Cinnamic Amides Research Articles

Pharmacochemical Study of Multitarget Amino Acids' Hybrids: Design, Synthesis, In vitro, and In silico Studies.

Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases. Herein, we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters. The synthesis was based on an In silico study of a library of cinnamic amide hybrids with glycine, γ- aminobutyric, and L - glutamic acids. Drug-likeness and ADMET properties were subjected to In silico analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1- hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of N,N,-diisopropyl-Nethylamine. The structure of the synthesized compounds was confirmed spectrophotometrically. The new compounds, such as lipoxygenase, cyclooxygenase-2, lipid peroxidation inhibitors, and antiinflammatories, were tested in vitro. The compounds exhibited LOX inhibition with IC50 values in the low μM region). Compounds 18a, 23b, and 11c are strong lipid peroxidation inhibitors (99%, 78%, and 92%). Compound 28c inhibits SLOX-1 with IC50 =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC50 6 and 5 μM Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The In silico ADMET properties of 14c and 11a support their drug-likeness.

Synthesis and Antioxidant Activities of Novel Pyrimidine Acrylamides as Inhibitors of Lipoxygenase: Molecular Modeling and In Silico Physicochemical Studies.

The pyrimidine ring is present in various biomolecules such as DNA and RNA bases, aminoacids, vitamins, etc. Additionally, many clinically used drugs including methotrexate and risperidone contain the pyrimidine heterocyclic scaffold as well. Pyrimidine derivatives present diverse biological activities including antioxidant and anticancer activities and can be considered as privileged scaffolds in drug discovery for the treatment of various diseases. Piperidine pyrimidine amides have gained significant attention due to their enzymatic inhibitory activity. Based on our experience and ongoing investigation on cinnamic acid derivatives, their hybrids and substituted pteridines acting as lipoxygenase inhibitors, antioxidants, anti-cancer, and anti-inflammatory agents a series of novel piperidine pyrimidine cinnamic acids amides have been designed and synthesized. The novel hybrids were studied for their antioxidant and anti-inflammatory potential. They exhibit moderate antioxidant activity in the DPPH assay which may be related to their bulkiness. Moreover, moderate to good lipid peroxidation inhibition potential was measured. With regards to their lipoxygenase inhibitory activity, however, two highly potent inhibitors out of the nine tested derivatives were identified, demonstrating IC50 values of 10.7 μM and 1.1 μM, respectively. Molecular docking studies to the target enzyme lipoxygenase support the experimental results.

Computational Insight and Anticancer Effect of Cinnamic Acid-Derivative Amide Compounds

In this research, a meticulous screening process was conducted using four servers: Drug Target Explorer, Swiss Target Predictor, SEA Predictor, and Target Hunter. The primary objective was to identify a series of potential biological targets related to the regulation of cell growth and apoptosis in cancer cells using cinnamic acid derivatives. This study focused on five specific targets, matrix metallopeptidase 9 (MMP9), apoptosis inducing factor (AIF), aldo-keto reductase family 1 member C3 (AKR1C3), aldo-keto reductase family 1 member B10 (AKR1B10), mitogenactivated protein kinase 14 (MAPK14), all of which are well known to play a significant role in cancer cell dynamics. To explore both molecular recognition and molecular dynamics, a series of in silico investigations (docking and molecular dynamics) were carried out using a collection of 14 cinnamic acid derivatives, including cinnamic acid phenethyl ester (CAPE) as a notable reference molecule due to its widely recognized anticancer effects. Furthermore, preliminary in vitro data revealed a potentially promising cytotoxic effect of (E)-N-[(3,4-dichlorophenyl)methyl]- 3-(4-phenoxyphenyl)-2-propenamide (LQM755) on a human gastric adenocarcinoma cell-line (AGS cells), which are characterized by the overexpression of the MMP9 protein. Therefore, the chemical compound LQM755 provides an initial perspective in the field of cancer therapy.

Discovery of Novel Hybrid-Type Strigolactone Mimics Derived from Cinnamic Amide.

Strigolactones (SLs) are a class of plant hormones and rhizosphere communication signals of great interest. They perform diverse biological functions including the stimulation of parasitic seed germination and phytohormonal activity. However, their practical use is limited by their low abundance and complex structure, which requires simpler SL analogues and mimics with maintained biological function. Here, new, hybrid-type SL mimics were designed, derived from Cinnamic amide, a new potential plant growth regulator with good germination and rooting-promoting activities. Bioassay results indicated that compound 6 not only displayed good germination activity against the parasitic weed O. aegyptiaca with an EC50 value of 2.36 × 10-8 M, but also exhibited significant inhibitory activity against Arabidopsis root growth and lateral root formation, as well as promoting root hair elongation, similar to the action of GR24. Further morphological experiments on Arabidopsis max2-1 mutants revealed that 6 possessed SL-like physiological functions. Furthermore, molecular docking studies indicated that the binding mode of 6 was similar to that of GR24 in the active site of OsD14. This work provides valuable clues for the discovery of novel SL mimics.

Antiviral Activity of Medicinal Plants against Human Coronavirus: a systematic scoping review of and experimentations.

To investigate the and studies of natural compounds and medicinal plants with anti-coronavirus activity. A systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Animal Research: Reporting of experiments guidelines to find data for medicinal plants and natural products effective against human coronaviruses in or studies. Studies published up to September 6, 2020 were included. Studies ( or ) reporting the effect of medicinal plants and natural products or their derivatives on human coronavirus were included RESULTS: Promising anti-coronavirus effects are seen with different herbal compounds like some diterpenoids, sesquiterpenoids, and three compounds in tea with 3CLpro inhibiting effect of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV); Hirsutenone, Six cinnamic amides and bavachinin are PLpro inhibitors and Tanshinones are active on both 3CLpro and PLpro. Some flavonoid compounds of Citrus fruits act on Immun-oregulation and target angiotensin-converting enzyme 2 which is used by SARS-COV for entry. Virus helicase is possibly inhibited by two compounds myricetin and scutellarein. This review shows that complementary medicine have the potential for new drug discovery against coronavirus. Further research is needed before definitive conclusions can be made concerning the safety and efficacy of the use of these medicinal plants.

The Potential of Medicinal Plants and Bioactive Compounds in the Fight Against COVID-19

The Potential of Medicinal Plants and Bioactive Compounds in the Fight Against COVID-19

Design and biological evaluation of cinnamic and phenylpropionic amide derivatives as novel dual inhibitors of HIV-1 protease and reverse transcriptase.

Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43μM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.

The polypharmacy reduction potential of cinnamic acids and some related compounds in pre- and post-onset management of type 2 diabetes mellitus.

This review assesses the polypharmacy reduction potential of cinnamic acids (CAs) and some related compounds in managing three or more of the cluster of seven, pre- and post-type 2 diabetes mellitus (T2DM)-related features (central obesity, hyperglycemia, hypertension, dyslipidemia, pro-thrombosis, oxidation, and inflammation). Google scholar and Pubmed were searched for cinnam*, chlorogenic acid, ferulic acid, and caffeic acid in conjunction with each of pre- and post-onset T2DM, central obesity, hyperglycemia, hypertension, dyslipidemia, pro-thrombosis, oxidation, and inflammation. The study was divided into an introduction followed by findings on the impacts of each of the CAs including trans-CA acid, the E isomer of a CA-based thiazolidinedione and a metabolite of that isomer, as well as p-methoxy CA, various cinnamic amides and some other CA-related compounds (chlorogenic acid, cinnamaldehyde, ferulic and caffeic acid). Trans-CA has a potential to manage three, while each of chlorogenic acid, cinnamalde-hyde, caffeic acid and ferulic acid has a potential to manage all seven members of the cluster. Other CA-related compounds identified may manage only one or two of the cluster of seven. Much of the work has been done in animal models of pre- and post-onset T2DM and non-pre- or post-onset T2DM humans and animals, along with some cell culture and in vitro work. Very little work has been done with human pre- and post-onset T2DM. While there is potential for managing 3 or more members of the cluster with many of these compounds, a definitive answer awaits large pre- and post-T2DM onset clinical trials with humans.

Targeting Inflammation with Conjugated Cinnamic Amides, Ethers and Esters

Background:Cinnamic acid is a key intermediate in shikimate and phenylpropanoid pathways. It is found both in free form, and especially in the form of esters in various essential oils, resins and balsams which are very important intermediates in the biosynthetic pathway of several natural products. The cinnamic derivatives play a vital role in the formation of commercially important intermediate molecules which are necessary for the production of different bioactive compounds and drugs. Different substitutions on basic moiety lead to various biological activities. Furthermore, combination of appropriate pharmacophore groups with cinnamic acid derivatives were developed to give hybrids in order to find out promising drug candidates as inhibitors of multiple biological targets associated with inflammation. We found interesting to continue our efforts to design and synthesise three series of novel cinnamic acid-based hybrids: a) nitrooxy esters of cinnamic acid, b) ethers and c) amides of cinnamic acids with arginine, as pleiotropic candidates against multiple targets of inflammation.Methods:The synthesis of cinnamic was established by a Knoevenagel-Doebner condensation of the suitable aldehyde either with malonic acid in the presence of pyridine and piperidine, or with phenylacetic acid in the precence of triethylamine in acetic anhydride. The synthesis of the corresponding esters was conducted in two steps. The ethers were synthesized in low yields, with 1,2 – dibromoethane in dry acetone, in the presence of K2CO3, to give oily products. The corresponding cinnamic amides were synthesised in a single step. The synthesised hybrids were tested as lipoxygenase (LOX) and cyclooxygenase (COX) inhibitors in vitro. In silico docking was applied to all the novel derivatives. Several molecular properties of the hybrids were calculated in order to evaluate their drug likeness.Results:A number of esters, ethers and amides of selected cinnamic acids, either phenyl substituted or not, has been synthesised and subjected to modelling studies. The compounds were studied in vitro/in vivo for their inhibitory activities on cox and lox, and as antioxidants. Log P values of all the title compounds except of 3a (5.38) were found to be less than 5 and are in agreement to Lipinski’s rule of five, suggesting satisfactory permeability across cell membrane. The molecular modelling study seems to be in accordance with the experimental results for LOX and COX-2. The result of antioxidant activity for amide 3b supports the anti-lox activity. Compound 5d presents the higher in vivo anti-inflammatory.Conclusion:According to the experimental findings compounds 3b and 5d can be used as lead compounds for the design of new molecules to target inflammation.

Chiral nanostructures self-assembled from nitrocinnamic amide amphiphiles: substituent and solvent effects.

Chiral nanostructures, such as α-helical proteins and double helix DNA, are widely found in biological systems and play a significant role in the biofunction of life. These structures are essentially fabricated through the covalent or noncovalent bonds between small chiral molecules. It is thus an important issue to understand how small chiral molecules can form chiral nanostructures. Here, using a series of isomeric nitrocinnamic amide derivatives, we have investigated the self-assembly behavior and the effect of the substituent position as well as the solvent on the formation of chiral nanostructures. It was found that totally different chiral nanostructures were formed due to the different positions of the nitro group on the cinnamic amide. Moreover, it was found that the chiral sense of the self-assembled nanostructures can be regulated by the solvent whereby helicity inversion was observed. This work provides a simple way to regulate the self-assembly pathway via molecular design and choice of solvent for the controlled creation of chiral nanostructures.

Novel Piperazine Amides of Cinnamic Acid Derivatives as Tyrosinase Inhibitors

Background: A series of novel cinnamic acid piperazine amide derivatives has been designed and synthesized, and their biological activities were also evaluated as potential tyrosinase inhibitors. Methods: Compounds 9, 11 and 17 showed the most potent biological activity (IC50 = 66.5, 61.1 and 66 µM, respectively). In silico docking simulation was performed to position compound 11 into the Agaricus bisporus mushroom tyrosinase’s active site to determine the putative binding interactions. Results and Conclusion: The results indicated that compound 11 could serve as a promising lead compound for further development of potent tyrosinase inhibitors.

Synthesis of cinnamic amide derivatives and their anti-melanogenic effect in α-MSH-stimulated B16F10 melanoma cells

Of the three enzymes that regulate the biosynthesis of melanin, tyrosinase and its related proteins TYRP-1 and TYRP-2, tyrosinase is the most important because of its ability to limit the rate of melanin production in melanocytes. For treating skin pigmentation disorders caused by an excess of melanin, the inhibition of tyrosinase enzyme is by far the most established strategy. Cinnamic acid is a safe natural product with an (E)-β-phenyl-α,β-unsaturated carbonyl motif that we have previously shown to play an important role in high tyrosinase inhibition. Since cinnamic acid is relatively hydrophilic, which hinders its absorption on the skin, fifteen less hydrophilic cinnamic amide derivatives (1–15) were designed as safe and more potent tyrosinase inhibitors and were synthesized through a Horner-Wadsworth-Emmons reaction. The use of conc-HCl and acetic acid for debenzylation of the O-benzyl-protected cinnamic amides 40–54 produced the following three results. 1) Cinnamic amides 43, 48, and 53 with a 2,4-dibenzyloxyphenyl group, irrespective of the amine type of the amides, produced complex compounds with high polarity. 2) Cinnamic amides 40–42, 44, 50–52, and 54 with a benzylamino, or diethylamino group produced the desired debenzylated cinnamic amides 1–3, 5, 10–13, and 15. 3) Cinnamic amides 45–47, and 49 with an anilino moiety provided 3,4-dihydroquinolinones 16–19 through intramolecular Michael addition of the anilide group. Notably, the use of BBr3 as an alternative debenzylating agent for debenzylation of cinnamic amides 45–49 with the anilino moiety provided our desired cinnamic amides 6–10 without inducing the intramolecular Michael addition. Debenzylation of cinnamic amides 43, 48, and 53 with a 2,4-dibenzyloxyphenyl group was also successfully accomplished using BBr3 to give 4, 9, and 14. Among the nine compounds that inhibited mushroom tyrosinase more potently at 25 μM than kojic acid, four cinnamic amides 4, 5, 9, and 14 showed 3-fold greater tyrosinase inhibitory activity than kojic acid. The docking simulation using tyrosinase indicated that these four cinnamic amides (−6.2 to −7.9 kcal/mol) bind to the active site of tyrosinase with stronger binding affinity than kojic acid (−5.7 kcal/mol). All four cinnamic amides inhibited melanogenesis and tyrosinase activity more potently than kojic acid in α-MSH-stimulated B16F10 melanoma cells in a dose-dependent manner without cytotoxicity. The strong correlation between tyrosinase activity and melanin content suggests that the anti-melanogenic effect of cinnamic amides is due to tyrosinase inhibitory activity. Considering that the cinnamic amides 4, 9, and 14, which exhibited strong inhibition on mushroom tyrosinase and potent anti-melanogenic effect in B16F10 cells, commonly have a 2,4-dihydroxyphenyl substituent, the 2,4-dihydroxyphenyl substituent appears to be essential for high anti-melanogenesis. These results support the potential of these four cinnamic amides as novel and potent tyrosinase inhibitors for use as therapeutic agents with safe skin-lightening efficiency.

General Method for the Preparation of Indole-2-Weinreb Amides

Indole-2-Weinreb amides are obtained via thermolysis of α-azidocinnamic acid Weinreb amides in a Hemetsberger–Knittel-type cyclization. The required vinyl azides are not accessible by Knoevenagel condensation, but are obtained by cerium(IV)-mediated oxidative azidation of the corresponding cinnamic Weinreb amides.

In Vitro Anti-Toxoplasma gondii and Antimicrobial Activity of Amides Derived from Cinnamic Acid.

Most cinnamic acids, their esters, amides, aldehydes, and alcohols present several therapeutic actions through anti-inflammatory, antitumor, and inhibitory activity against a great variety of microorganisms. In this work, eight amines derived from cinnamic acid were synthesized and tested against host cells infected with Toxoplasma gondii and the bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and three strains of Staphylococcus aureus. Compounds 3 and 4 showed the best result against intracellular T. gondii, presenting antiparasitic activity at low concentrations (0.38 and 0.77 mM). The antibacterial activity of these compounds was also evaluated by the agar microdilution method, and amides 2 and 5 had a minimum inhibitory concentration of 250 µg mL−1 against two strains of S. aureus (ATCC 25923 and bovine strain LSA 88). These also showed synergistic action along with a variety of antibiotics, demonstrating that amines derived from cinnamic acid have potential as pharmacological agents.

Anti-Helicobacter pylori activities of selected N-substituted cinnamamide derivatives evaluated on reference and clinical bacterial strains.

In this study, thirty-five N-substituted derivatives of cinnamic acid amide (cinnamamide) were evaluated for anti-Helicobacter pylori activity using an agar disc-diffusion method. Qualitative screening was performed on a reference H. pylori strain (ATCC 43504), resulting in the identification of the three most active compounds, 8 (R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide, minimal inhibitory concentration, MIC = 7.5 µg/mL), 23 ((2E)-3-(4-chlorophenyl)-N-(2-hydroxycyclohexyl)prop-2-enamide, MIC = 10 µg/mL), and 28 ((2E)-3-(4-chlorophenyl)-N-(4-oxocyclohexyl)prop-2-enamide, MIC = 10 µg/mL). These compounds were further tested on twelve well-characterized clinical strains, yielding MIC values that ranged from 10 to 1000 µg/mL. Preliminary safety assessments of the compounds were made using the MTT viability test for cytotoxicity and Ames test for mutagenicity, which showed them to be generally safe, although compounds 8 and 28 showed mutagenic activity at some of the tested concentrations. The results of this study showed the anti-H. pylori potential of cinnamamide derivatives.

ChemInform Abstract: Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders — A Review of Structure—Activity Relationships

AbstractReview: 30 refs.

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders--A Review of Structure-Activity Relationships.

The cinnamamide scaffold has been incorporated in to the structure of numerous organic compounds with therapeutic potential. The scaffold enables multiple interactions, such as hydrophobic, dipolar, and hydrogen bonding, with important molecular targets. Additionally, the scaffold has multiple substitution options providing the opportunity to optimize and modify the pharmacological activity of the derivatives. In particular, cinnamamide derivatives have exhibited therapeutic potential in animal models of both central and peripheral nervous system disorders. Some have undergone clinical trials and were introduced on to the pharmaceutical market. The diverse activities observed in the nervous system included anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative properties. Over the last decade, research has focused on the molecular mechanisms of action of these derivatives, and the data reported in the literature include targeting the γ-aminobutyric acid type A (GABAA ) receptors, N-methyl-D-aspartate (NMDA) receptors, transient receptor potential (TRP) cation channels, voltage-gated potassium channels, histone deacetylases (HDACs), prostanoid receptors, opioid receptors, and histamine H3 receptors. Here, the literature data from reports evaluating cinnamic acid amide derivatives for activity in target-based or phenotypic assays, both in vivo and in vitro, relevant to disorders of the central and peripheral nervous systems are analyzed and structure-activity relationships discussed.

ChemInform Abstract: Synthesis of 7‐Arylquinolinones and 6‐Arylindoles from 3‐Aminobiphenyls Through Regioselective Cyclization Reactions.

Abstract 7-Arylquinolinones were obtained in two steps from 3-aminobiphenyls through conversion into cinnamic amides. The highly regioselective cyclization under elimination of anisole proceeded in the presence of phosphoric acid and phosphorous pentoxide. 6-Arylindoles were accessible, although in lower yields, from 3-aminobiphenyls via 3-(biphenylamino)acrylates and palladium-catalyzed cyclization reactions.

UV light-mediated difunctionalization of alkenes through aroyl radical addition/1,4-/1,2-aryl shift cascade reactions.

UV light-mediated difunctionalization of alkenes through an aroyl radical addition/1,4-/1,2-aryl shift has been described. The resulted aroyl radical from a photocleavage reaction added to acrylamide compounds followed by cyclization led to the formation of oxindoles, whereas the addition to cinnamic amides aroused a unique 1,4-aryl shift reaction. Furthermore, the difunctionalization of alkenes of prop-2-en-1-ols was also achieved through aroyl radical addition and a sequential 1,2-aryl shift cascade reaction.

Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity.

Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC) of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships.