Detailed Investigation of the Outstanding Peroxyl ... - ACS Publications

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Cite This: J. Chem. Inf. Model. XXXX, XXX, XXX−XXX

Detailed Investigation of the Outstanding Peroxyl Radical Scavenging Activity of Two Novel Amino-Pyridinol-Based Compounds Misaela Francisco-Marquez† and Annia Galano*,‡ †

Instituto Politécnico Nacional−UPIICSA, Té 950, Col. Granjas México, C.P. 08400 México City, México Departamento de Química, Universidad Autónoma Metropolitana−Iztapalapa, San Rafael Atlixco 186, Col. Vicentina. Iztapalapa, C.P. 09340, Mexico City, México

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‡

S Supporting Information *

ABSTRACT: The ability of two novel amino-pyridinol based compounds (NPyr6 and NPyr7) as peroxyl radical scavengers was investigated in silico. The gathered data indicate that they are exceptionally efficient in that role. However, solvent polarity influences their relative efficiency for that purpose. NPyr6 was identified as the best peroxyl radical scavenger in lipid solution, while NPyr7 takes that place in aqueous solution. Both compounds present two acid−base equilibria, which influence their reactivity in aqueous solution. The associated pKa values were estimated. Several reaction mechanisms were explored. Hydrogen transfer from the phenolic group was identified as the chemical route with the highest contribution to the antioxidant behavior of the investigated compounds in both, nonpolar medium and aqueous solution (at 2 ≤ pH ≤ 10). At higher pH other reaction pathways become the most relevant ones. In addition, their bioavailability, cell permeability, safety, and manufacturability were evaluated. According to these, particularly toxicity, NPyr7 seems to be a better candidate for use as an oral drug to fight oxidative stress than NPyr6.

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INTRODUCTION Oxidative stress (OS) is a chemical phenomenon with deleterious consequences for human health. It is considered a triggering factor in diverse neurodegenerative disorders,1−16 some types of cancer,17−32 a variety of cardiovascular diseases,33−41 diabetes,15,42,43 and pulmonary44−55 and renal failures.56−64 OS arises when the production of oxidants in biological systems overcomes their consumption.65 Among such oxidants, free radicals are particularly concerning due to their high reactivity and their ability to initiate chain-like reactions, which contribute to propagate molecular damage. Therefore, finding chemicals that act as antioxidants by scavenging free radicals is an active area of research. Such molecules might offer protection by preventing, protecting, or repairing biomolecules.66 Recently, a series of 6-amino-3pyridinols have been investigated as peroxyl (LOO•) radical scavengers and were described as a novel class of phenolic antioxidants.67 In particular, two of them (originally labeled as 7 and 6, and here referred to as NPyr7 and NPyr6, respectively, Scheme 1) were identified as particularly efficient peroxyl radical-trapping chain-breaking antioxidants. According to theoretical calculations, based on O−H bond dissociation energies and ionization potentials, these compounds (Scheme 1) were predicted to be good antioxidants with reasonable air-stability.67 This prediction was experimen© XXXX American Chemical Society

Scheme 1. Structures of NPyr7 and NPyr6 and Site Numbering

tally confirmed. In addition, the inhibition rate constant was measured (based on LOO• trapping and O2 uptake). Such measurements allow classifying NPyr6 and NPyr7 as some of the fastest peroxyl radical-trapping chain-breaking antioxidants reported so far. Later investigations on these compounds also supported this finding. It was reported that NPyr6 and NPyr7 efficiently inhibit styrene autoxidation.68 Moreover, they were found to be 28 and 88 times more efficient for that purpose, respectively, than α-tocopherol (α-TOH). In addition, there Received: June 24, 2019 Published: July 2, 2019 A

DOI: 10.1021/acs.jcim.9b00517 J. Chem. Inf. Model. XXXX, XXX, XXX−XXX

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Journal of Chemical Information and Modeling

for the kinetic calculations. When using this approach is used, the rate constants (k) are calculated using the conventional TST (“transition state theory”),94−96 the 1 M standard state, harmonic vibrational frequencies, and Eckart tunneling.97 The Marcus theory is used to obtain the Gibbs free energy of activation of electron transfer reactions.98 Diffusion is considered, and the calculated rate constants (k) are corrected, accordingly. To that purpose, the Collins−Kimball theory,99 the steady-state Smoluchowski rate constant,100 and the Stokes−Einstein101,102 approach are used.

is evidence that NPyr6 is about 30-fold more reactive toward peroxyl radicals than α-TOH; it protects lipoprotein tryptophan residues in human low-density lipoprotein and does not efficiently mediate lipid peroxidation.69 However, it seems that further investigations on these compounds are still necessary to fully understand their protective actions. To the extent of our knowledge, there is still no full mechanistic study on the role of NPyr6 and NPyr7 as peroxyl radical scavengers. There is no information on the influence of the environment’s polarity on such a role. There is no quantitative data regarding the role of their different acid− base species, which have been shown to be very important, in this context.70 Accordingly, the main goal of the investigation presented here is to address these particular aspects, using a computational approach.

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RESULTS AND DISCUSSION Acid Base Equilibria. The first pKa value of NPyr6 and NPyr7 were previously estimated to be higher than 7.0 (7.0− 7.2).68 The values were approximated because the titrations yielded somewhat distorted plots, probably due to decomposition of the anionic species. The fact that these pKa values are higher than that of pyridinium cation (5.25) was expected and attributed to the presence of electron-donating substituents. Here, the PF method was used to estimate two pKa values for each of the investigated molecules. The first one corresponds to the protonated pyridinium moiety and the second one to the phenolic OH. The estimated pKa values, in aqueous solution, at physiological pH (7.4), are reported in Table 1. In the same table, the molar fractions (at the same

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COMPUTATIONAL DETAILS Software: the Gaussian 09 package of programs.71 Level of theory: M06-2X/6-311+G(d,p). Solvent effects: SMD (“Solvation Model based on Density”).73 Water and pentyl ethanoate were chosen as solvents to mimic aqueous and lipid solution. The M06-2X choice was made based on previous recommendations, that considering performance for kinetic calculations and reactions of open shell systems.72,74−84 SMD was chosen because its low errors in solvation free energies for solutes of diverse charges.73 The number of imaginary frequencies (if) were used to identify the stationary points as local minima and transition states (if = 0 or if = 1, respectively). IRC (“intrinsic reaction coordinate”) calculations were carried out to confirm that the located transition state (TS) corresponds to the intended reaction pathway. The reported relative energies include thermodynamic corrections at 298.15 K. The pKa values were estimated using the PF (“parameters fitting”) method, which produces only small deviations with respect to experimental measurements.85−87 Once the pKa values are known, the molar fractions of the protonated (H2NPyr+), neutral (HNPyr), and anionic (NPyr−) species of the investigated compounds were calculated, at the pH of interest, as M

f (H NPyr+) = 2

1 + 10

pKa 2

Table 1. Calculated pKa Values of NPyr6 and NPyr7 and Molar Fractions of Their Acid−Base Species at pH = 7.4a pKa1 pKa2 M f(H2NPyr+) × 100 M f(HNPyr) × 100 M f(NPyr−) × 100 a

1 [H ] + 10 pKa 2 + pKa1[H+]2

f (HNPyr) =

10 pKa 2[H+] 1 + 10 pKa 2[H+] + 10 pKa 2 + pKa1[H+]2

M

f (NPyr−) =

10 pKa 2 + pKa1[H+]2 1 + 10 pKa 2[H+] + 10 pKa 2 + pKa1[H+]2

NPyr7

7.8 10.4 71.50 28.47 0.03

6.9 10.5 24.01 75.93 0.06

Expressed as a percent of the total population.

pH) are provided. In addition to the standard procedure associated with the PF and using the recommended parameters for the level of theory used here, a further correction was made. It consisted on estimating the pKa values of phenol and pyridinium cation using the exact methodology and the corresponding deviations with respect to the experimental values. These deviations were in turn been used to improve the calculated pKa values of the molecules of interest. The acid−base species, with largest populations at pH = 7.4 (Table 1), are protonated for NPyr6 (H2NPyr6+) and the product of the first deprotonation for NPyr7 (HNPyr7). However, non-negligible amounts of HNPyr6 and H2NPyr7+ are expected at this pH. The anions of both molecules are predicted to exist only to a minor extent under the same condition. Reaction Mechanisms. Five reaction mechanisms were considered for aqueous solution: • HT: “hydrogen transfer” • RAF: “radical adduct formation” • SET: “single electron transfer” • SPLET: “sequential proton loss electron transfer” • SPLHT: “sequential proton loss hydrogen transfer” • SdPLET: “sequential double-proton loss electron transfer”

+

M

NPyr6

More details on molar fractions calculations can be found elsewhere.88−91 The hydroperoxyl radical (HOO•) was chosen to model the free radical scavenging activity of the target molecules with peroxyl radicals (ROO•). HOO• is the member of the ROO• family with smallest size and has been suggested as crucial to the toxic side effects of aerobic respiration.92 In addition, HOO• can be used also as a model for the reactions of nonhalogenated aliphatic ROO• in kinetic calculations. This strategy was recently validated.93 The QM-ORSA (“quantum mechanism-based test for overall free radical scavenging activity”) protocol88 was used B


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Journal of Chemical Information and Modeling • SdPLHT: “sequential double-proton loss hydrogen transfer” HT and RAF can take place through different reactions pathways. HT was modeled considering as H donor the O in the phenolic group and any sp3 C atom in NPyr6 and NPyr7. RAF was modeled considering any sp2 C atom in the investigated molecules as reaction sites. Regarding SET, SPLET, and SdPLET, they differ in the particular acid−base species that is acting as the electron donor (H2NPyr+, HNPyr, and NPyr−, respectively). The same applies for HT, SPLHT, and SdPLHT, which correspond to hydrogen transfers from the different acid−base species. For reactions in lipid media those mechanisms involving charged species were not included because such species are expected to exist to a significant extent only when the medium is a polar and protic solvent. Thus, in lipid solution only two reaction mechanism were considered as possible: HT and RAF, and the molecules of interest were modeled as neutral species (HNPyr). Thermochemistry. The Gibbs free energies (ΔG) of each reaction pathway in lipid and aqueous solutions are reported in Tables 2 and 3, respectively. Only two of them were found to

exergonicity in both cases (Table 2). Neutral species (HNPyr), in aqueous solution, have a similar behavior (Table 3). However, the exergonicity increases to some extent with the polarity of the solvent. For the charged species the number of thermochemically viable reaction pathways increases to 3 for H2NPyr6+, to 4 for H2NPyr7+, and to 5 for NPyr6− and NPyr7− (Table 3). For the protonated species, which have the phenolic moiety, HT from this site is the most exergonic channel. On the other hand, in the anions yielded by deprotonation of the phenolic group, this pathway is not possible. The most negative ΔG value for the reactions of NPyr6− and NPyr7− with HOO• corresponds to the SdPLET mechanism. Since the reactions of HOO• with all the acid−base species of NPyr6 and NPyr7 involves some thermochemically viable pathways, in principle all of them might contribute to the peroxyl radical scavenging activity of the investigated aminopyridinols. However, kinetic calculations are required to estimate the extent of such contributions. Kinetics. The reaction pathways identified as endergonic in the previous section were excluded from the kinetic calculations. It is not expected that the products yielded through these pathways will be experimentally observed, even if they might be formed at a significant rate. On the other hand, moderately endergonic pathways might be non-negligible, provided that their products evolve fast enough into other species through reactions that are significantly exergonic. These may be the case for the SPLET mechanism, which yields radical anions that are expected to be highly reactive. Thus, this mechanism was taken into consideration in the kinetic analyses, despite of being moderately endergonic. The most relevant structural features of the TS are shown in Figures 1−4. Their imaginary frequencies are reported in Table S1 (Supporting Information), while the corresponding tunneling corrections are provided in Table S2. The energy barriers of all the reactions pathways considered for kinetics are reported in Table S3. Total rate constants in lipid solution, and for each acid−base species in aqueous solution, were calculated as

Table 2. Gibbs Free Energies of Reaction (ΔG, in kcal/mol, at 298.15 K) for the Modeled Pathways, in Lipid Solution HT, OH site HT, 2a site HT, 4a site HT, 7a site HT, 8 site HT, 9 site HT, 10 site RAF, C2 site RAF, C3 site RAF, C4 site RAF, C5 site RAF, C6 site

HNPyr6

HNPyr7

−14.03 3.56 6.11 3.93 2.48 11.30 −2.00 9.39 9.99 19.05 11.16 16.88

−14.66 3.39 7.32 4.94 0.77 −3.53 8.10 10.66 20.55 10.97 20.60

be thermochemically viable in lipid solution for both NPyr6 (HT from the OH site and HT from site 10) and NPyr7 (HT from the OH site and HT from site 9). The reaction pathway involving HT from the phenolic site has the largest

HNPyr k total,PE =

n1

m1

HNPyr HNPyr + ∑ kRAF ∑ kHT i

i=1

j

j=1

Table 3. Gibbs Free Energies of Reaction (ΔG, in kcal/mol, at 298.15 K) for the Modeled Pathways, in Aqueous Solution

HT, OH site HT, 2a site HT, 4a site HT, 7a site HT, 8 site HT, 9 site HT, 10 site RAF, C2 site RAF, C3 site RAF, C4 site RAF, C5 site RAF, C6 site SET SPLET SdPLET

H2NPyr6+

HNPyr6

NPyr6−

−9.42 −1.53 3.38 5.79 2.55 9.83 −2.65 0.93 11.59 17.16 14.76 16.49 25.68

−17.11 1.34 3.73 1.88 0.30 8.99 −4.04 7.16 9.24 18.53 8.90 12.20

−3.88 −2.12 2.24 1.66 9.41 −4.06 −1.77 9.56 4.42 15.38 5.99

9.95

H2NPyr7+

HNPyr7

NPyr7−

−11.57 −2.68 4.33 4.18 3.98 −4.68

−17.68 0.76 3.94 3.35 1.23 −3.93

−5.36 −0.75 3.75 2.43 −3.57

−1.56 11.12 16.14 8.44 13.01 23.61

6.40 8.46 19.44 7.10 14.99

−4.49 9.04 4.53 10.29 4.07

6.73 −13.58 C

−15.16 DOI: 10.1021/acs.jcim.9b00517 J. Chem. Inf. Model. XXXX, XXX, XXX−XXX

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Figure 1. Optimized geometries of the transition states of neutral species, in lipid solution. Distances are reported in angstroms. H2 NPyr + k total,W

n2

=

∑

H 2NPyr + kHT + i

i=1

HNPyr k total,W

n1

=

∑

−

∑

H 2NPyr + kRAF j

Figure 3. Optimized geometries of the transition states of the neutral species (HNPyr), in aqueous solution. Distances are reported in angstroms.

+ k SET

j=1

HNPyr kHT + i

i=1

NPyr k total,W =

m2

m1

∑

HNPyr kRAF j

The difference between these two expressions is a consequence of the acid−base equilibrium of HOO• in aqueous solution (pKa = 4.8).92 In lipid solution (Table 4) NPyr6 reacts faster than NPyr7 with peroxyl radicals. In this medium, NPyr6 was identified as the best peroxyl radical scavenger identified so far (Table S4, Supporting Information). This statement is based on comparisons of total rate constants, calculated using similar computational protocols.66,103,104 NPyr7 is also excellent for this purpose and surpassed only by lycopene and torulene, which react 1.9 and 1.1 times faster with HOO• in nonpolar media (koverall = 1.69 × 106 and 9.47 × 105 M−1 s−1, respectively).105 Under the same conditions, NPyr6 and NPyr7 react 700 and 278 times faster than Trolox.106 They are also faster in scavenging peroxyl radicals than gallic acid,107 resveratrol,108 and ascorbic acid.109 HT is the only mechanism contributing to the peroxyl radical scavenging activity of NPyr6 and NPyr7, in lipid solution, with the phenolic site accounting for ∼100% of such

+ k SPLET

j=1

n3

m3

−

NPyr NPyr + ∑ kRAF ∑ kHT i

−

j

i=1

+ k SdPLET

j=1

Overall rate constants, in aqueous solution at each pH of interest, for the reactions with model ROO• and HOO• were calculated as +

pH

pH

HNPyr H 2NPyr W,pH M koverall,ROO f (H NPyr+) k total,W + M f (HNPyr) k total,W • = 2

pH

−

NPyr + M f (NPyr−) k total,W

pH

W,pH W,pH M koverall,HOO f (HOO•) koverall,ROO • = •

Figure 2. Optimized geometries of the transition states of the protonated species (H2NPyr+), in aqueous solution. Distances are reported in angstroms. D


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Figure 4. Optimized geometries of the transition states of the anionic species (NPyr6−), in aqueous solution. Distances are reported in angstroms.

The reactions of both molecules with HOO• are predicted to be slower than with other ROO• (Table 5), at pH= 7.4, which is a consequence of the small fraction of HOO• that is present at this pH (∼0.25%). NPyr6 and NPyr7 are both excellent for scavenging peroxyl radicals, in aqueous solution at physiological pH. In fact, NPyr7 is the best antioxidant identified so far for that purpose (Table S6, Supporting Information), while NPyr6 is only surpassed by 3,5-dihydroxy4-methoxybenzyl alcohol (DHMBA) and piceatannol (koverall,ROO• = 1.40 × 109 and 1.13 × 109 M−1 s−1, respectively).110,111 The finding that NPyr6 and NPyr7 are outstanding peroxyl radical scavengers, regardless of the solvent polarity, might be attributed to the presence of a nitrogen atom in the aromatic ring. It is expected to increase the electronic density, consequently, to stabilize the radical products yielded through the reactions with free radicals. In addition, phenolic compounds with increased electrodonating capabilities are expected to be more reactive toward oxidants including Ocentered free radicals, such as ROO•. The acid−base equilibria of the investigated aminopyridinols have a significant influence on the kinetics of their reactions with peroxyl radicals and, consequently, on their capability as peroxyl radical scavengers. This activity increases with the deprotonation degree (Table 5), H2NPyr+ being significantly less efficient for that purpose than HNPyr and

Table 4. Rate Constants (k, M−1 s−1) of the Reactions between Amino-pyridinols and Peroxyl Radicals, in Lipid Solution kHNPyr6 total,PE HT, OH site HT, 9 site HT, 10 site total

kHNPyr7 total,PE

2.38 × 10

8.78 × 105 7.16 × 100

6

3.11 × 101 2.38 × 106

8.78 × 105

activity (Table S5, Supporting Information). Thus, at least, in this medium the phenolic moiety is identified as responsible for the antioxidant behavior of the investigated compounds. In aqueous solution, the chemistry involved in the peroxyl radical scavenging activity of NPyr6 and NPyr7 becomes significantly more complex, mainly as a consequence of the acid−base behavior of the chemicals involved in the process. Branching ratios for the different reaction pathways are reported in Table S5 (Supporting Information). According to the overall calculated rate constants (Table 5), both NPyr6 and NPyr7 are predicted to react with ROO• at (or near to) diffusion-limited rates, in aqueous solution at physiological pH. Under such conditions, the reaction involving NPyr7 is predicted to be about 2.7 times faster than that involving NPyr6. Both results are in agreement with previous experimental evidence.67

Table 5. Rate Constants (k, M−1 s−1) of the Reactions between Amino-Pyridinol Species and Peroxyl Radicals, in Aqueous Solution

HT, OH site HT, 2a site HT, 4a site HT, 9 site HT, 10 site RAF, C2 site SET SPLET SdPLET total overall, model ROO•, pH = 7.4 overall, HOO•, pH = 7.4

H2NPyr6+

HNPyr6

2.28 × 10 1.62 × 10−1

2.70 × 10

2.83 × 10

9.65 × 10

4

0

NPyr6− 9

HNPyr7

1.05 × 10 2.13 × 10−1

2.70 × 10

7.56 × 100

1.46 × 102

5

2.27 × 109 1.75 × 107 8.19 × 10 2.13 × 109

1

NPyr7−

H2NPyr7+

9

7

1.79 × 10−7

9.73 × 102 2.65 × 10−5

3.13 × 105

2.74 × 109 4.27 × 105

7.42 × 10 1.19 × 1010 9

2.28 × 104

2.65 × 109 5.13 × 106 6.17 × 108

2.70 × 109 7.71 × 108 1.93 × 106 E

1.06 × 105

2.70 × 109 2.06 × 109 5.16 × 106

7.37 × 109 1.34 × 1010


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Journal of Chemical Information and Modeling NPyr−. The neutral and anionic fractions both react at diffusion limited rates with peroxyl radicals. The values of the total rate constants for each acid−base species and the overall rate constants at pH values ranging from 2.0 to 12.0 are provided for the reactions of NPyr6 and NPyr7 with model ROO• and HOO• in Tables S8 and S9 (Supporting Information), respectively. To facilitate discussion, the dependence of koverall with pH is also presented in Figure 5. The contributions (%) of acid−base species to the

at different pHs, are provided in Tables S11 and S12 (Supporting Information) for NPyr6 and NPyr7, respectively. It was found that NPyr7 reacts faster with peroxyl radicals than NPyr6, for most of the investigated pH range (Figure 5). The exception occurs from pH ∼ 8.5 to pH ∼ 10.4, where both compounds react almost equally fast with these radicals. For the reactions with HOO•, the overall rate constant for NPyr7 surpasses the 107 M−1 s−1 value in the 4.8−7.0 pH range. The maximum reactivity of NPyr6 is reached in the same pH interval, although the values of the corresponding overall rate constants are 6 to 8 times lower. For the reactions with HOO•, on the other hand, the rate constants of both NPyr7 and NPyr6 systematically increases with the pH. The value of koverall is larger than 107 M−1 s−1 at pH values higher than ∼4.4 and ∼5.4, for NPyr7 and NPyr6, respectively. The contributions of the different acid−base species to the overall reactivity of the investigated amino-pyridinols toward peroxyl radicals (Table S10, Supporting Information) are not exactly in line with their relative abundances (Figure 6). The neutral species (HNPyr) are the most abundant ones at pH values ranging from 7.8 to 10.4 and from 6.9 to 10.5 for NPyr6 and Npyr7, respectively. In spite of this, HNPyr species are the key players in the peroxyl radical scavenging activity exhibited by both compounds in a wider range (3.0 ≤ pH ≤ 9.5). In other words, although at pH = 6 (for example) the protonated species (H2Pyr+) are the most abundant ones, the antioxidant activity is ruled by HNPyr for both NPyr6 and Npyr7. In addition, there are several reaction pathways for each acid−base species of the investigated amino-pyridinols that might contribute to their antioxidant behavior as peroxyl radical scavengers. The branching ratios corresponding to

Figure 5. Dependence of kinetics with pH for the reactions between amino-pyridinols and peroxyl radicals, in aqueous solution.

overall rate constants, at different pHs, are reported in Table S10 (Supporting Information). The branching ratios (%) of each reaction channel, with respect to the overall rate constant,

Figure 6. Influence of pH on molar fractions and contributions of acid−base species to the overall rate constants. F


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Figure 7. Dependence with pH of branching ratios (%, vs koverall) of the significant reaction pathways for the reactions between amino-pyridinols and peroxyl radicals, in aqueous solution: (A) NPyr6, (B) NPyr7.

Bioavailability and cell permeability may be affected by several physicochemical properties. To explore the behavior of NPyr7 and Npyr6, in this context, several parameters were estimated and used as indicators for ADME (“absorption, distribution, metabolism, and excretion”) properties. They allow checking if the target molecules satisfy Lipinski’s,112 Ghose’s,113 and Veber’s114 criteria, according to the target values shown in Table 6. The ADME properties logP, XAt, MW, HB A , HB D , and RB were obtained using the Molinspiration Property Calculation Service, while MR and PSA were estimated with the DruLiTo software. The values of the calculated ADME properties and toxicity descriptors are reported in Table 7. Five commonly used medical drugs were also included in this table for comparison purposes. It was found that most of the ADME properties for NPyr6 and NPyr7 are within the target values. The exceptions are XAt for both of them (XAtNPyr6 = 14 and XAtNPyr7 = 13) and M R for NPyr6 (MRNPyr6 = 38.18). Regarding XAt, it should be considered that most of the reference medical drugs also have

these pathways, in the 2−12 pH range were estimated (Tables S11 and S12, Supporting Information). Those contributing to a non-negligible extension to the overall activity of NPyr6 and NPyr7 are plotted in Figure 7. It was found that for neutral species (HNPyr) the only relevant pathway is the HT from the phenolic OH, along the whole pH range investigated here. The same applies for the protonated species (H2NPyr+). On the contrary, there are several reaction pathways that significantly contribute to the ROO• scavenging activity of the anionic species (NPyr−), albeit the contributions of the SdPLET route are the largest, by far, for this fraction. Other Relevant Considerations. According to the data discussed in the previous section, both NPyr7 and Npyr6 are highly promising antioxidants. Moreover, their efficiency as peroxyl radical scavengers seems to be among the highest reported so far. Thus, they might be used to protect biomolecules from these oxidants and perhaps as oral antioxidants. However, to even consider such a possibility there are other important factors to take into account. G


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suggest that the synthesis of these compounds should be of medium complexity (or medium-easy, since they are close to the first threshold). Therefore, this is not expected to be an issue. Moreover, the SA value of omeprazole (which is commercially viable) is higher (4.15). Probably the most critical aspect regarding potential oral drugs is toxicity. NPyr6 was found to have positive mutagenicity (M = 0.53), while NPyr7 is predicted to be nonmutagenic (M = 0.18). Although there are currently used drugs, such as diclofenac with similar M values (also 0.53), it is preferable to avoid this risk. The LD50 values also indicate that the toxicity of NPyr7 is lower than that of NPyr6. In addition, the LD50 for NPyr7 is higher than the average of the currently used medical drugs, used here as references, while that of NPyr6 is lower. Therefore, according to the estimated toxicity descriptors, NPyr7 seems to have higher potential than NPyr6 as an oral drug to be used for fighting OS.

Table 6. ADME Properties and Their Target Values (TVal), Chosen to Satisfy Lipinski’s, Ghose’s, and Veber’s Criteria property

acronym

TVal

partition coefficient octanol/water polar surface area number of non-hydrogen atoms molecular weight number of H bond acceptors number of H bond donors number of rotatable bonds molar refractivity

logP PSA X At MW HBA HBD RB M R

−0.4−5.0 ≤140 20−70 160−480 ≤10 ≤5 ≤10 40−130

units Å2 g/mol

m3/mol

values lower than 20, omeprazole being the only exception. Since for NPyr6 XAt is the only violation to Lipinski’s, Ghose’s, and Veber’s criteria, while there are two violations for NPyr7, NPyr6 seems to be a better candidate to be used as an oral drug to fight OS. However, all the above-mentioned criteria are general guidelines, not strict rules. For example, paracetamol present two violations of these criteria (XAt and MW) and is a widely used oral drug. In addition, viable drugs must also have other important features, including safety and manufacturability.115 Thus, these aspects were also investigated here. Two toxicity descriptors were used in this work, namely: • M: known as Ames mutagenicity. A chemical is positive if it induces revertant colony growth in any strain of Salmonella typhimurium. When M < 0.5, the chemical is considered not mutagenic. • LD50: amount of chemical per body weight (mg/kg) leading to 50% of rats dying. The larger the LD50 value, the lower the toxicity. They were estimated using T.E.S.T. (Toxicity Estimation Software Tool), which makes predictions based on QSAR (“quantitative structure activity relationships”), and computed with the consensus method.116 Synthetic accessibility (SA) was used to assess manufacturability. It was estimated with the SYLVIA-XT program,117 which uses several contributing criteria, scaled and weighted to produce SA values between 1 and 10, with a larger value indicating a compound more difficult to synthesize. Here, the following classification is used: easy (SA ≤ 3), medium (3 < SA ≤ 6), and hard (SA > 6). Regarding manufacturability, both NPyr6 and NPyr7 have similar SA values (3.58 and 3.51, respectively). These values

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CONCLUSIONS The peroxyl radical scavenging activity of two novel aminopyridinol based compounds was investigated here (namely, NPyr6 and NPyr7). They were found to be exceptionally good for that purpose. NPyr6 is at the top of the peroxyl radical scavengers, in lipid solution, identified so far; while NPyr7 was identified as the most efficient in aqueous solution. These compounds present two acid−base equilibria, which influence their reactivity in aqueous solution. The associated pKa values were estimated and are reported here for the first time. Different reaction mechanisms were explored, and H transfer from the phenolic group was identified as the chemical pathway with the highest contribution to the antioxidant behavior of the investigated compounds. This was the case for nonpolar medium and for most of the pH range investigated here for aqueous solution. Only at rather high pH other reaction pathways become the most relevant ones. According to the thermochemical and kinetic data gathered here, both NPyr7 and Npyr6 are both highly promising antioxidants that might be used as oral antioxidants to protect biomolecules for OS. To evaluate the likeliness of such a possibility other important factors were considered (bioavailability, cell permeability, safety, and manufacturability). For that purpose several ADME properties, toxicity descriptors. and synthetic availability were estimated. According to them,

Table 7. Estimated ADME Properties and Toxicity Descriptors for the Investigated Amino-pyridinol Thiols and Some Currently Used Oral Medical Drugs HNPyr6

HNPyr7

melatonin

logP PSA X At MW HBA HBD RB M R

2.18 36.36 14 192.26 3 1 0 38.18

1.66 23.47 13 178.24 3 1 0 45.24

1.45 54.12 17 232.28 4 2 4 66.28

M LD50

0.53 665.83

0.18 1020.63

0.05 1298.11

SA

3.58

3.51

2.46

aspirin ADME 1.43 63.6 13 180.16 4 1 3 43.95 Toxicity 0.43 757.21 Manufacturability 2.20 H

paracetamol (acetaminophen)

diclofenac

omeprazole

0.68 49.33 11 151.16 2 0 1 40.83

4.57 49.33 19 296.15 3 2 4 75.46

2.41 77.11 24 345.42 6 1 5 93.81

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particularly toxicity, NPyr7 seems to be a better candidate for being used as an oral drug to fight OS than NPyr6.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jcim.9b00517. Imaginary frequencies of the HT and RAF transition states. Tunneling corrections for the HT reaction pathways. Gibbs energy of activation for the different reaction pathways. Kinetic data for the reactions of other antioxidants with peroxyl radicals. Branching ratios. Dependence with pH of the rate constants. Contributions of acid−base species to the overall rate constant at different pHs (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. Phone: (52) 5558044600. ORCID

Annia Galano: 0000-0002-1470-3060 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the “Laboratorio de Visualización y Cómputo Paralelo” at Universidad Autónoma Metropolitana−Iztapalapa. This investigation is inserted in research projects IFC-2016/ 1828 and SIP 20182008.

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REFERENCES

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