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Cinnamic Acids Hybrids with Biological Interest

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 October 2014) | Viewed by 62864

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Special Issue Editor

Prof. Dr. Dimitra Hadjipavlou-Litina

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Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: synthesis and biological studies on anti-inflammatory and antioxidant agents, on inhibitors of enzymes implicated in the inflammation and in the coagulation process in general; correlation of inflammation with cancer; neurodegeneration; antioxidant activity; theoretical and experimental calculation of physicochemical parameters implicated in biological response; use of computational chemistry in drug design as well as bioactive compounds of natural origin, e.g., essential oils
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Dear Colleagues,

Cinnamic acid derivatives from natural and synthetic sources have attracted much attention due to their significant biological activities (e.g., antioxidant, antitumor, antimicrobial activities). Recently, intensive research has been conducted on cinnamic acid hybrids, with the goal of creating new polyfunctional drugs based on them. Piplartin, an alkaloid and a trans-cinnamic acid derivative, which is isolated from Piper tuberculatum, has been shown to have antitumor and antiproliferative properties. A whole series of drugs has been created on the basis of cinnamic acid presenting antiallergic activity (e.g., Cinnarizine, Cinanserin, Tranilast).

Molecular hybridization consists of a molecular modification approach to obtain multifunctional ligands and drugs with better pharmacokinetic properties and the concomitant administration of two different agents. The design principle is aimed at combining the synergistic property of cinnamic acid with the sequestering activity of other biologically active chemical entities or molecules, so as to get compounds with better activities.

In this issue, we will present a number of several cinnamic hybrids, their syntheses, and biological evaluation, as well as reviews in related subjects.

Prof. D. Hadjipavlou-Litina
Guest Editor

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Keywords

cinnamic acids
caffeic acid
inflammation
antioxidant activity
anticancer
conjugates
adducts
hybrids
multitarget

Published Papers (6 papers)

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Research

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866 KiB

Open AccessArticle

Synthesis and Antioxidant Activity of Polyhydroxylated trans-Restricted 2-Arylcinnamic Acids

by Mitko Miliovsky, Ivan Svinyarov, Elena Prokopova, Daniela Batovska, Simeon Stoyanov and Milen G. Bogdanov

Molecules 2015, 20(2), 2555-2575; https://doi.org/10.3390/molecules20022555 - 02 Feb 2015

Cited by 10 | Viewed by 6282

Abstract

A series of sixteen polyhydroxylated trans-restricted 2-arylcinnamic acid analogues 3a–p were synthesized through a one-pot reaction between homophthalic anhydrides and various aromatic aldehydes, followed by treatment with BBr₃. The structure of the newly synthesized compounds was confirmed by spectroscopic methods and the configuration around the double bond was unequivocally estimated by means of gated decoupling ¹³C-NMR spectra. It was shown that the trans-cinnamic acid fragment incorporated into the target compounds’ structure ensures the cis-configuration of the stilbene backbone and prevents further isomerization along the carbon–carbon double bond. The antioxidant activity of compounds 3a–p was measured against 1,1-diphenyl-2-picrylhydrazyl (DPPH^●), hydroxyl (OH^●) and superoxide (O₂^●^▬) radicals. The results obtained showed that the tested compounds possess higher activities than natural antioxidants such as protocatechuic acid, caffeic acid and gallic acid. Moreover, it was shown that a combination of two different and independently acting fragments of well-known pharmacological profiles into one covalently bonded hybrid molecule evoke a synergistic effect resulting in higher than expected activity. To rationalize the apparent antioxidant activity and to establish the mechanism of action, a SAR analysis and DFT quantum chemical computations were also performed. Full article

(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)

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697 KiB

Open AccessArticle

Antiprotozoal Activity of (E)-Cinnamic N-Acylhydrazone Derivatives

by Samir Aquino Carvalho, Marcel Kaiser, Reto Brun, Edson Ferreira da Silva and Carlos Alberto Manssour Fraga

Molecules 2014, 19(12), 20374-20381; https://doi.org/10.3390/molecules191220374 - 05 Dec 2014

Cited by 15 | Viewed by 6070

Abstract

A series of 14 (E)-cinnamic N-acylhydrazone derivatives, designed through molecular hybridization between the (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide, were tested for in vitro antiparasitic activity upon axenic amastigote forms of Leishmania donovani and bloodstream forms of Trypamosoma brucei rhodesiense. The derivative (2E)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N'-[(1E)-phenylmethylene]acrylohydrazide showed moderate antileishmanial activity (IC₅₀ = 6.27 µM) when compared to miltefosine, the reference drug (IC₅₀ = 0.348 µM). However, the elected compound showed an excellent selectivity index; in one case it was not cytotoxic against mammalian L-6 cells. The most active antitrypanosomal compound, the derivative (E)-N'-(3,4-dihydroxybenzylidene)cinnamohydrazide (IC₅₀ = 1.93 µM), was cytotoxic against mammalian L-6 cells. Full article

(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)

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3855 KiB

Open AccessArticle

Multitarget Molecular Hybrids of Cinnamic Acids

by Aikaterini Peperidou, Dorothea Kapoukranidou, Christos Kontogiorgis and Dimitra Hadjipavlou-Litina

Molecules 2014, 19(12), 20197-20226; https://doi.org/10.3390/molecules191220197 - 02 Dec 2014

Cited by 31 | Viewed by 7636

Abstract

In an attempt to synthesize potential new multitarget agents, 11 novel hybrids incorporating cinnamic acids and paracetamol, 4-/7-hydroxycoumarin, benzocaine, p-aminophenol and m-aminophenol were synthesized. Three hybrids—2e, 2a, 2g—and 3b were found to be multifunctional agents. The hybrid 2e derived from the phenoxyphenyl cinnamic acid and m-acetamidophenol showed the highest lipoxygenase (LOX) inhibition and analgesic activity (IC₅₀ = 0.34 μΜ and 98.1%, whereas the hybrid 3b of bromobenzyloxycinnamic acid and hymechromone exhibited simultaneously good LOX inhibitory activity (IC₅₀ = 50 μΜ) and the highest anti-proteolytic activity (IC₅₀= 5 μΜ). The hybrid 2a of phenyloxyphenyl acid with paracetamol showed a high analgesic activity (91%) and appears to be a promising agent for treating peripheral nerve injuries. Hybrid 2g which has an ester and an amide bond presents an interesting combination of anti-LOX and anti-proteolytic activity. The esters were found very potent and especially those derived from paracetamol and m-acetamidophenol. The amides follow. Based on 2D-structure–activity relationships it was observed that both steric and electronic parameters play major roles in the activity of these compounds. Molecular docking studies point to the fact that allosteric interactions might govern the LOX-inhibitor binding. Full article

(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)

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2539 KiB

Open AccessArticle

Effect of Chlorogenic Acid on Melanogenesis of B16 Melanoma Cells

by Hao-Rong Li, Maidina Habasi, Lian-Zhen Xie and Haji Akber Aisa

Molecules 2014, 19(9), 12940-12948; https://doi.org/10.3390/molecules190912940 - 25 Aug 2014

Cited by 90 | Viewed by 8975

Abstract

Chlorogenic acid (CGA), the ester formed between caffeic acid and l-quinic acid, is a widespread phenolic compound. It is part of the human diet, found in foods such as coffee, apples, pears, etc. CGA is also was widely used in cosmetics, but the effects of CGA on melanogenesis are unknown. In this study, we analyzed the effects of CGA on cell proliferation, melanin content and tyrosinase of B16 murine melanoma cells. Additionally, the enzymatic reactions of CGA in B16 melanoma cells lytic solution were detected by UV spectrophotometry. Results showed CGA at 30 and 60 μM significantly suppresses cell proliferation. 8-MOP at 100 μM significantly promotes cell proliferation, but CGA can counter this. Incubated for 24 h, CGA (500 μM) improves melanogenesis while suppressing tyrosinase activity in B16 melanoma cells or 8-methoxypsoralen (8-MOP) co-incubated B16 melanoma cells. After 12 h, B16 melanoma cell treatment with CGA leads to an increase in melanin accumulation, however, after 48 h there is a decrease in melanin production which correlates broadly with a decrease in tyrosinase activity. CGA incubated with lytic solution 24 h turned brown at 37 °C. The formation of new products (with a maximum absorption at 295 nm) is associated with reduction of CGA (maximum absorption at 326 nm). Therefore, CGA has its two sidesroles in melanogenesis of B16 melanoma cells. CGA is a likely a substrate of melanin, but the metabolic product(s) of CGA may suppress melanogenesis in B16 melanoma cells by inhibiting tyrosinase activity. Full article

(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)

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Review

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4070 KiB

Open AccessReview

Bioinspired Syntheses of Dimeric Hydroxycinnamic Acids (Lignans) and Hybrids, Using Phenol Oxidative Coupling as Key Reaction, and Medicinal Significance Thereof

by George E. Magoulas and Dionissios Papaioannou

Molecules 2014, 19(12), 19769-19835; https://doi.org/10.3390/molecules191219769 - 28 Nov 2014

Cited by 24 | Viewed by 13038

Abstract

Lignans are mainly dimers of 4-hydroxycinnamic acids (HCAs) and reduced analogs thereof which are produced in Nature through phenol oxidative coupling (POC) as the primary C-C or C-O bond-forming reaction under the action of the enzymes peroxidases and laccases. They present a large structural variety and particularly interesting biological activities, therefore, significant efforts has been devoted to the development of efficient methodologies for the synthesis of lignans isolated from natural sources, analogs and hybrids with other biologically interesting small molecules. We summarize in the present review those methods which mimic Nature for the assembly of the most common lignan skeleta by using either enzymes or one-electron inorganic oxidants to effect POC of HCAs and derivatives, such as esters and amides, or cross-POC of pairs of HCAs or HCAs with 4-hydrocycinnamyl alcohols. We, furthermore, provide outlines of mechanistic schemes accounting for the formation of the coupled products and, where applicable, indicate their potential application in medicine. Full article

(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)

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466 KiB

Open AccessReview

Natural Cinnamic Acids, Synthetic Derivatives and Hybrids with Antimicrobial Activity

by Juan David Guzman

Molecules 2014, 19(12), 19292-19349; https://doi.org/10.3390/molecules191219292 - 25 Nov 2014

Cited by 283 | Viewed by 19640

Abstract

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. Full article

(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)

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