CoumarinâChalcone Hybrids as Peroxyl Radical Scavengers

Subscriber access provided by CITY UNIV LIB

Article

Coumarin-Chalcone Hybrids as Peroxyl Radical Scavengers: Kinetics and Mechanisms Gloria Mazzone, Annia Galano, Juan Raul Alvarez-Idaboy, and Nino Russo J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.6b00006 • Publication Date (Web): 21 Mar 2016 Downloaded from http://pubs.acs.org on March 23, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of Chemical Information and Modeling is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Chemical Information and Modeling

Coumarin-Chalcone Hybrids as Peroxyl Radical Scavengers: Kinetics and Mechanisms Gloria Mazzone,*a Annia Galano,*b Juan R. Alvarez-Idaboyc and Nino Russoa. a

Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, I-87036

Arcavacata di Rende, Italy b

Departamento de Química. Universidad Autónoma Metropolitana-Iztapalapa. San Rafael

Atlixco 186, Col. Vicentina. Iztapalapa. C. P. 09340. México D. F. México. c

Departamento de Física y Química Teórica, Facultad de Química, Universidad Nacional

Autónoma de México, México DF 04510, México.

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

ABSTRACT

The primary antioxidant activity of coumarin-chalcone hybrids have been investigated using the density functional and the conventional transition state theories. Their peroxyl radical scavenging ability was studied in solvents of different polarity and taking into account different reaction mechanisms. It was found that the activity of the hybrids increases with the polarity of the environment and the number of phenolic sites. In addition their peroxyl radical scavenging activity is larger than those of the corresponding non-hybrid coumarin and chalcone molecules. This finding is in line with previous experimental evidence. All the investigated molecules were found to react faster than Trolox with •OOH, regardless of the polarity of the environment. The role of deprotonation on the overall activity of the studied compounds was assessed. The rate constants and branching ratios for the reactions of all the studied compounds with •OOH are reported for the first time.

1. INTRODUCTION Free radicals (FR) are highly reactive chemical species that can be either harmful or beneficial to living systems, depending on their concentration. When there is an imbalance between their production and consumption, leading to an excess of FR, oxidative stress (OS) arises. It is considered a chemical stress, which has been associated with the onset and development of a large number of health disorders, including pulmonary,1-3 renal,4-6 and ocular7-9 diseases; rheumatoid arthritis,10-12 fetal growth restriction and pre-eclampsia.13-15 It has also been established that OS is responsible, at least partially, for cancer development16-18 and several neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, memory loss, and depression.19-25 Consequently, searching for efficient free radical scavengers,


2

Page 3 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


that can inhibit OS, has become an active area of research. Polyphenols are one of the most prominent families of compounds in this context. Chalcones (1,3-diphenyl-2-propen-1-ones) and coumarins (2H-1-benzopyran-2-ones), Scheme 1, are among the polyphenols with well documented benefits to human health. In addition to be considered as the precursors of flavonoids and isoflavonoids, chalcones and their derivatives exhibit antimicrobial,26-29 anti-bacterial,30 antifungal,31 anti-inflammatory,32-34 anti-cancer,33,35-40 antioxidant,26-28,33,38,41-47 and free radical scavenging48 properties. On the other hand, cumarins also possess a wide spectrum of biological activities due to their antiviral,49 antibacterial,50 antifungal,51

anti-inflammatory,52,53

analgesic,54

anticoagulant,55

antitumoral,56-58

neuroprotective,59,60 free radical scavenging,61,62 and antioxidant52,63-73 effects. Along with the natural sources of chalcones and coumarins there are abundant synthetic routes that have been developed while searching for compounds with enhanced properties. The coumarin-chalcone hybrids (Scheme 1) seems to be particularly promising candidates for free radical scavenging and antioxidant activities, which are believed to be responsible for many of the benefits provided by these two families of compounds. Sashidhara et al.74 obtained and tested the in vitro cytotoxicity of several coumarin-chalcone hybrids. Based on their findings they proposed some of them as potent anticancer agents. Hamdi et al.75 synthesized a series of coumarin derivatives containing a chalcone moiety with significant antibacterial and free radical scavenging activities. Another series of coumarin-chalcone hybrids was obtained by Perez-Cruz el al.,76 which found that these compounds exhibit great antioxidant activity, higher than those of other well-known antioxidant such as quercetin and catechin. In addition, it was observed that the free radicals (•CH3, •OH, O2•−) scavenging activity is related to the number and position of hydroxyl substituents, in particular to the presence of catechol moieties, which increases the


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 26

antioxidant capacity. These results are in line with those reported by Vazquez-Rodriguez et al.77 More recently, Xi and Liu78 found that the coumarin moiety can enhance the abilities of chalcones to scavenge radicals and to inhibit DNA oxidation. The relevance of the hydroxyl groups for such activities was confirmed. Thus, considering the gathered data altogether it can be anticipated that coumarin-chalcone hybrids are potential candidates for inhibiting the free radicals overproduction in oxidative stress related diseases.

Scheme 1. Basic structures of coumarins, chalcones, and coumarin-chalcone hybrids.

However, further studies are still needed. For example there is no kinetic data reported on the chemical reactions involved in the free radical scavenging activity of these newly developed hybrids. More detailed studies on the main reaction mechanisms involved are also desirable, since they would allow to anticipate the main products yielded in such processes. In addition, the influence of the environment (polarity of the solvent, pH in aqueous solution, etc.) has not been assessed yet. Accordingly, it is the main goal of the present study to provide quantitative information on those aspects. In addition, the antioxidant behavior of the studied coumarinchalcone hybrids was compared with those of their equivalent non-hybrid parents.


4

Page 5 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2. COMPUTATIONAL DETAILS All the electronic calculations were performed with Gaussian 09 package of programs.79 Geometry optimizations and frequency calculations were carried out at the M05-2X/6-31+G(d,p) level of theory. The continuum solvation model based on density (SMD)80 was used in all the calculations. Pentyl ethanoate and water were chosen as solvents to mimic lipid and aqueous environments, respectively. The M05-2X functional has been recommended for kinetic calculations by its developers,81 and its reliability has been independently confirmed by other authors.82-92 It is among the best performing functionals for kinetic calculations in solution,93 and for calculating reaction energies involving free radicals.94 SMD was chosen for mimicking the solvent effects because it can be consistently used for any charged or uncharged solute in any solvent or liquid medium.80 Local minima and transition states were identified by the number of imaginary frequencies (0 or 1, respectively). In the case of the transition states, intrinsic reaction coordinate calculations (IRC) were performed to verify that the imaginary frequency corresponds to the proper motion along the reaction coordinate. Unrestricted calculations were used for open shell systems. Thermodynamic corrections at 298.15 K were included in the calculation of relative energies. The rate constants (k) were calculated using the conventional transition state theory (TST)95-97 and 1M standard state. The used computational protocol is in line with the quantum mechanics based test for overall free radical scavenging activity (QM-ORSA),98 which has been validated by comparison with experimental results. It is a reliable protocol for kinetics with uncertainties that have been proven to be no larger than those arising from experiments.98


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 26

3. RESULTS AND DISCUSSION Two coumarin-chalcone hybrids have been chosen for this investigation (Scheme 2). One of them (Hyb4) was proposed by Vazquez-Rodriguez et al.77 as a potential candidate for further studies on antioxidant activity. The other one (Hyb9) has not been synthesized yet, but based on a previous theoretical study it was identified as one of the most promising options in this context.99 The acronyms have been chosen to be coherent with previous works. In addition the pure coumarine and chalcone (non-hybrid) parent molecules of Hyb9 have also been included in this study (Scheme 3) to help quantifying the enhancement of the hybrid properties.

Scheme 2. Structures and numbering of the coumarin-chalcone hybrids studied in this work.

Scheme 3. Structures and numbering of pure coumarin and chalcone (non-hybrid) parent molecules of Hyb9.


6

Page 7 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


As it is the case for many phenolic compounds, those studied here present acid-base equilibria, which might influence their properties. However, to our best knowledge their pKas have not been previously reported. Thus, the first pKa value for each of the studied compounds have been estimated in this work. To that purpose the isodesmic method, also known as the proton exchange method, or the relative method,100,101 was used. It is based on the following reaction scheme:

HA + Ref − ↔ A− + HRef where HRef-Ref- is the acid-base pair of a reference compound, which should be as structurally similar as possible to the system of interest, and its experimental pKa should be known. In the present case we have chosen HRef = 4,7-dihydroxycoumarin (pKa1=4.74).102 Within this approach the pKa is calculated as: pKa ( HA ) =

∆ Gs + pKa ( HRef ) RT ln (10 )

pKa calculations still represent a significant challenge to computations.103-107 The difficulties are numerous and involve the way in which solvent effects are modeled, as well as the fact that errors arising from calculations are typically larger for ionic than for non-charged species. Therefore the most significant errors do not always cancel out when energies of reactions are calculated. One of the advantage in using the isodesmic method is that it maximizes error cancelation, thus overcoming this last difficulty. The values obtained that way are reported in Table 1, together with the molar fractions of the neutral and mono-anionic species at physiological pH (pH=7.4). As the values in the table show, the dominant form of both Hyb4 and Hyb9 at the pH of interest is the mono-anion; while for Cum9 and Chl9 the neutral form prevails. However, for all the studied molecules significant


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 26

population of neutral and anionic species are expected at pH=7.4. Therefore both kind of species have been included when modeling reactions in aqueous solution. In addition, there are several sites from which deprotonation can occur to yield the mono-anions. Therefore, the most likely deprotonation site was investigated by comparing the energies of the possible monoanions. Site 5a was identified as the site with the lowest deprotonation energy, thus the corresponding monoanions are those used in this work.

Table 1. First pKa values and molar fraction of the neutral (Mfneutral) and anionic (Mfanion) species, at pH=7.4 Hyb4 Hyb9 Cum9 Chl9

pKa1 6.8 6.4 7.7 8.0

M

fneutral 0.205 0.086 0.651 0.801

M

fanion 0.795 0.914 0.349 0.199

To explore the free radical scavenging activity of the studied compounds, the hydroperoxyl radical (•OOH) have been chosen. There are several reasons for this choice. Peroxyl radicals (ROO•) are among those of biological relevance that can be successfully scavenged to retard OS.108 This is because their half-lives are long enough to assure that they can be efficiently intercepted by phenolic compounds.109 Within the context of oxidative stress, ROO• are among the most important reaction partners for phenolic compounds.109 In fact, it has been suggested that the key antioxidant function of phenols is just to deactivate peroxyl radicals.110,111 ROO• radicals have low to moderate reactivity, which is considered as a desirable characteristic for studying trends in free radical scavenging activities.112,113 Highly reactive radicals are typically involved in reactions with diffusion-limited rates, thus using the kinetic data from these reactions as the comparative criterion might lead to miss-conclude that all the studied compounds have


8

Page 9 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


similar antioxidant capacity. •OOH is the smallest member of the peroxyl family, and it has been proposed to plays an essential role in the toxic side effects associated with aerobic respiration.114 In the same work it was also pointed out that more information is still needed on the reactivity of this particular radical. There are several possible reaction mechanisms that may be involved in the free radical scavenging activity of phenolic compounds. They are: -

Single electron transfer (SET): HnHyb + •OOH → HnHyb +• + −OOH

-

Sequential proton loss electron transfer (SPLET): HnHyb → Hn-1Hyb− + H+ Hn-1Hyb− + •OOH → Hn-1Hyb• + −OOH

-

Hydrogen transfer (HT): HnHyb + •OOH → Hn-1Hyb• + HOOH

-

Radical adduct formation (RAF): HnHyb + •OOH → [HnHyb-OOH]•

3. 1 Coumarin-Chalcone Hybrids. All the HT and RAF reaction sites were included in the investigation of the hybrids, and it was found that most of the RAF pathways are thermochemically unfeasible (Table 2). The only exceptions to that trend are RAF reactions at sites 4 and 9 in the anion of Hyb9. On the contrary, most of the HT pathways were found to be exergonic, with the largest exergonicity systematically corresponding to phenolic sites. Regarding the electron transfer mechanisms, they are unlikely to take place from the neutral molecules, regardless of the polarity of the environment. On the other hand when the electron


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 26

donor species is a phenolate ion the endergonicity of the reaction significantly decreases, especially for Hyb9. Therefore, the SPLET mechanism may become relevant, depending on the pH. It was found that the thermochemical viability of the reactions of •OOH is systematically higher for Hyb9 than for Hyb4, i.e., regardless of the reaction pathway, the solvent and the reacting species (neutral or anionic). In addition, the number of viable reaction pathways is larger for Hyb9 than for Hyb4. The largest exothermicity corresponds to different HT sites for both hybrids. For Hyb9 it corresponds to site 5a for the neutral species in both water and lipid solutions (-13.3 and -13.1 kcal/mol, respectively), and for site 8a for the anion in aqueous solution (-20.8 kcal/mol). On the other hand, for Hyb4 the two viable reaction paths have similar exergonicities (ranging from -1.9 to -1.0 kcal/mol) regardless of the solvent, and of the reacting species. All these findings indicate that Hyb9 should be a better peroxyl scavenger than Hyb4.

Table 2. Gibbs free energies of reaction (∆G, kcal/mol), computed at 298.15 K for coumarinchalcone hybrids, Hyb9 and Hyb4. (a)

SET (c) HT 3’a HT 4’a HT 5a HT 6a HT 7a HT 8a RAF 3 RAF 4 RAF 5 RAF 6 RAF 7 RAF 8 RAF 9

PE 72.9 -5.2 -4.8 -13.3 -9.5 2.2 -2.5 6.8 5.8 2.0 12.0 7.7 10.6 4.8

Hyb9 Wneutral(b) Wanion(b) 26.6 2.3 -2.7 -6.9 -2.9 -11.3 -13.1 -4.7 -15.8 0.6 -0.7 -5.8 -20.8 10.6 9.8 8.4 -12.2 1.7 2.8 10.6 1.6 5.4 3.9 9.8 2.9 3.8 -5.3

(a)

PE 77.1 -1.9 -1.9 5.0

Hyb4 Wneutral(b) Wanion(b) 35.6 17.3 -1.8 -1.5 -1.0 -1.5 4.6

6.6

6.5

3.6

9.9 11.5 13.1 17.5 14.2 17.6 17.2

12.6 11.1 12.6 11.1 12.2 16.6 13.1

20.1 9.7 17.9 11.3 17.0 11.6 7.5


10

Page 11 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


RAF 10 RAF 1’ RAF 2’ RAF 3’ RAF 4’ RAF 5’ RAF 6’ (a) (c)

2.9 20.2 13.2 11.8 9.9 17.0 14.3

3.6 21.4 10.1 12.3 8.4 17.2 11.8

2.7 19.3 10.3 10.8 8.0 15.2 11.1

26.5 20.4 16.1 11.9 10.8 17.8 12.1

15.6 15.5 26.7 20.7 14.5 11.3 8.8

23.6 20.1 14.2 11.2 9.1 17.0 12.2

PE = pentyl ethanoate (lipid) solution; (b) W = water (aqueous) solution; SET from the anion = SPLET

Kinetic calculations were performed only for the exergonic reaction pathways. The endergonic ones were not included in this part of the study because they would be reversible to a significant extent, and consequently the corresponding products will not be experimentally observed. On the other hand, when products evolve into other species through fast enough reactions, endergonic processes might still represent significant reaction pathways. This would be especially important when such reactions are significantly exergonic and have rather low reaction barriers. The SPLET mechanism, is expected to fulfill these requirements, since the yielded products frequently are highly reactive radicals. Therefore this mechanism has also been included in the kinetic analyses. The Cartesian coordinates of the fully optimized geometries of the transition states (TS) are provided as Supporting Information. The imaginary frequencies of the TS, the reaction barriers, and the tunneling corrections used in the calculations of each rate constant are reported in Tables S1 to S3 (Supporting Information). The rate constants for each reaction pathway, together with the total rate coefficients (ktotal) for each reacting species, and the overall rate coefficients (koverall) for the reactions in each solvent are reported in Table 3. The ktotal and koverall values are identical in lipid solution, since there is only one possible reacting species, the neutral one. They were calculated as the sum of the rate constants of each individual pathway. In aqueous solution, on


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 26

the other hand, the ktotal values for the neutral and the anionic species were obtained, separately, also by summing up the rate coefficient corresponding at the viable pathway for each of them. To calculate koverall in aqueous solution, the molar fractions of the different acid-base species, at the pH of interest (physiological pH, 7.4) were taking into account: n PE koverall = ktotPEal = ∑ kiHX

(1)

i =1

n W , HX ktot = ∑ kiHX al

(2)

i =1

−

n

ktoWtal, X = ∑ kiX

−

(3)

i =1

W , pH = 7.4 koverall =

M

pH = 7.4 W , HX M f( HX ) ktotal + f

pH = 7.4

(X ) −

W ,X ktota l

−

(4),

where HX and X− represent the neutral and anionic forms of the investigated compounds, PE = pentyl ethanoate, and W = aqueous solution. It was found that Hyb9 reacts about 3 and 5 orders of magnitude faster than Hyb4 in lipid, and water solutions, respectively. Thus, the kinetic data confirms that Hyb9 should be a much better peroxyl radical scavenger than Hyb4, regardless of the polarity of the environment. This finding agrees with previous evidence suggesting that the number and position of hydroxyl substituents in coumarin-chalcones hybrids, in particular the presence of catechol moieties, is directly related to their scavenging ability towards free radicals O2•−, •CH3, and •OH.76,77 On the other hand the polarity of the solvent has opposite effects on the reactivity of the studied coumarin-chalcone hybrids. While the peroxyl scavenging activity of Hyb9 is increased by the polarity of the environment, being about 60 times faster in aqueous than in lipid solution; Hyb4 reacts about 3 times faster in the non-polar media than in water. Another difference in the


12

Page 13 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


reactivity of these hybrids is related to the acid-base species. In aqueous solution, the total rate constants for the neutral and the anionic species of Hyb4 are very similar, while for Hyb9 the anion reacts about 1340 times faster than the non-deprotonated molecule. Accordingly, it is expected that the pH increases the reactivity of Hyb9 but has almost no effect on the reactivity of Hyb4. Compared to Trolox, which is frequently used as a reference antioxidant, both hybrids are predicted to be more efficient for scavenging peroxyl radicals in lipid media. Their reactions with •OOH were found to be about 2.8×104 and 1.5 times faster than that of Trolox for Hyb9 and Hyb4, respectively. In aqueous solution, on the other hand, Hyb9 reacts 6.7×104 times faster than Trolox, while the reaction of Hyb4 becomes about 4.5 times slower than that of the reference compound.

Table 3. Rate constants of each individual pathway and overall rate coefficients (M-1 s-1), computed at 298.15 K for coumarin-chalcone hybrids, Hyb9 and Hyb4.

PE

(a)

Hyb9 Wneutral(b)

(c)

SET HT 3’a HT 4’a HT 5a HT 6a HT 7a HT 8a RAF 4 RAF 9 Total Overall (a) (c)

1.95E+05 6.17E+04 8.04E+07 1.50E+07 9.65E+03

9.56E+07 9.56E+07

4.57E+03 1.15E+03 3.41E+06 1.05E+06 4.38E+00 3.87E+05

4.85E+06

(b)

PE

(a)

Hyb4 Wneutral(b)

Wanion 3.85E+08 2.68E+04 6.10E+04

2.24E+04 1.90E+04

1.26E+04 2.91E+03

2.79E+09 8.54E+01 2.79E+09 2.07E+07 4.96E+08 6.49E+09 5.98E+09

4.14E+04 4.14E+04

1.55E+04

Wanion(b) 1.20E+00 1.09E+04 3.46E+03

1.43E+04 1.45E+04



13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 26

Regarding the reactivity of the different reaction sites, it was found that the fastest pathways for neutral Hyb9 and Hyb4 are in ring A and C, respectively. In addition, while the SPLET mechanism is also very fast for Hyb9 it is very slow for Hyb4. To analyze in more detail the contributions of the different mechanisms and reaction pathways to the overall HOO• scavenging activity of the studied compounds, the corresponding branching ratios (Γ) have been estimated according to: Γ iPE =

ki

× 100

(5)

f i pH = 7.4 ki × 100 W ,pH = 7.4 koverall

(6),

koverall M

ΓWi ,pH =7.4 =

where i represents each individual reaction pathway. The values obtained that way are reported in Table 4. It was found that in lipid solution the most important pathway for Hyb9 corresponds to the HT reaction from site 5a (84.0 %), while the contributions from site 6a are much smaller (15.7%) but not negligible. All the other possible reaction pathways are unimportant. For Hyb4, on the other hand both sites 3’a and 4’a have large contributions to the overall reactivity, albeit that of site 3’a is the largest one.

Table 4. Branching ratios (%),computed at 298.15 K for coumarin-chalcone hybrids, Hyb9 and Hyb4.

PE SET (c) HT 3’a HT 4’a HT 5a HT 6a

(a)

0.2 0.1 84.0 15.7

Hyb9 Wneutral(b) ~0.0 ~0.0 ~0.0 ~0.0

Wanion

(b)

5.9 ~0.0 ~0.0

PE

(a)

54.2 45.8

Hyb4 Wneutral(b)

Wanion(b)

15.49 3.59

0.01 61.36 19.56

43.0


14

Page 15 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


HT 7a HT 8a RAF 4 RAF 9

~0.0

(a) (c)

~0.0 ~0.0

~0.0 43.0 0.3 7.6


In aqueous solution, at pH=7.4, the differences between Hyb9 and Hyb4 are even more dramatic. For example, the only acid-base species contributing to the overall reactivity of Hyb9 under such conditions is the anion, while for Hyb4 the contributions from the neutral species is about 19%. The SPLET pathway contributes about 6% to the overall reactivity of Hyb9, while its importance is almost negligible for Hyb4. The reaction pathways contributing the most to the overall peroxyl scavenging activity of Hyb9 are the HT from sites 6a and 8a in the anion, while for Hyb9 HT from site 3’a is the main reaction channel. Albeit all these differences, what remains common for both hybrids is that the anion seems to be the key species regarding the peroxyl radical scavenging activity. Therefore the main reaction mechanism can be classified as sequential proton loss hydrogen atom transfer (SPLHAT), following the name proposed by Estevez et al.110

3. 2 Comparison with non-hybrid analogs. In order to assess how much influence the hybrid structure has on the reactivity of coumarin-chalcone species, the free radical scavenging activity of Hyb9 has been compared with those of its equivalent non-hybrid parents (Scheme 3). Hyb9 was chosen to this purpose, instead of Hyb4 due to its higher activity. The investigated reaction pathways are those previously identified as viable for Hyb9. Albeit this analysis would be mainly based on kinetic considerations, in particular on the calculated rate constants and coefficients, the Gibbs free energies of reaction, the cartesian coordinates and the imaginary


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 26

frequencies of the TS, the reaction barriers, and the tunneling corrections are provided as Supporting Information (Tables S4 to S7). The values of the rate constants for Cum9 and Chl9 reported in Table 5, show that both nonhybrid molecules react with peroxyl radicals faster than Trolox in both polar and non-polar environments. Our results also indicate that Hyb9 reacts faster with •OOH than any of the nonhybrid parent molecules. That is the case regardless of the polarity of the environment. In lipid media Hyb9 reacts 8.5 and 25.6 times faster than Cum9 and Chl9; and in aqueous solution these ratios become equal to 1.9. These results are in line with the findings of Xi and Liu78 that the abilities of chalcones to scavenge radicals can be enhanced by the coumarin moiety.

Table 5. Rate constants of each individual pathway and overall rate coefficients (M-1 s-1), at 298.15 K.

PE SET (c) HT 3’a HT 4’a HT 5a HT 6a HT 7a HT 8a RAF 4 RAF 9 Total Overall, pH=7.4

(a)

7.62E+06 3.63E+06

Cum9 Wneutral(b)

1.06E+04

6.09E+06 5.44E+05 2.35E+00 2.70E+05

1.13E+07

6.91E+06

1.13E+07

(b)

Wanion 2.79E+09

PE

(a)

2.79E+09 4.88E+06 1.15E+07 8.39E+09

2.36E+04

3.47E+04 9.04E+03 1.56E+07 1.67E+06 2.81E+01 3.24E+05

3.73E+06

1.76E+07

3.11E+09

3.73E+06

2.79E+09

5.31E+04 1.31E+04 2.28E+06 1.36E+06

Chl9 Wneutral(b)

(a)

PE = pentyl ethanoate (lipid) solution; (b) W = water (aqueous) solution;

(c)

SET from the anion = SPLET

Wanion(b) 3.35E+09 2.79E+09 2.79E+09 2.79E+09 2.06E+01 2.79E+09 8.68E+05 4.42E+06 1.45E+10 3.12E+09

Regarding the reactivity of their sites, the main reaction channel corresponds to HT from site 5a for both Cum9 and Chl9 (Table S8). This trend remains the same in both investigated


16

Page 17 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


solvents. In addition, contrary to what was found for Hyb9, for the non-hybrid molecules the neutral species are more reactive towards peroxyl radicals than the corresponding anions.

4. CONCLUSIONS Two coumarin-chalcone hybrids were investigated, namely Hyb9 and Hyb4. It was found that Hyb9 is a much better peroxyl radical scavenger than Hyb4, regardless of the polarity of the environment. This finding supports the hypothesis that the activity of these kind of compounds is influenced by the number and position of phenolic groups. Different reaction mechanisms were investigated and it was found that the largest contributions to the overall peroxyl radical scavenging activity of the studied compounds is the H transfer in lipid media, and the sequential proton loss hydrogen atom transfer (SPLHAT) in aqueous solution. Compared to Trolox, both hybrids are predicted to be more efficient for scavenging peroxyl radicals in lipid media. In aqueous solution, on the other hand, only Hyb9 reacts faster than Trolox. Accordingly, the solvent polarity is predicted to significantly affect the primary antioxidant activity of the investigated compounds. It influences the overall reactivity, the dominant reaction mechanism and also the product distribution for the reactions of the studied compounds with peroxyl radicals. In addition, it was found that Hyb9 reacts twice faster than the corresponding non-hybrid coumarin and chalcone parent molecules in lipid solution, while in aqueous solution this ratio increases several times.


17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 26

ASSOCIATED CONTENT

Supporting Information Gibbs free energies of activation. Imaginary frequencies. Tunneling corrections. Branching ratios. Cartesian coordinates of the optimized geometries of the transition states. This material is available free of charge via the Internet at http://pubs.acs.org

AUTHOR INFORMATION

Corresponding Author * Gloria Mazzone, [email protected]; Annia Galano, [email protected].

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT We gratefully acknowledge the Laboratorio de Visualización y Cómputo Paralelo at Universidad Autónoma Metropolitana-Iztapalapa and DGTIC, UNAM for computing time. This work was partially supported by projects SEP-CONACyT 167491 and 167430, DGAPA PAPIIT- IN220215, the Università della Calabria and FP7-PEOPLE-2011-IRSES, Project no. 295172.

REFERENCES (1)

Shadab, M.; Agrawal, D. K.; Aslam, M.; Islam, N.; Ahmad, Z. Occupational Health Hazards Among Sewage Workers: Oxidative Stress and Deranged Lung Functions. J. Clin. Diagnostic Res. 2014, 8, BC11-BC13.


18

Page 19 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(2)

(3)

(4) (5) (6)

(7)

(8)

(9) (10)

(11)

(12)

(13) (14) (15)

(16)

(17)

Zhao, W.; Gan, X.; Su, G.; Wanling, G.; Li, S.; Hei, Z.; Yang, C.; Wang, H. The Interaction Between Oxidative Stress and Mast Cell Activation Plays a Role in Acute Lung Injuries Induced by Intestinal Ischemia-Reperfusion. J. Surg. Res. 2014, 187, 542-552. Ghasemzadeh, N.; Patel, R. S.; Eapen, D. J.; Veledar, E.; Kassem, H. A.; Manocha, P.; Khayata, M.; Zafari, A. M.; Sperling, L.; Jones, D. P.; Quyyumi, A. A. Oxidative Stress is Associated With Increased Pulmonary Artery Systolic Pressure in Humans. Hypertension 2014, 63, 1270-1275. Yang, S. K.; Xiao, L.; Li, J.; Liu, F.; Sun, L. Oxidative Stress, a Common Molecular Pathway for Kidney Disease: Role of the Redox Enzyme p66Shc. Ren. Fail. 2014, 36, 313-320. Aruna, G.; Ambika Devi, K. Oxidative Stress in Chronic Renal Failure. Int. J. Pharma Bio Sci. 2014, 5, B127-B133. Araujo, A. M.; Reis, E. A.; Athanazio, D. A.; Ribeiro, G. S.; Hagan, J. E.; Araujo, G. C.; Damiao, A. O.; Couto, N. S.; Ko, A. I.; Noronha-Dutra, A.; Reis, MG. Oxidative Stress Markers Correlate With Renal Dysfunction and Thrombocytopenia in Severe Leptospirosis. Am. J. Trop. Med. Hyg. 2014, 90, 719-723. Rosenstein, R. E.; Pandi-Perumal, S. R.; Srinivasan, V.; Spence, D. W.; Brown, G. M.; Cardinali, D. P. Melatonin as a Therapeutic Tool in Ophthalmology: Implications for Glaucoma and Uveitis. J. Pineal Res. 2010, 49, 1-13. Uchino, Y.; Kawakita, T.; Ishii, T.; Ishii, N.; Tsubota, K. A New Mouse Model of Dry Eye Disease: Oxidative Stress Affects Functional Decline in the Lacrimal Gland. Cornea 2012, 31, S63-S67. Kaur, J.; Kukreja, S.; Kaur, A.; Malhotra, N.; Kaur, R., The Oxidative Stress in Cataract Patients. J. Clin. Diagn. Res. 2012, 6, 1629-1632. Veselinovic, M.; Barudzic, N.; Vuletic, M.; Zivkovic, V.; Tomic-Lucic, A.; Djuric, D.; Jakovljevic, V. Oxidative Stress in Rheumatoid Arthritis Patients: Relationship to Siseases Activity. Mol. Cell. Biochem. 2014, 391, 225-232. Kundu, S.; Ghosh, P.; Datta, S.; Ghosh, A.; Chattopadhyay, S.; Chatterjee, M., Oxidative Stress as a Potential Biomarker for Determining Disease Activity in Patients With Rheumatoid Arthritis. Free Radical Res. 2012, 46, 1482-1489. Wruck, C. J.; Fragoulis, A.; Gurzynski, A.; Brandenburg, L. O.; Kan, Y. W.; Chan, K.; Hassenpflug, J.; Freitag-Wolf, S.; Varoga, D.; Lippross, S.; Pufe, T. Role of Oxidative Stress in Rheumatoid Arthritis: Insights from the Nrf2-knockout Mice. Ann. Rheum. Dis. 2011, 70, 844-850. Braekke, K.; Harsem, N. K.; Staff, A. C. Oxidative Stress and Antioxidant Status in Fetal Circulation in Preeclampsia. Pediatr. Res. 2006, 60, 560-564. Hracsko, Z.; Orvos, H.; Novak, Z.; Pal, A.; Varga, I. S. Evaluation of Oxidative Stress Markers in Neonates With Intra-Uterine Growth Retardation. Redox Rep. 2008, 13, 11-16. Mert, I.; Oruc, A. S.; Yuksel, S.; Cakar, E. S.; Buyukkagnici, U.; Karaer, A.; Danisman, N. Role of Oxidative Stress in Preeclampsia and Intrauterine Growth Restriction. J. Obstet. Gynaecol. Res. 2012, 38, 658-664. Wang, J.; Li, J. Z.; Lu, A. X.; Zhang, K. F.; Li, B. J. Anticancer Effect of Salidroside on A549 Lung Cancer Cells Through Inhibition of Oxidative Stress and Phospho-p38 Expression. Oncol. Lett. 2014, 7, 1159-1164. Granados-Principal, S.; El-Azem, N.; Pamplona, R.; Ramirez-Tortosa, C.; Pulido-Moran, M.; VeraRamirez, L.; Quiles, J. L.; Sanchez-Rovira, P.; Naudí, A.; Portero-Otin, M.; Perez-Lopez, P.; Ramirez-Tortosa, M. Hydroxytyrosol Ameliorates Oxidative Stress and Mitochondrial


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(18)

(19) (20)

(21) (22) (23) (24)

(25)

(26)

(27) (28)

(29) (30)

(31) (32) (33)

(34)

Page 20 of 26

Dysfunction in Doxorubicin-induced Cardiotoxicity in Rats With Breast Cancer. Biochem. Pharmacol. 2014, 90, 25-33. Tekiner-Gulbas, B.; Westwell, A. D.; Suzen, S. Oxidative Stress in Carcinogenesis: New Synthetic Compounds With Dual Effects Upon Free Radicals and Cancer. Curr. Med. Chem. 2013, 20, 44514459. Halliwell, B. Role of free radicals in the neurodegenerative diseases: Therapeutic Implications for Antioxidant Areatment. Drugs Aging 2001, 18, 685-716. López, N.; Tormo, C.; De Blas, I.; Llinares, I.; Alom, J. Oxidative Stress in Alzheimer's Disease and Mild Cognitive Impairment with High Sensitivity and Specificity. J. Alzheimer's Dis. 2013, 33, 823-829. Pohanka, M. Alzheimer's Disease and Oxidative Stress: A Review. Curr. Med. Chem. 2014, 21, 356-364. Yana, M. H.; Wang, X.; Zhu, X. Mitochondrial Defects and Oxidative Stress in Alzheimer Disease and Parkinson Disease. Free Radical Biol. Med. 2013, 62, 90-101. Eskici, G.; Axelsen, P. H. Copper and Oxidative Stress in the Pathogenesis of Alzheimer's Disease. Biochemistry 2012, 51, 6289-6311. Pimentel, C.; Batista-Nascimento, L.; Rodrigues-Pousada, C.; Menezes, R. A. Oxidative Stress in Alzheimer's and Parkinson's Diseases: Insights from the Yeast Saccharomyces Cerevisiae. Oxid. Med. Cell. Longev. 2012, 2012, 132146. Schrag, M.; Mueller, C.; Zabel, M.; Crofton, A.; Kirsch, W. M.; Ghribi, O.; Squitti, R.; Perry, G. Oxidative Stress in Blood in Alzheimer's Disease and Mild Cognitive Impairment: A MetaAnalysis. Neurobiol. Dis. 2013, 59, 100-110. Adibi, H.; Mojarrad, J. S.; Asgharloo, H.; Zarrini, G. Synthesis, in vitro Antimicrobial and Antioxidant Activities of Chalcone and Flavone Derivatives Holding Allylic Substitutions. Med. Chem. Res. 2011, 20, 1318-1324. Lone, I. H.; Khan, K. Z.; Fozdar, B. I.; Hussain, F. Synthesis Antimicrobial and Antioxidant Studies of New Oximes of Steroidal Chalcones. Steroids 2013, 78, 945-950. Sadula, A.; Peddaboina, U. R.; Prameela Subhashini, N. J. Synthesis and Characterization of Novel Chalcone Linked Imidazolones as Potential Antimicrobial and Antioxidant Agents. Med. Chem. Res. 2015, 24, 851-859. Baviskar, B. A.; Baviskar, B.; Shiradkar, M. R.; Deokate, U. A.; Khadabadi, S. S. Synthesis and Antimicrobial Activity of Some Novel Benzimidazolyl Chalcones. E-J. Chem. 2009, 6, 196-200. Thanh-Dao, T.; Thi-Thao-Nhu, N.; Tuong-Ha, D.; Thi-Ngoc-Phuong, H.; Cat-Dong, T.; KhacMinh, T. Synthesis and Antibacterial Activity of Some Heterocyclic Chalcone Analogues Alone and in Combination With Antibiotics. Molecules 2012, 17, 6684-6696. Lacka, I.; Konieczny, M. T.; Bulakowska, A.; Rzymowski, T.; Milewski, S. Antifungal Action of the Oxathiolone-fused Chalcone Derivative. Mycoses 2011, 54, E407-E414. Kontogiorgis, C.; Mantzanidou, M.; Hadjipavlou-Litina, D. Chalcones and Their Potential Role in Inflammation. Mini-Rev. Med. Chem. 2008, 8, 1224-1242. Bandgar, B. P.; Gawande, S. S.; Bodade, R. G.; Totre, J. V.; Khobragade, C. N. Synthesis and Biological Evaluation of Simple Methoxylated Chalcones as Anticancer, Anti-inflammatory and Antioxidant Agents. Biorg. Med. Chem. 2010, 18, 1364-1370. Jin, F.; Jin, X. Y.; Jin, Y. L.; Sohn, D. W.; Kim, S.-A.; Sohn, D. H.; Kim, Y. C.; Kim, H. S. Structural Requirements of 2',4',6'-tris(methoxymethoxy) Chalcone Derivatives for Anti-


20

Page 21 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(35) (36) (37)

(38)

(39)

(40) (41)

(42) (43)

(44)

(45)

(46) (47)

(48)

(49) (50)

inflammatory Activity: The Importance of a 2'-hydroxy Moiety. Arch. Pharm. Res. 2007, 30, 13591367. Boumendjel, A.; Ronot, X.; Boutonnat, J. Chalcones Derivatives Acting as Cell Cycle Blockers: Potential Anti Cancer Drugs? Curr. Drug Targets 2009, 10, 363-371. Sharma, V.; Kumar, V.; Kumar, P. Heterocyclic Chalcone Analogues as Potential Anticancer Agents. Anticancer Agents Med. Chem. 2013, 13, 422-432. Singh, P.; Raj, R.; Kumar, V.; Mahajan, M. P.; Bedi, P. M. S.; Kaur, T.; Saxena, A. K. 1,2,3Triazole Tethered Beta-Lactam-Chalcone Bifunctional Hybrids: Synthesis and Anticancer Evaluation. Eur. J. Med. Chem. 2012, 47, 594-600. Shenvi, S.; Kumar, K.; Hatti, K. S.; Rijesh, K.; Diwakar, L.; Reddy, G. C. Synthesis, Anticancer and Antioxidant Activities of 2,4,5-trimethoxy chalcones and analogues from asaronaldehyde: Structure-activity relationship. Eur. J. Med. Chem. 2013, 62, 435-442. Echeverria, C.; Francisco Santibanez, J.; Donoso-Tauda, O.; Escobar, C. A.; Ramirez-Tagle, R. Structural Antitumoral Activity Relationships of Synthetic Chalcones. Int. J. Mol. Sci. 2009, 10, 221-231. Syam, S.; Abdelwahab, S. I.; Al-Mamary, M. A.; Mohan, S. Synthesis of Chalcones With Anticancer Activities. Molecules 2012, 17, 6179-6195. Serifi, O.; Tsopelas, F.; Kypreou, A.-M.; Ochsenkuehn-Petropoulou, M.; Kefalas, P.; Detsi, A. Antioxidant Behaviour of 2'-hydroxy-chalcones: A Study of Their Electrochemical Properties. J. Phys. Org. Chem. 2013, 26, 226-231. Sivakumar, P. M.; Prabhakar, P. K.; Doble, M. Synthesis, Antioxidant Evaluation, and Quantitative Structure-Activity Relationship Studies of Chalcones. Med. Chem. Res. 2011, 20, 482-492. Vasil'ev, R. F.; Kancheva, V. D.; Fedorova, G. F.; Batovska, D. I.; Trofimov, A. V. Antioxidant Activity of Chalcones: The Chemiluminescence Determination of the Reactivity and the Quantum Chemical Calculation of the Energies and Structures of Reagents and Intermediates. Kinet. Catal. 2010, 51, 507-515. Wu, J.-Z.; Cheng, C.-C.; Shen, L.-L.; Wang, Z.-K.; Wu, S.-B.; Li, W.-L.; Chen, S.-H.; Zhou, R.-P.; Qiu, P.-H. Synthetic Chalcones with Potent Antioxidant Ability on H2O2-Induced Apoptosis in PC12 Cells. Int. J. Mol. Sci. 2014, 15, 18525-18539. Kumar, C. S. C.; Loh, W.-S.; Ooi, C. W.; Quah, C. K.; Fun, H.-K. Structural Correlation of Some Heterocyclic Chalcone Analogues and Evaluation of their Antioxidant Potential. Molecules 2013, 18, 11996-12011. Vogel, S.; Ohmayer, S.; Brunner, G.; Heilmann, J. Natural and Non-Natural Prenylated Chalcones: Synthesis, Cytotoxicity and Anti-Oxidative Activity. Biorg. Med. Chem. 2008, 16, 4286-4293. El-Sayed, Y. S.; Gaber, M. Studies on Chalcone Derivatives: Complex Formation, Thermal Behavior, Stability Constant and Antioxidant Activity. Spectrochim. Acta. A Mol. Biomol. Spectrosc. 2015, 137, 423-431. Todorova, I. T.; Batovska, D. I.; Stamboliyska, B. A.; Parushev, S. P. Evaluation of the Radical Scavenging Activity of a Series of Synthetic Hydroxychalcones Towards the DPPH Radical. J. Serb. Chem. Soc. 2011, 76, 491-497. Kostova, I. Coumarins as Inhibitors of HIV Reverse Transcriptase. Curr. HIV Res. 2006, 4, 347363. Chimenti, F.; Bizzarri, B.; Bolasco, A.; Secci, D.; Chimenti, P.; Granese, A.; Carradori, S.; Rivanera, D.; Zicari, A.; Scaltrito, M. M.; Sisto, F. Synthesis, Selective Anti-Helicobacter Pylori


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

Page 22 of 26

Activity, and Cytotoxicity of Novel N-substituted-2-oxo-2H-1-benzopyran-3-carboxamides. Bioorg. Med. Chem. Lett. 2010, 20, 4922-4926. Sarmento Guerra, F. Q.; Aquino de Araujo, R. S.; de Sousa, J. P.; Pereira, F. d. O.; MendoncaJunior, F. J. B.; Barbosa-Filho, J. M.; Lima, E. d. O. Evaluation of Antifungal Activity and Mode of Action of New Coumarin Derivative, 7-hydroxy-6-nitro-2H-1-benzopyran-2-one, against Aspergillus spp. J. Evid. Based Complementary Altern. Med. 2015, 25096-25096. Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Natural and Synthetic Coumarin Derivatives with Anti-Inflammatory/Antioxidant Activities. Curr. Pharm. Des. 2004, 10, 3813-3833. Witaicenis, A.; Luchini, A. C.; Hiruma-Lima, C. A.; Felisbino, S. L.; Garrido-Mesa, N.; Utrilla, P.; Galvez, J.; Di Stasi, L. C. Suppression of TNBS-induced Colitis in Rats by 4-methylesculetin, a Natural Coumarin: Comparison with Prednisolone and Sulphasalazine. Chem. Biol. Interact. 2012, 195, 76-85. Gupta, J. K.; Sharma, P. K.; Dudhe, R.; Chaudhary, A.; Singh, A.; Verma, P. K.; Mondal, S. C.; Yadav, R. K.; Kashyap, S. Analgesic Study of Novel Pyrimidine Derivatives Linked with Coumarin Moiety. Med. Chem. Res. 2012, 21, 1625-1632. Maitland-van der Zee, A. H.; Daly, A. K.; Kamali, F.; Manolopoulous, V. G.; Verhoef, T. I.; Wadelius, M.; de Boer, A.; Pirmohamed, M.; Grp, E.-P. S. Patients Benefit from Genetics-guided Coumarin Anticoagulant Therapy. Clin. Pharmacol. Ther. 2014, 96, 15-17. Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli, C.; Zunino, F. Design, Synthesis and Anticancer Activities of Stilbene-Coumarin Hybrid Compounds: Identification of Novel Proapoptotic Agents. Biorg. Med. Chem. 2010, 18, 3543-3550. Kim, S.-N.; Kim, N. H.; Park, Y. S.; Kim, H.; Lee, S.; Wang, Q.; Kim, Y. K. 7-diethylamino-3(2'benzoxazolyl)-coumarin is a Novel Microtubule Inhibitor with Antimitotic Activity in Multidrug Resistant Cancer Cells. Biochem. Pharmacol. 2009, 77, 1773-1779. Francisco, C. S.; Rodrigues, L. R.; Cerqueira, N. M. F. S. A.; Oliveira-Campos, A. M. F.; Rodrigues, L. M. Synthesis of Novel Benzofurocoumarin Analogues and their Anti-Proliferative Effect on Human Cancer Cell Lines. Eur. J. Med. Chem. 2012, 47, 370-376. Kontogiorgis, C. A.; Xu, Y.; Hadjipavlou-Litina, D.; Luo, Y. Coumarin Derivatives Protection Against ROS Production in Cellular Models of Abeta Toxicities. Free Radic. Res. 2007, 41, 11681180. Binda, C.; Milczek, E. M.; Bonivento, D.; Wang, J.; Mattevi, A.; Edmondson, D. E. Lights and Shadows on Monoamine Oxidase Inhibition in Neuroprotective Pharmacological Therapies. Curr. Top. Med. Chem. 2011, 11, 2788-2796. Yang, Y.; Liu, Q.-W.; Shi, Y.; Song, Z.-G.; Jin, Y.-H.; Liu, Z.-Q. Design and Synthesis of Coumarin-3-acylamino Derivatives To Scavenge Radicals and To Protect DNA. Eur. J. Med. Chem. 2014, 84, 1-7. Kancheva, V. D.; Boranova, P. V.; Nechev, J. T.; Manolov, I. I. Structure-Activity Relationships of New 4-hydroxy bis-Coumarins as Radical Scavengers and Chain-Breaking Antioxidants. Biochimie 2010, 92, 1138-1146. Potapovich, M. V.; Metelitza, D. I.; Shadyro, O. I. Antioxidant Activity of Hydroxy Derivatives of Coumarin. Appl. Biochem. Microbiol. 2012, 48, 250-256.


22

Page 23 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(64) Roussaki, M.; Kontogiorgis, C. A.; Hadjipavlou-Litina, D.; Hamilakis, S.; Detsi, A. A Novel Synthesis of 3-aryl Coumarins and Evaluation of their Antioxidant and Lipoxygenase Inhibitory Activity. Bioorg. Med. Chem. Lett. 2010, 20, 3889-3892. (65) Xi, G.-L.; Liu, Z.-Q. Antioxidant Effectiveness Generated by One or Two Phenolic Hydroxyl Groups in Coumarin-substituted Dihydropyrazoles. Eur. J. Med. Chem. 2013, 68, 385-393. (66) Vianna, D. R.; Bubols, G.; Meirelles, G.; Silva, B. V.; da Rocha, A.; Lanznaster, M.; Monserrat, J. M.; Garcia, S. C.; von Poser, G.; Eifler-Lima, V. L. Evaluation of the Antioxidant Capacity of Synthesized Coumarins. Int. J. Mol. Sci. 2012, 13, 7260-7270. (67) Matos, M. J.; Mura, F.; Vazquez-Rodriguez, S.; Borges, F.; Santana, L.; Uriarte, E.; Olea-Azar, C. Study of Coumarin-Resveratrol Hybrids as Potent Antioxidant Compounds. Molecules 2015, 20, 3290-3308. (68) Symeonidis, T.; Chamilos, M.; Hadjipavlou-Litina, D. J.; Kallitsakis, M.; Litinas, K. E. Microwave-assisted Synthesis and Antioxidant Properties of Hydrazinyl Thiazolyl Coumarin Derivatives. Bioorg. Med. Chem. Lett. 2009, 19, 1139-1142. (69) Tabart, J.; Kevers, C.; Pincemail, J.; Defraigne, J.-O.; Dommes, J. Comparative Antioxidant Capacities of Phenolic Compounds Measured by Various Tests. Food Chem. 2009, 113, 12261233. (70) Perez-Cruz, F.; Serra, S.; Delogu, G.; Lapier, M.; Diego Maya, J.; Olea-Azar, C.; Santana, L.; Uriarte, E. Antitrypanosomal and Antioxidant Properties of 4-hydroxycoumarins Derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 5569-5573. (71) Joao Matos, M.; Perez-Cruz, F.; Vazquez-Rodriguez, S.; Uriarte, E.; Santana, L.; Borges, F.; OleaAzar, C. Remarkable Antioxidant Properties of a Series of hydroxy-3-arylcoumarins. Biorg. Med. Chem. 2013, 21, 3900-3906. (72) Osman, H.; Arshad, A.; Lam, C. K.; Bagley, M. C. Microwave-assisted Synthesis and Antioxidant Properties of Hydrazinyl Thiazolyl Coumarin Derivatives. Chem. Cent. J. 2012, 6:32, 1-10. (73) Morabito, G.; Trombetta, D.; Brajendra, K. S.; Ashok, K. P.; Virinder, S. P.; Naccari, C.; Mancari, F.; Saija, A.; Cristani, M.; Firuzi, O.; Saso, L. Antioxidant Properties of 4-methylcoumarins in in vitro cell-free Systems. Biochimie 2010, 92, 1101-1107. (74) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Synthesis and in vitro Evaluation of Novel Coumarin-Chalcone Hybrids as Potential Anticancer Agents. Bioorg. Med. Chem. Lett. 2010, 20, 7205-7211. (75) Hamdi, N.; Fischmeister, C.; Carmen Puerta, M.; Valerga, P. A Rapid Access to New Coumarinyl Chalcone and Substituted chromeno[4,3-c]pyrazol-4(1H)-ones and their Antibacterial and DPPH Radical Scavenging Activities. Med. Chem. Res. 2011, 20, 522-530. (76) Perez-Cruz, F.; Vazquez-Rodriguez, S.; Joao Matos, M.; Herrera-Morales, A.; Villamena, F. A.; Das, A.; Gopalakrishnan, B.; Olea-Azar, C.; Santana, L.; Uriarte, E. Synthesis and Electrochemical and Biological Studies of Novel Coumarin-Chalcone Hybrid Compounds. J. Med. Chem. 2013, 56, 6136-6145. (77) Vazquez-Rodriguez, S.; Figueroa-Guinez, R.; Joao Matos, M.; Santana, L.; Uriarte, E.; Lapier, M.; Diego Maya, J.; Olea-Azar, C. Synthesis of Coumarin-Chalcone Hybrids and Evaluation of their Antioxidant and Trypanocidal Properties. Medchemcomm 2013, 4, 993-1000. (78) Xi, G.-L.; Liu, Z.-Q. Coumarin Moiety Can Enhance Abilities of Chalcones to Inhibit DNA Oxidation and to Scavenge Radicals. Tetrahedron 2014, 70, 8397-8404.


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 26

(79) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01,Gaussian 09, Gaussian, Inc.: Wallingford, CT, USA, 2009. (80) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378-6396. (81) Zhao, Y.; Schultz, N. E.; Truhlar, D. G. Design of Density Functionals by Combining the Method of Constraint Satisfaction with Parametrization for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions. Journal of Chemical Theory and Computation 2006, 2, 364-382. (82) Velez, E.; Quijano, J.; Notario, R.; Pabón, E.; Murillo, J.; Leal, J.; Zapata, E.; Alarcón, G. A Computational Study of Stereospecifity in the Thermal Elimination Reaction of Menthyl Benzoate in the Gas Phase. J. Phys. Org. Chem. 2009, 22, 971-977. (83) Black, G.; Simmie, J. M. Barrier Heights for H-atom Abstraction by HO2 from η-butanol-A Simple Yet Exacting Test for Model Chemistries? J. Comput. Chem. 2010, 31, 1236-1248. (84) Furuncuoǧlu, T.; Uǧur, I.; Degirmenci, I.; Aviyente, V. Role of Chain Transfer Agents in Free Radical Polymerization Kinetics. Macromolecules 2010, 43, 1823-1835. (85) Ando, H.; Fingerhut, B. P.; Dorfman, K. E.; Biggs, J. D.; Mukamel, S. Femtosecond Stimulated Raman Spectroscopy of the Cyclobutane Thymine Dimer Repair Mechanism: A Computational Study. J. Am. Chem. Soc. 2014, 136, 14801-14810. (86) Alves, T. V.; Alves, M. M.; Roberto-Neto, O.; Ornellas, F. R. Direct Dynamics Investigation of the Reaction S(3P) + CH4 → CH3 + SH(2π). Chem. Phys. Lett. 2014, 591, 103-108. (87) Altarawneh, M.; Dlugogorski, B. Z. A Mechanistic and Kinetic Study on the Formation of pbdd/fs from pbdes. Environ. Sci. Technol. 2013, 47, 5118-5127. (88) Li, W.; Su, Z.; Hu, C. Mechanism of Ketone Allylation with Allylboronates as Catalyzed by Zinc Compounds: A DFT Study. Chem. Eur. J. 2013, 19, 124-134. (89) Dargiewicz, M.; Biczysko, M.; Improta, R.; Barone, V. Solvent Effects on Electron-Driven ProtonTransfer Processes: Adenine-Thymine Base Pairs. Phys. Chem. Chem. Phys. 2012, 14, 8981-8989. (90) Prasanthkumar, K. P.; Alvarez-Idaboy, J. R. An Experimental and Theoretical Study of the Kinetics and Mechanism of Hydroxyl Radical Reaction with 2-aminopyrimidine. RSC Advances 2014, 4, 14157-14164. (91) Henao, D.; Murillo, J.; Ruiz, P.; Quijano, J.; Mejía, B.; Castañeda, L.; Notario, R. A Computational Study of the Thermolysis of β-hydroxy Ketones in Gas Phase and in m-xylene Solution. J. Phys. Org. Chem. 2012, 25, 883-887.


24

Page 25 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(92) Murillo, J.; Henao, D.; Vélez, E.; Castaño, C.; Quijano, J.; Gaviria, J.; Zapata, E. Thermal Decomposition of 4-hydroxy-2-butanone in m-xylene Solution: Experimental and Computational study. Int. J. Chem. Kinet. 2012, 44, 407-413. (93) Galano, A.; Alvarez-Idaboy, J. R. Kinetics of Radical-Molecule Reactions in Aqueous Solution: A Benchmark Study of the Performance of Density Functional Methods. J. Comput. Chem. 2014, 35, 2019-2026. (94) Zhao, Y.; Truhlar, D. G. How Well Can New-Generation Density Functionals Describe the Energetics of Bond-Dissociation Reactions Producing Radicals? J. Phys. Chem. A 2008, 112, 10951099. (95) Eyring, H. The Activated Complex in Chemical Reactions. J. Chem. Phys. 1935, 3, 63-71. (96) Evans, M. G.; Polanyi, M. Some Applications of the Transition State Method to the Calculation of Reaction Velocities, especially in Solution. Trans. Faraday Soc. 1935, 31, 875-894. (97) Truhlar, D. G.; Garrett, B. C.; Klippenstein, S. J. Current Status of Transition-State Theory. J. Phys. Chem. 1996, 100, 12771-12800. (98) Galano, A.; Alvarez-Idaboy, J. R. A Computational Methodology for Accurate Predictions of Rate Constants in Solution: Application to the assessment of primary antioxidant activity. J Comput Chem 2013, 34, 2430-2445. (99) Mazzone, G.; Malaj, N.; Galano, A.; Russo, N.; Toscano, M. Antioxidant Properties of Several Coumarin-Chalcone Hybrids from Theoretical Insights. RSC Advances 2015, 5, 565-575. (100) Ho, J.; Coote, M. L. A Universal Approach for Continuum Solvent pk(a) Calculations: Are we there yet? Theor. Chem. Acc. 2010, 125, 3-21. (101) Rebollar-Zepeda, A. M.; Campos-Hernández, T.; Ramírez-Silva, M. T.; Rojas-Hernández, A.; Galano, A. Searching for Computational Strategies to Accurately Predict pkas of Large Phenolic Derivatives. Journal of Chemical Theory and Computation 2011, 7, 2528-2538. (102) Wolfbeis, O. S.; Uray, G. Fluorescence Spectra, Photodissociation, and Phototautomerism of some 4-hydroxycoumarines. Monatshefte für Chemie 1978, 109, 123-136. (103) Warshel, A. Computer Modeling of Chemical Reactions in Enzymes and Solutions, Wiley 1997. (104) McCoy, R. S.; Braun-Sand, S. B. Semimicroscopic Investigation of Active Site pKa Values in Peptidylarginine Deiminase 4. Theor Chem Acc 2012, 131, 1293:. (105) Schutz, C. N.; Warshel, A. What are the "Dielectric Constants" of Proteins and how to Validate Electrostatic Models? Proteins: Struct. Funct. Genet. 2001, 44, 400-417. (106) Warshel, A.; Sharma, P.K.; Kato, M.; Parson, W.W. Modeling Electrostatic Effects in Proteins. Biochim. Biophys. Acta - Proteins Proteom. 2006, 1764,1647–1676. (107) Borštnar, R.; Repič, M.; Kamerlin, S. C. L.; Vianello, R.; Mavri, J. Computational Study of the pKa Values of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B. J. Chem. Theor. Comput. 2012, 8, 3864–3870. (108) Terpinc, P.; Abramovič, H. A Kinetic Approach for Evaluation of the Antioxidant Activity of Selected Phenolic Acids. Food Chem. 2010, 121, 366-371. (109) Sies, H. Oxidative Stress: Oxidants and Antioxidants. Exp. Physiol. 1997, 82, 291-295. (110) Masuda, T.; Yamada, K.; Maekawa, T.; Takeda, Y.; Yamaguchi, H. Antioxidant Mechanism Studies on Ferulic Acid: Isolation and Structure Identification of the Main Antioxidation Product from Methyl Ferulate. Food Sci. Technol. Res. 2006, 12, 173-177.


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 26

(111) Masuda, T.; Yamada, K.; Maekawa, T.; Takeda, Y.; Yamaguchi, H. Antioxidant Mechanism Studies on Ferulic Acid: Identification of Oxidative Coupling Products from Methyl Ferulate and Linoleate. J. Agric. Food Chem. 2006, 54, 6069-6074. (112) Rose, R. C.; Bode, A. M. Biology of Free Radical Scavengers: An Evaluation of Ascorbate. FASEB J. 1993, 7, 1135-1142. (113) Galano, A.; Tan, D. X.; Reiter, R. J. Melatonin as a Natural Ally against Oxidative Stress: A Physicochemical Examination. Journal of Pineal Research 2011, 51, 1-16. (114) De Grey, A. D. N. J. HO2·: The Forgotten Radical. DNA Cell Biol. 2002, 21, 251-257. (115) Estévez, L.; Otero, N.; Mosquera, R. A. A Computational Study on the Acidity Dependence of Radical-Scavenging Mechanisms of Anthocyanidins. J. Phys. Chem. B 2010, 114, 9706-9712.

TOC


26

CoumarinâChalcone Hybrids as Peroxyl Radical Scavengers

Recommend Documents

CoumarinâChalcone Hybrids as Peroxyl Radical Scavengers