatching. The analogues' mixtures tested were less active than ferulic or chlorogenic acid alone. The activity of ferulic and chlorogenic acids against eggs was associated with larvae failing to hatch, and the two compounds exhibited antagonistic effects when evaluated together. All standards had an EC(50) lower than 0.42 mM in the LEIT. Caffeic acid had the best activity in the LEIT (EC(50) 0.04 mM), followed by ferulic acid (EC(50) 0.11 mM) (P < 0.05). There was no clear, definitive structure-activity relationship for these non-flavonoid polyphenols against eggs or larvae of H. contortus in vitro. This study is the first to directly evaluate cinnamic acid and its derivatives as active compounds against eggs and larvae of H. contortus.

Chemical composition and biological activity of the essential oil from the root of Jatropha pelargoniifolia Courb. native to Saudi Arabia.[Pubmed:30662311]

Saudi Pharm J. 2019 Jan;27(1):88-95.

The chemical composition of the essential oil from Jatropha pelargoniifolia roots was determined via GC-FID. There were 80 compounds, representing 99.99% of the total oil constituents. Among these, 77.31% were sesquiterpenes, 14.62% were fatty acids, 7.21% were other components (i.e., phenolics, hydrocarbons, etc.), and 0.85% were monoterpenes. The major compounds in the oil were gamma-eudesmol (35.31%), 5-guaien-11-ol (14.43%), epi-cedrol (8.19%), oleic acid (5.23%), bulnesol (4.45%), alpha-linoleic acid (4.20%), 3,4-Dimethoxycinnamic Acid (3.83%), palmitic acid (2.69%), isolongifolanone (2.68%), eicosane (1.41%), and cedrol (1.14%). Oxygenated sesquiterpenes were found to represent more than 50% percent of the total oil content. Moreover, the essential oil was evaluated for anti-inflammatory, antioxidant, antipyretic, and antinociceptive activities using in vivo and in vitro models. Additionally, the antioxidant potential of the oil was evaluated using various in vitro antioxidant tests, including DPPH(*), ABTS(*+) and FRAP. At a dose of 240 microl/kg, the oil showed anti-inflammatory (59.12%), antipyretic (37.00 +/- 0.11), and antinociceptive (47.58%) activities and showed significant (p < 0.001) effect as compared to a standard drug (phenylbutazone and indomethacin). These findings demonstrated that the essential oil of Jatropha pelargoniifolia root could be used as a natural source for their anti-inflammatory, antinociceptive, antipyretic, and antioxidant effects.