Cinnamaldehyde Derivatives Research Articles

Synthesis and Antifungal Activities of Cinnamaldehyde Derivatives against Penicillium digitatum Causing Citrus Green Mold

Penicillium digitatum (green mold) is pathogenic fungi and causes citrus fruit postharvest rotting that leads to huge economic losses across the world. The current study was aimed to develop a new derivative of cinnamaldehyde (4-methoxycinnamaldehyde) through the cross-hydroxyaldehyde condensation method with benzaldehyde substituted by a benzene ring under the catalysis of alkaline reagent and, moreover, to test their antifungal potential against P. digitatum, the major citrus fruit rotting fungi. Multiple derivatives of cinnamaldehyde viz. 4-nitro CA, 4-chloro CA, 4-bromo CA, 4-methyl CA, 4-methoxy CA, and 2,4-dimethoxy CA were synthesized in the current study whereas the 4-methoxy CA showed highest antifungal actions for citrus fruit postharvest rotting fungi P. digitatum. Moreover, 4-methoxy CA was found to reduce the spore germination and growth by damaging the fungal cell membrane, as well as declined the levels of reducing sugars.

Correction to Structure-Dependent Effects of Cinnamaldehyde Derivatives on TRPA1-Induced Serotonin Release in Human Intestinal Cell Models.

Correction to Structure-Dependent Effects of Cinnamaldehyde Derivatives on TRPA1-Induced Serotonin Release in Human Intestinal Cell Models.

Electrochemical Formation of Cinnamaldehyde by the Electrolyte System N,N‐Diisopropylethylamine and 1,1,1,3,3,3‐Hexafluoropropan‐2‐ol

AbstractThe use of a supporting electrolyte has been a significant issue in electro‐organic chemistry because it can be wasteful and increase steps in terms of separation from target products. However, it is ideal for an electrolyte to play multiple roles in reactions, for example, as a feedstock or catalyst. We have discovered that the combination of N,N‐diisopropylethylamine (DIPEA) and 1,1,1,3,3‐hexafluoropropan‐2‐ol (HFIP) not only works as an electrolyte but also facilitates the electrochemical formation of cinnamaldehyde from benzaldehydes. We demonstrate that the synthesis of 20 cinnamaldehyde derivatives can be achieved by using this reaction. Isotope‐labeling experiments and 13C NMR investigations revealed the mechanistic aspects of this process, and confirmed that DIPEA is the C2 synthon of acetaldehyde and HFIP could also function as a Brønsted acid.

Structure-Dependent Effects of Cinnamaldehyde Derivatives on TRPA1-Induced Serotonin Release in Human Intestinal Cell Models.

Activation of the transient receptor potential (TRP) channel TRPA1 by cinnamaldehyde has been shown to stimulate serotonin release in enterochromaffin QGP-1 cells. However, the impact of cinnamaldehyde on serotonin release in enterocytes is less well understood. In addition, since the neurotransmitter serotonin plays a regulatory role in a large variety of gastrointestinal and metabolic functions, it is of interest to study which structural characteristics determine cinnamaldehyde-induced serotonin release by enterocytes. Thus, the present study analyzed serotonin release in differentiated Caco-2 cells as a model for enterocytes in comparison to enterochromaffin QGP-1 cells after stimulation with cinnamaldehyde and 17 naturally occurring structurally related compounds by means of a serotonin ELISA. Stimulation with cinnamaldehyde induced a dose-dependent increase in serotonin release starting from 0.5 mM in both cell lines, with a larger effect size in Caco-2 enterocytes compared to that in QGP-1 enterochromaffin cells. Serotonin release in Caco-2 cells induced by additional 17 structurally related compounds correlated with serotonin release in QGP-1 cells, showing the highest effects for coniferylaldehyde with a 15.84 ± 3.23-fold increase in Caco-2 cells, followed by the parent compound cinnamaldehyde (13.45 ± 2.15), cinnamyl alcohol (6.68 ± 1.08), and α-methyl-cinnamaldehyde (6.59 ± 0.93). Analysis of structural and molecular characteristics that modulate serotonin release in Caco-2 enterocytes revealed that the ability of a compound to activate TRPA1, demonstrated by means of HEK293 cells transiently expressing hTRPA1, is a decisive factor to stimulate serotonin release in Caco-2 enterocytes, preferring small, electrophilic compounds with a lower polar surface area. In addition, blocking of TRPA1 using 30 μM AP-18 significantly reduced the cinnamaldehyde-induced serotonin release by 30.0 ± 5.24%, confirming a TRPA1-dependent component in serotonin release by Caco-2 cells.

Azole Based Acetohydrazide Derivatives of Cinnamaldehyde Target and Kill Candida albicans by Causing Cellular Apoptosis.

Opportunistic fungal pathogens including Candida albicans are responsible for the alarming rise in hospital acquired infections and millions of deaths worldwide. The current treatment modalities are not enough to handle this situation, and therefore, new treatment modalities and strategies are desperately needed. In this direction, we synthesized a series of azole based acetohydrazide derivatives of cinnamaldehyde and subjected it to antifungal activity evaluation. Preliminary antifungal activity evaluation revealed tremendous antifungal potential of some of the derivatives against fluconazole susceptible and resistant clinical isolates of Candida albicans. Although all the compounds in the series are structurally similar except for the presence of different substituents on the phenyl ring of the acetohydrazide pendent, they sharply differed in their activity profile. Further mechanism of action studies revealed that these compounds have an apoptotic effect on C. albicans confirmed via Annexin V-FITC staining and TUNEL assay.

Curcumin derivatives as photosensitizers in photodynamic therapy: photophysical properties and in vitro studies with prostate cancer cells

Photodynamic therapy (PDT) is a minimally invasive approach to treat various forms of cancer, based on the ability of certain non-toxic molecules (photosensitizers) to generate reactive oxygen species (ROS) after excitation by light of a certain wavelength and eventually induce strong phototoxic reactions against malignant cells and other pathogens. Curcumin is one of the most extensively investigated phytochemcals with a wide range of therapeutic properties and has been shown to induce strong photocytotoxic effects in micromolar concentrations against a variety of cancer cell lines. Curcumin (1) is comparatively evaluated with the naturally occurring bisdemethoxy Curcumin (2), which lacks the two methoxy groups, as well as two newly synthesized curcuminoids, the cinnamaldehyde derivative (3) and the dimethylamino one (4), designed to increase the absorption maximum and hence the tissue penetration. The synthetic curcuminoids were successfully synthesized in sufficient amounts and their photophysical properties such as absorption, fluorescence, photobleaching and free radical generation were investigated Compound 4 exhibited a significant increase in peak absorption (497 nm) and strong fluorescent emission signals were recorded for all curcuminoids. Photobleaching of 4 was comparable to 1 whereas 2 and 3 showed more extended photobleaching but much higher ROS production in very short irradiation times. Compounds 2 and 4 exhibited specific intracellular localization. After dark and light cytotoxicity experiments against LNCaP prostate cancer cell line for all curcuminoids, concentration of 3 µM and irradiance of 6 mW cm−2 were selected for the PDT application which resulted in remarkable results with very short LD50. Curcuminoids 2 and 4 exhibited a significant dose-dependent PDT effect. The biphasic doseresponse photodynamic effect observed for 1 and 3 may provide a strategy against prolonged and sustained photosensitivity.

Synthesis and Optical Properties of Cinnamylidene Derivatives of Malononitrile Trimer

Potassium salts of cinnamylidene derivatives of malononitrile trimer were obtained by the reactions of malononitrile trimer with cinnamaldehyde derivatives. The optical properties of the synthesized salts were studied to show that they absorb, depending on the substituent, in the range of 358–460 nm. The solid-state fluorescence with an emission maximum at 458–460 nm is practically independent of the nature of the substituent and is due to the tetracyanopropene fragment.

Phytochemical and chemotaxonomic studies on the twigs of Cinnamomum cassia (Lauraceae)

A phytochemical investigation on the twigs of Cinnamomum cassia led to the isolation of 39 compounds, including 12 flavonoid glycosides (1−12), three cinnamic acid amides (13–15), 12 lignans (16–27), five sesquiterpenoids (28–32), three cinnamaldehyde derivatives (33–35), two phenols (36 and 37), and two indole derivatives (38 and 39). Their structures were elucidated on the basis of spectroscopic data as well as by comparison with the reported spectroscopic data. Among them, 32 compounds (1–17, 19, 21, 24–29, 31, 32, and 35–39) are reported from this plant for the first time, while 23 compounds (1–8, 12, 13, 17, 19, 25–27, 29, 31, 32, and 35–39) and ten compounds (2–6, 8, 26, 27, 32, and 38) were isolated from the genus Cinnamomum and the family Lauraceae for the first time, respectively. The chemotaxonomic significance of these compounds was summarized.

Cinnamic acid derivatives in cosmetics: current use and future prospects.

Cinnamic acid derivatives are widely used in cosmetics and possess various functions. This group of compounds includes both naturally occurring and synthetic substances. On the basis of the Cosmetic Ingredient Database (CosIng) and available literature, this review summarizes their functions in cosmetics, including their physicochemical and biological properties as well as reported adverse effects. A perfuming function is typical of many derivatives of cinnamaldehyde, cinnamyl alcohol, dihydrocinnamyl alcohol and cinnamic acid itself; these substances are commonly used in cosmetics all over the world. Some of them show allergic and photoallergic potential, resulting in restrictions in maximum concentrations and/or a requirement to indicate the presence of some substances in the list of ingredients when their concentrations exceed certain fixed values in a cosmetic product. Another important function of cinnamic acid derivatives in cosmetics is UV protection. Ester derivatives such as ethylhexyl methoxycinnamate (octinoxate), isoamyl p-methoxycinnamte (amiloxiate), octocrylene and cinoxate are used in cosmetics all over the world as UV filters. However, their maximum concentrations in cosmetic products are restricted due to their adverse effects, which include contact and a photocontact allergies, phototoxic contact dermatitis, contact dermatitis, estrogenic modulation and generation of reactive oxygen species. Other rarely utilized functions of cinnamic acid derivatives are as an antioxidant, in skin conditioning, hair conditioning, as a tonic and in antimicrobial activities. Moreover, some currently investigated natural and synthetic derivatives of cinnamic acid have shown skin lightening and anti-ageing properties. Some of them may become new cosmetic ingredients in the future. In particular, 4-hydroxycinnamic acid, which is currently indexed as a skin-conditioning cosmetics ingredient, has been widely tested in vitro and in vivo as a new drug candidate for the treatment of hyperpigmentation.

Oxidative Functionalization of Cinnamaldehyde Derivatives: Control of Chemoselectivity by Organophotocatalysis and Dual Organocatalysis.

The catalytic and chemoselective oxidation of cinnamaldehyde derivatives having a C═C bond and formyl group was studied by using two organocatalysts. The visible-light-induced catalysis using rhodamine 6G as an organophotocatalyst promoted the methoxyhydroxylation of the C═C bond in a chemoselective manner. In contrast, the cooperation between rhodamine 6G and N-heterocyclic carbene (NHC) allowed the oxidative esterification of formyl group.

Evaluation of cinnamaldehyde and cinnamic acid derivatives in microbial growth control

The conspicuous absence of novel and effective strategies to control microbial growth, both in the food and healthcare industries and evidence of increasing microbial resistance to conventional biocides has led to a search for novel antimicrobials and growth prevention strategies. In this study, 15 phytochemicals and derivatives, structurally-related to cinnamic acid and cinnamaldehyde, were assessed for their effects on the growth of Escherichia coli, Staphylococcus aureus and Enterococcus hirae. Their effects were compared to seven commonly used biocides (hydrogen peroxide, sodium hypochlorite, chlorhexidine, cetyltrimethylammonium bromide, triclosan, o-phthalaldehyde and lactic acid). All phytochemicals and derivatives increased lag phase and culture doubling time of the tested bacteria. Cinnamic acid and other derivatives inhibited bacterial growth. The MIC of cinnamaldehyde was comparable to o-phthalaldehyde and sodium hypochlorite and lower than hydrogen peroxide and lactic acid. The effect of methyl trans-cinnamate on bacterial growth was more evident against Gram-negative bacteria. It also inhibited quorum sensing in Chromobacterium violaceum. The effect of phytochemicals against sessile bacteria was low: <1 log CFU.cm−2. Inhibition of quorum sensing and of bacterial growth supports the fact that phytochemicals are an interesting source of antimicrobials with potential use as biocides or more likely as additives to improve the efficacy of current biocidal formulations and preservative systems.

Antioxidant Activities of Cinnamaldehyde Derivatives

The modification structures of cinnamaldehyde, which was isolated from cinnamon oil, has been carried out. The synthesized compounds were tested their antioxidant activity by using 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging assay and the IC50 was done by spectrophotometric assay method compared with standard vitamin E. The cinnamaldehyde derivatives, e.g. cinnamic acid 2, methyl cinnamate 3 and cinnamyl alcohol 5 had significantly higher antioxidant activity than that of their starting materials, cinnamaldehyde. However, although cinnamic amine 5 had a hydroxyl group, it gave no antioxidant activity possibly due to its bulky structure.

The reaction of cinnamaldehyde and cinnam(o)yl derivatives with thiols

Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried out a systematic study of the “native” reactivity of these compounds with dodecanethiol and cysteamine as models, respectively, of simple thiols and reactive protein thiols that can benefit from iminium ion catalysis in Michael reactions. Cinnamoyl esters and amides, as well as cinnamyl ketones and oximes, did not show any reactivity with the two probe thiols, while cinnamaldehyde (1a) reacted with cysteamine to afford a mixture of a thiazoline derivative and compounds of multiple addition, and with aliphatic thiols to give a single bis-dithioacetal (6). Chalchones and their vinylogous C5-curcuminoid derivatives were the only cinnamoyl derivatives that gave a thia-Michael reaction. From a mechanistic standpoint, loss of conjugation in the adduct might underlie the lack of a native Michael reactivity. This property is restored by the presence of another conjugating group on the carbonyl, as in chalcones and C5-curcuminoids. A critical mechanistic revision of the chemical and biomedical literature on cinnamaldehyde and related compounds seems therefore required.

Heterogeneous One‐Pot Carbonylation and Mizoroki–Heck Reaction in a Parallel Manner Following the Cleavage of Cinnamaldehyde Derivatives

AbstractInvited for the cover of this issue is the group of Yasunari Monguchi and Hironao Sajiki at the Pharmaceutical University of Gifu. The image depicts that palladium on carbon is an excellent conductor for the simultaneous performance of carbonylation of iodoarenes and Mizoroki–Heck type reaction starting from cinnamaldehyde (G‐clef) with good harmony. Read the full text of the article at 10.1002/chem.201606048.

Cover Picture: Heterogeneous One‐Pot Carbonylation and Mizoroki–Heck Reaction in a Parallel Manner Following the Cleavage of Cinnamaldehyde Derivatives (Chem. Eur. J. 34/2017)

Cover Picture: Heterogeneous One‐Pot Carbonylation and Mizoroki–Heck Reaction in a Parallel Manner Following the Cleavage of Cinnamaldehyde Derivatives (Chem. Eur. J. 34/2017)

Heterogeneous One-Pot Carbonylation and Mizoroki-Heck Reaction in a Parallel Manner Following the Cleavage of Cinnamaldehyde Derivatives.

Carbon monoxide (CO) and styrene derivatives that can be both generated by a palladium on carbon (Pd/C)-catalyzed carbon-carbon (C-C) bond cleavage reaction of cinnamaldehyde derivatives were effectively utilized in further palladium-catalyzed C-C bond forming reactions in a direct and practical way. CO derived from simple and affordable CO carriers such as cinnamaldehyde or terephthalaldehyde was efficiently employed in the in situ CO fixation with various aromatic iodides through a palladium-catalyzed carbonylation followed by an inter- or intramolecular coupling reaction with alcohols to afford the corresponding esters or lactones, respectively. Styrene derivatives were also efficient substrates in an in situ Mizoroki-Heck-type cross-coupling reaction with aryl iodides, leading to the effective formation of asymmetric stilbenes. The decarbonylation of cinnamaldehyde derivatives and the subsequent independent syntheses of both esters/lactones and 1,2-diarylethenes could be achieved in a virtual one-pot and in situ reaction using a H-shaped pressure-tight glass-sealed tube consisting of two independent but laterally connected reaction tubes in the gas space.

Structure-activity relationships of cinnamaldehyde and eugenol derivatives against plant pathogenic fungi

Rhizoctonia solani and Fusarium oxysporum are very well known phytopathogens with worldwide spread that cause one of the most destructive diseases, resulting significant yield losses in crop production. In order to find effective fungicides for controlling phytopathogen, the structure-activity relationships of cinnamaldehyde and eugenol derivatives against R. solani and F. oxysporum were evaluated. Additionally, the composition and fungicidal activity of Cinnamomum cassia and Syzygium aromatica essential oils was assessed. Cinnamaldehyde (49.75%) is the major compound in cinnamon bark oil, and eugenol (89.17%) is most abundant in clove bud oil. The clove bud oil exhibited good antifungal activities against R. solani and F. oxysporum (IC50=106.5 and 149.9μg/mL, respectively). Cinnamon bark oil showed a lower activity than clove bud oil. The fungicidal activity of cinnamaldehyde (IC50=75.4 and 156.9μg/mL, respectively) and eugenol (IC50=58.9 and 52.9μg/mL, respectively) against R. solani and F. oxysporum was also evalutated. Comparisons of the antifungal activities of cinnamaldehyde and eugenol derivatives revealed that α-methylcinnamaldehyde, α-methylcinnamic acid, methyleugenol, acetyleugenol, isoeugenol, methylisoeugenol, and acetylisoeugenol showed good antifungal activities against R. solani and F. oxysporum. In structure-activity relationships, the fungicidal activity of cinnamaldehyde derivatives could be related to conjugated double bond and the length of CH chain outside the ring. In addition, the presence of the lipophilicity may have a considerable influence on the toxicity of phenylpropenes. The present approach may help future work in the search for fungicidal compounds.

In vitro antioxidant and in vivo antidepressant activity of green synthesized azomethine derivatives of cinnamaldehyde.

OBJECTIVES:In this study, three (CS-1 to CS-3) azomethine derivatives of cinnamaldehyde were green synthesized, characterized, and their antioxidant and antidepressant activities were explored.MATERIALS AND METHODS:The antioxidant effect of these compounds was initially performed in vitro using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay methods before subjecting them to in vivo experiments. Compounds showing potent antioxidant activity (CS-1 and CS-2) were investigated further for their antidepressant activity using the forced swim test (FST) and tail suspension test (TST). Ascorbic acid (AA) and fluoxetine (20 mg/kg, p.o) were used as reference drugs for comparison in the antioxidant and antidepressant experiments, respectively.RESULTS:It was observed that CS-2 and CS-3 exhibited highest DPPH (half maximal inhibitory concentration [IC50]: 16.22 and 25.18 μg/mL) and ABTS (IC50: 17.2 and 28.86 μg/mL) radical scavenging activity, respectively, compared to AA (IC50: 15.73 and 16.79 μg/mL) and therefore, both CS-2 and CS-3 were tested for their antidepressant effect using FST and TST as experimental models. Pretreatment of CS-2 and CS-3 (20 mg/kg) for 10 days considerably decreased the immobility time in both the FST and TST models.CONCLUSION:The antioxidant and antidepressant effect of CS-2 and CS-3 may be attributed to the presence of azomethine linkage in the molecule.

Discovery of potent inhibitors targeting Vibrio harveyi LuxR through shape and e-pharmacophore based virtual screening and its biological evaluation.

Quorum sensing is widely recognized as an efficient mechanism in the regulation and production of several virulence factors, biofilm formation and stress responses. For this reason, quorum sensing circuit is emerging as a novel drug target for the development of anti-infective. Recently, cinnamaldehyde derivatives have been found to interfere with master quorum sensing transcriptional regulator and thereby decreasing the DNA binding ability of LuxR. However, the exact mode of cinnamaldehyde binding with LuxR and receptor interaction still remains inconclusive. In the current study, combined method of molecular docking and molecular dynamics simulations were performed to investigate the binding mode, dynamic and energy aspects of cinnamaldehyde derivatives into the binding site of LuxR. Based on the experimental and computational evidences, LuxR-3,4-dichloro-cinnamaldehyde complex was chosen for the development of e-pharmacophore model. Further, shape and e-pharmacophore based virtual screening were performed against ChemBridge database to find potent and suitable ligands for LuxR. By comparing the results of shape and e-pharmacophore based virtual screening; best 9 hit molecules were selected for further studies including ADMET prediction, molecular dynamics simulations and Prime MM-GBSA calculations. From the 9 hit molecules, the top most compound 3-(2,4-dichlorophenyl)-1-(1H-pyrrol-2-yl)-2-propen-1-one (ChemBridge-7364106) was selected for invitro assays using Vibrio harveyi. The result revealed that ChemBridge-7364106 significantly reduced the bioluminescence production in a dose dependent manner. In addition, ChemBridge-7364106 showed a significant inhibition in biofilm formation and motility in V.harveyi. The results from the study suggest that ChemBridge-7364106 could serve as an anti-quorum sensing molecule for V.harveyi.

Quantitative Structure Activity Relationship of Cinnamaldehyde Compounds against Wood-Decaying Fungi.

Cinnamaldehyde, of the genius Cinnamomum, is a major constituent of the bark of the cinnamon tree and possesses broad-spectrum antimicrobial activity. In this study, we used best multiple linear regression (BMLR) to develop quantitative structure activity relationship (QSAR) models for cinnamaldehyde derivatives against wood-decaying fungi Trametes versicolor and Gloeophyllun trabeum. Based on the two optimal QSAR models, we then designed and synthesized two novel cinnamaldehyde compounds. The QSAR models exhibited good correlation coefficients: R2Tv = 0.910 for Trametes versicolor and R2Gt = 0.926 for Gloeophyllun trabeum. Small errors between the experimental and calculated values of two designed compounds indicated that these two QSAR models have strong predictability and stability.