When the Hindered Phenols Were Used as Antioxidants Reviews
Molecules. 2020 May; 25(10): 2370.
Synthesis, Redox Backdrop and Antibacterial Activity of Hindered Phenols Linked to Heterocycles
Paola Di Donato, Bookish Editor and Brigida Silvestri, Bookish Editor
Received 2020 Apr 21; Accepted 2020 May xix.
Abstract
A serial of benzotriazole, cyclic amides and pyrimidine derivatives, containing 2,six-di-tert-butyl-phenol fragments, were synthesized. The redox backdrop of obtained compounds were studied using the cyclic voltammetry on a platinum electrode in acetonitrile. The oxidation potentials of all substances were comparable to those of BHT. The obtained compounds were tested for their antibacterial activity, and Northward-(2-(3,5-di-tert-butyl-iv-hydroxyphenyl)-2-oxoethyl)isatin (32 μg/mL) exerted expert activity against Staphylococcus aureus.
Keywords: hindered phenols, heterocycles, antioxidants, antibacterial activity
one. Introduction
Oxidative devastation plays an important role in biochemical processes. Free radicals and reactive oxygen species induce the oxidative damage of cell membranes, lipids, proteins, and Deoxyribonucleic acid repair system breakup that is connected with many degenerative diseases, such equally cancer, atherosclerosis, Alzheimer'southward disease [one,2,3]. The principal defence force mechanism of the body is the employ of antioxidants, aiming to scavenge free radicals and inhibit oxidative stress processes, because of their power to break the chain procedure of gratuitous radical oxidation [four]. They either naturally generated in situ (endogenous antioxidants), or are externally provided through foods (exogenous antioxidants) [5]. Sterically hindered phenols have been used as antioxidant agents for more than one-half a century [6,seven]. One of the all-time known representatives of this class of antioxidant agents is 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene, BHT), primarily used in food, cosmetics and pharmaceuticals [5,eight,9,ten], and its derivatives are widely used in the oil industry [11,12]. The efficacy of 2,half dozen-di-tert-butylphenols as inhibitors of oxidative destruction of hydrocarbons is determined past the nature of ortho-alkyl groups and the group in the para-position of the effluvious band, which affects the stability of the phenoxyl radicals generated during oxidation [13,14,15].
In recent years, a great deal of endeavor has been devoted to finding multipotent antioxidants, substances which combine antioxidant activity and other pharmacological furnishings: anti-inflammatory, anticoagulant, anticarcinogenesis activities [xvi].
Among them, a large number of pharmacologically active substances exhibiting a wide variety of chemotherapeutic activity have been synthesized on the ground of sterically hindered phenols and various heterocyclic compounds.
Anti-inflammatory activeness is nigh often constitute in compounds of these series [17,18,xix]. The drugs containing BHT or ii,6-di-tert-butylphenol and heterocycles used to treat inflammatory atmospheric condition, which include tazofelone, darbufelone, prifelone, and tebufelone, are available commercially [twenty].
Additionally, many heterocycles, containing ii,half-dozen-di-tert-butylphenol fragment, that are active confronting various types of cancer, have been plant. Experimental data report on the cytotoxicity confronting tumor lines of epithelioid carcinoma of the cervix uteri (1000-Hela) and chest adenocarcinoma (MCF-vii) of ii,half dozen-diaminopyridine derivatives [21]. Symmetric Southward-BHT derivatives containing ane,3,4-thiadiazole fragments showed antioxidant authorisation and potential to exist useful and promising selective agents confronting breast and colon cancer [22].
Information technology is known that hindered phenols, which are part of natural extracts and synthetic particles, exhibit antibacterial backdrop. [23,24,25,26,27]. However, the number of antibacterial agents based on heterocycles with hindered phenol fragments is not and so broad. In recent years, metal complexes of phthalocyanines and azomethines containing fragments of 2,6-di-tert-butylphenol have been institute to exhibit anti-bacterial activity confronting Gram-negative bacteria East. coli [28,29,30].
Moreover, two,3-dihydropyrrolo [1,ii-a]imidazole I showed high antimicrobial activity when tested for biocidal activity in jet fuels [31]. Compound II was found to have loftier protistocidal action, 10–xv times greater than that of Baycox, which is used for the treatment of coccidiosis in poultry [32]. 1,3,4-Thiadiazole III (Figure i) [33] exhibited a high caste of protection in extending the lifespan of nematodes following S. aureus infection.
Examples of substances, exhibiting antibacterial activeness.
To sum upwards, multipotent antioxidants with antibacterial backdrop are of dandy involvement; in item, for the food manufacture, because both furnishings are highly desirable to keep foods as fresh as possible. Promising results showed above prompted u.s.a. to investigate the chemical diversity of heterocyclic substituents of hindered phenol, which take not yet been explored. The most up-to-engagement rational pattern approach for multipotent antioxidants is to connect an antioxidant group with other pharmacophores [16]. Heterocycles, which we incorporated into the structure of antioxidant: benzotriazole, phthalimide, isatin, succinimide, 2,4-dihydroxypyrimidine, 3,4-dihydropirimidin-ii(1H)-ane, are the basis of antibacterial agents [34,35,36,37,38,39] and, in addition, have an NH grouping available for modification in the cycle. The antioxidant properties can both improve and decrease quite significantly with the introduction of a substituent in the phenol structure [twoscore]; therefore, it is necessary to study the antioxidant backdrop of the obtained compounds.
The aim of this report was to synthesize new multipotent antioxidants, coupling 2,vi-di-tert-butylphenol and a series of heterocycles. The compounds synthesized were assayed for antioxidant and antibacterial activity.
2. Results and Discussions
2.1. Synthesis
The training of the target compounds is outlined in the following; Scheme ane, Scheme 2 and Scheme three. Initially, two-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone one was conveniently obtained from two,6-di-tert-buthylphenol through acylation with acetyl chloride [41] and subsequent bromination [42].
The further synthesis entailed an alkylation heterocycles: benzotriazole, phtalimide, isatin, succinimide, uracil and 5-methyluracil (thymine) by bromo-acetophenon 1 in DMF with KiiCO3. The reaction was carried out at 100 °C for an hour, with the exception of interaction i with uracil and methyluracil: in these cases, the reaction gave black resin, and optimal conditions to obtain compounds vi and 7 were institute to be 70 °C and 4 h.
In the 1H NMR spectra of compounds two–5, all peaks, corresponding to phenol fragment are observed: the singlet peak near 5.83 ppm is attributed to the O–H of the hindered phenol, peaks at vii.82–7.88 ppm with the integration of two protons was assigned to the two symmetrical aromatic band protons, singlet peaks at four.93–5.17, corresponding to CHii-N protons, and in that location are no peaks of NH-protons of starting cyclic imides and benzotriazole.
During the alkylation of uracil and its derivatives, the assail of the alkylating reagent is possible in two directions: N-i atom and N-3 atom [43]. The construction of compounds 6 and 7 was also confirmed with HMBC and HSQC spectra (Figure 2 for seven and Supplementary Cloth for six). The spectrum contains correlation peaks betwixt C-3 and H-6, C-2 and H-six, C-vi and H-2. This indicates that bromo-acetophenone i attacked the N-1 atom of v-methyluracil and uracil.
NMR oneH-13C HMBC spectra of seven.
To expand the range of pyrimidine derivatives, a number of 3,4-dihydropyrimidine (thiones)ones with a hindered phenol fragment were obtained by Biginelli reaction, co-ordinate to Scheme 3.
The most common catalysts reported for the Biginelli reaction are mineral acids (HiiTheniv [44], HCl [45], TFA [46]), Lewis acids (CoClii, ZnCl2 [47]), and other catalytic systems: FeCl3 + HCl [48], TMSCl + NaI [49]. However, in our easily, the products were non obtained when all these weather condition were employed. Previously, researchers from the Vorozhtsov Novosibirsk Establish of Organic Chemistry have synthesized chemical compound 9a in the presence of FeCl3●6H2O equally a catalyst [50]. These conditions (with some correction) turned out to be suitable for the synthesis of compounds 9a–c with yields 55–64%.
In the 1H NMR spectra of compounds 9a–c, there are no peaks in the region of ten.iv ppm corresponding to the proton of the aldehyde grouping. Peaks at vii.02–7.66 ppm respective to the proton of the phenolic group are present in all spectra. Peaks of NH protons in the spectrum of derivatives with C=South groups are shifted to a college-field (7.ii–8 ppm), in comparing with derivatives with the C=O group (7.eight–9 ppm).
2.two. Redox Properties
The antioxidant action of phenolic compounds is revealed, mainly due to their redox backdrop, which tin play an important role in absorbing and neutralizing free radicals, quenching reactive oxygen species, such as singlet and triplet oxygen, or decomposing peroxides [51]. Accented values of oxidation potentials characterize the reducing ability of antioxidant agents and therefore the manifestation of their antioxidant upshot [half-dozen]. Circadian voltammetry is ane of the well-nigh robust methods for studying the redox properties of compounds, as well as evaluating their antioxidant power [52,53,54].
Cyclic voltammogrames of synthesized compounds exhibit one irreversible two-electron peak corresponding to the phenolic fragment oxidation in the anodic region. Table 1 shows the oxidation potentials of the studied compounds. In the case of substances 2–vii the pinnacle potentials are shifted to a more than positive region compared to the BHT, which indicates the enhancement of the electron-windrowing character of the substituent in the para-position to the hydroxy grouping. The compound v, which contains a succinimide fragment, has the highest value of Epa (oxidation potential). Epa of the other compounds are close to those of BHT. The oxidation potentials of compounds 9a–c are lower than those of BHT, for 2 possible reasons.
Table ane
Oxidation potentials (Epa) of compounds 2–7, 9a–c.
| № | 2 | three | 4 | v | half dozen | 7 | 9a | 9b | 9c | BHT |
|---|---|---|---|---|---|---|---|---|---|---|
| Epa, V | 1.54 | 1.57 | i.52 | 1.68 | i.61 | 1.58 | one.49 | 1.48 | 1.46 | 1.52 |
Firstly, compounds two–7 comprise the electron-withdrawing carbonyl group, which decreases the efficacy of phenolic fragment [55]. Notably, the oxidation potential, however, is nonetheless comparable to those of BHT. Secondly, the CH group of the pyridine band affects the oxidation potential; information technology contributes to a shift in the electron density due to the effect of hyperconjugation with the benzene ring [56]. Furthermore, the products of oxidation of compounds 9a–c tin can exist stabilized by the heterocyclic ring, continued directly to the phenolic i [57].
Furthermore, slight differences in the oxidation potentials of compounds 9a, 9b and 9c are observed. Compounds 9b and 9c have exhibited lower value of anodic potential peak compared to compound 9a, due to the strongest electron-withdrawing effect of the ester grouping in the pirimidin ring, compared to the acetyl grouping in compounds 9b and 9c. This can be explained by the fact that the acceptor effect of the thionic group of the pyrimidine ring is weaker than that of the carbonyl group. At the same time, the electron-withdrawing effect of the acetyl group is weaker than of the ester grouping, which explains the everyman oxidation potential of compound 9c.
2.iii. Antibacterial Activity
The antibacterial activity of the synthesized compounds was tested confronting five strains of pathogenic bacteria: Staphylococcus aureus (SA), Escherichia coli (EC), Klebsiella pneumonia (Kp), Acinetobacter baumannii (Ab), Pseudomonas aeruginosa (Pa). The investigation was carried out in the international laboratory CO-Add together based in Institute of Molecular Biological science, Academy of Queensland (Brisbane, Australia). Examination substances were administered at a concentration of 32 μg/mL. Substance may be considered agile if inhibition values equal to or above 80% of inhibition for either replicate (n = ii on unlike plates). The antibacterial activeness for all studied compounds is given in Table ii. The product of isatin alkylation iv exerted good activity against Staphylococcus aureus. Although there is no explicit correlation between antioxidant activeness and antibacterial capacity of investigated substances, we can suppose that the activity of compound 4 is linked with isatin moiety, which is known to possess antibacterial activity [58,59]. This compound was selected as "hit" and tested for the minimum inhibitory concentration (MIC), cytotoxicity against human being embryonic kidney cells and haemolytic activity. It was shown that compound 4 does not inhibit the growth of leaner in smaller concentrations too as the one of human cells.
Table two
Inhibition of bacterial growth, %.
| Sample | Sa | Ec | Kp | Pa | Ab |
|---|---|---|---|---|---|
| 2 | 17.42 | 4.05 | fourteen.45 | 8.08 | eighteen.75 |
| 3 | 16.81 | vii.56 | twenty.34 | 10.92 | 12.56 |
| 4 | 96.6 | −2.04 | thirteen.96 | 0.04 | 41.59 |
| 5 | −viii.94 | 2.53 | 3.38 | xiii.97 | 2.47 |
| 6 | twenty.06 | seven.29 | 10.32 | 18.62 | −1.13 |
| 7 | xiv.9 | vi.12 | 10.36 | 13.half-dozen | 0.53 |
| 9a | xix.thirteen | 8.94 | 9.46 | 18.08 | −v.78 |
| 9b | 26.31 | −two.72 | −3.54 | −ix.39 | −11.19 |
iii. Materials and Methods
3.i. General Information
The NMR 1H and 13C spectra of solutions in DMSO-d6 and CDCl3 were recorded on a Bruker AM-300 spectrometer (Karlsruhe, Federal republic of germany). All experiments were performed according to the standard methods of Bruker. Chemical shifts were reported relative to Me4Si. The values of SSCCs are given in Hz. The mass spectra were recorded on an MS-30 Kratos device (Eu, 70 eV). A peak of the molecular ion M+ was observed for all synthesized compounds. The melting points of the compounds obtained were determined in an open capillary. Elemental assay was carried out using Elemental analyzer Vario micro cube (Langenselbold, Federal republic of germany). The course of reactions and purity of the compounds obtained was monitored past TLC on silica gel plates in a 10:1 benzene-ethanol (10:1 chloroform-ethanol besides can be used) solvent system.
3.2. Synthesis and Analytical Data of Preparated Compounds
three.2.i. Synthesis of Compounds 2–5
A solution of bromoacetophenone i (three mmol) with benzotriazole, phthalimide, isatin or succinimide (3 mmol) and anhydrous K2CO3 (9 mmol) was stirred for 1 h at 100 °C in 15 mL of DMF. Subsequently cooling, it was poured into h2o and the precipitate was filtered off. The precipitate was boiled first in hexane, and so in water. The resulting crystals were recrystallized from an appropriate solvent.
ii-(1H-1,2,3-benzotriazol-1-yl)-1-(3,v-di-tert-butyl-4-hydroxyphenyl)ethanone 2. White solid. Yield 71%. m.p. 166–167 °C (EtOH:HiiO 3:1). NMR iH (DMSO-dsix, δ, ppm, threeJHH, Hz): ane.43 (s, 18H, two(CH3)iii); 6.50 (south, 2H, CH2 N); 7.41 (t, 1H, 5-C CH in benzotriazole, J = 8.1); 7.52 (t, 1H, 6-C CH in benzotriazole, J = 8.1); 7.79 (d, 1H, iv-C CH in benzotriazole, J = x.3), 7.88 (s, 2H, Ar), 8.06 (d, 1H, vii-C CH in benzotriazole, J = eight.06). NMR13C (DMSO-d6, δ, ppm): thirty.4; 35.0; 54.ii; 111.4; 118.three; 119.5; 124.2; 126.0; 126.2; 127.6; 134.five; 138.viii; 145.6; 160.3; 191.five. Elemental assay found: C, 72.15; H, 7.65; N, 11.41. Calculated for C22H27N3O2: C, 72.xxx; H, seven.45; N, 11.50.
two-[2-(3,v-Di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-1H-isoindole-one,3-(2H)–dione 3. White solid. Yield 67%. thousand.p. 188–189 °C (benzene). NMR 1H (DMSO-d6, δ, ppm, 3JHH, Hz): i.41 (s, 18H, 2(CHthree)3); v.17 (s, 2H, CH2 N); 7.82 (s, 2H, Ar in phenol); 7.90 (m, 4H, Ar in phtalimide). NMR13C (DMSO-d6, δ, ppm): 30.4 (2(CHiii)3); 35.1; 44.7 (CHtwo N); 109.vi (phtalimide); 123.viii; 126.0 (phtalimide); 132.one; 135.2; 138.9 (phtalimide); 160.2 (Ar phtalimide); 168.1 (2C=O in imide); 191.3 (C=O). Elemental analysis constitute: C, 73.16; H, vii.08; N, three.51. Calculated for C24H27NO4: C, 73.26; H, 6.92; N, 3.56.
one-[2-(iii,5-Di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-1H-indole-2,3-dione 4. Yellow solid. Yield lx%. m.p. 195–196 °C (EtOH:HtwoO 2:i). NMR oneH (DMSO-d6, δ, ppm, iiiJHH, Hz): 1.41 (s, 18H, 2(CH3)3); 5.08 (southward, 2H, CHiiNorthward); 5.83 (bs, 1H, OH); half-dozen.68 (d, 1H, 7-C CH in isatin, J = 7.3); vii.05 (t, 1H, v-C CH in isatin, J = viii.1); vii.46 (t, 1H, 6-C CH in isatin, J = 8.1); 7.56 (d, 1H, four-C in isatin, J = 7.iii); seven.83 (s, 2H, Ar). NMR13C (DMSO-d6, δ, ppm): 30.ane (2(CH3)3); 34.five; 46.1 (CH2N); 109.6; 110.8; 117.7; 123.nine; 125.4; 126.ane; 136.5; 138.4; 151.2; 158.five (x Ar); 159.6 (C=O 2-C in isatin); 181.6 (C=O 3-C in isatin); 196.vii (C=O). Elemental assay establish: C, 73.18; H, 7.05; N, three.38. Calculated for C24H27NO4: C, 73.26; H, half dozen.92; Due north, three.56.
1-[two-(3,5-Di-tert-butyl-4-hydroxyphenyl)-two-oxoethyl]pyrrolidin-ii,5-dione 5. White solid. Yield 74%. g.p. 259–260 °C (acetonitrile). NMR 1H (CDCliii, δ, ppm, 3JHH, Hz): 1.47 (s, 18H, two(CH3)3); ii.86 (s, 4H, 2CH2 in imide); 4.93 (southward, 2H, CH2N); five.83 (bs, 1H, OH); vii.85 (southward, 2H, Ar). NMRxiiiC (CDCliii, δ, ppm): 28.4 (2CH2 in imide); xxx.ane (two(CHthree)3); 34.4; 44.5 (CH2N); 109.six; 125.9; 136.ix; 159.3 (four Ar); 176.viii (2C=O in imide); 189.two (C=O). Elemental analysis found: C, 69.37; H, 7.97; N, three.95. Calculated for C20H27NO4: C, 69.54; H, 7.88; N, 4.05.
3.ii.ii. Synthesis of Compounds 6, 7.
A solution of bromoacetophenone ane (three mmol) with uracil or 5-metyluracil (3 mmol) and anhydrous K2COiii (9 mmol) was stirred for 4 h at 70 °C in 15 mL of DMF. Afterward cooling, reaction mixture was poured into water and the precipitate was filtered off. The precipitate was refluxed in hexane, and so dissolved in acetone. The unsolved part was filtered off, and acetone was evaporated under residue pressure to give crystalline product, which was recrystallized from an advisable solvent.
1-(ii-(3,5-Di-tert-butyl-four-hydroxyphenyl)-2-oxoethyl)pyrimidine-2,4(1H,3H)-dione vi. Yellow solid. Yield 52%. m.p. 192–193 °C (EtOH:HtwoO iii:1). NMR 1H (DMSO-dhalf dozen, δ, ppm, iiiJHH, Hz): one.43 (s, 18H, ii(CH3)iii); 5.26 (d, 1H, CH in uracil, J = 3.nine); 5.61 (d, 1H, CH in uracil, J = 4.0); 7.53 (due south, 1H, OH); 7.77 (s, 2H, Ar); xi.32 (s, NH). NMR13C (DMSO-dhalf-dozen, δ, ppm): thirty.4 (2(CH3)3); 35.0; 53.7 (CHtwoDue north); 101.2; 125.6; 138.8; 146.ix; 151.vi (C=O); 160.6; 164.iv (C=O); 192.0 (C=O). Elemental analysis plant: C, 67.15; H, 7.22; N, vii.68. Calculated for C20H26Due northiiO4: C, 67.02; H, vii.31; N, 7.82.
ane-[ii-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-5-methylpyrimidin-2,iv (1H, 3H)-dione 7. Yellow solid. Yield 58%. 1000.p. 145–146 °C (EtOH:H2O 2:one). NMR 1H (DMSO-d6, δ, ppm, 3JHH, Hz): 1.43 (s, 18H, two(CH3)3); 1.77 (s, 3H, CH3); v.22 (s, 2H, CH2N); 7.42 (s, 1H, CH-N); vii.77 (s, 2H, Ar); 7.99 (s, 1H, OH); 11.31 (s, 1H, NH). NMR13C (DMSO-dhalf dozen, δ, ppm): 12.4 (CH3); thirty.41 (2(CHthree)3); 35.0; 53.half-dozen (CHtwoN); 108.7; 125.6; 126.iii; 138.9; 142.vi; 151.half-dozen (C=O); 160.0; 164.9 (C=O); 192.four (C=O). Elemental analysis found: C, 67.82; H, 7.74; N, 7.l. Calculated for C21H28NtwoO4: C, 67.72; H, 7.58; N, 7.52.
3.2.3. Synthesis of Compounds 9a–c.
A mixture of aldehyde eight (4 mmol), urea or thiourea (eight mmol) and appropriate dicarbonyl compound (five.two mmol), was dissolved in 13 mL of ethanol. Then, FeCl3●6H2O (4 mmol) was added to the mixture as a catalyst. The reaction proceeded for 18 h; its progress was monitored by TLC. Afterwards cooling the reaction mixture, a precipitate formed which was filtered under vacuum, washed with benzene, and recrystallized from an appropriate solvent.
Ethyl-4-(three,five-di-tert-butyl-4-hydroxyphenyl)-vi-methyl-2-oxo-1,ii,3,4-tetrahydro-pyrimidine-5-carboxylate 9a. White solid. Yield 55%. chiliad.p. 227–228 °C (EtOH:HiiO four:1). NMR 1H (CDCl3, δ, ppm, iiiJHH, Hz): 1.11 (t, 3H, CHiii, J = 7.1 Hz,); 1.41 (s, 18H, t-Bu); 2.27 (due south, 3H, CH3); four.02 (q, 2H, CH2, J = seven.i Hz,); 5.12 (s, 1H, CH); 5.80 (s, 1H, OH); seven.03 (s, 2H, Ar); vii.66 (s, 1H, NH); nine.78 (s, 1H, NH). NMR13C (CDCl3, δ, ppm): fourteen.2; eighteen.half-dozen; 30.2; 34.3; 55.vii; 59.9; 102.0, 123.1; 134.six; 136.0; 145.8; 153.4; 162.3, 165.9. Elemental analysis found: C, 68.11; H, 8.48; Northward, vii.13. Calculated for C22H32Due northtwoO4: C, 68.01; H, viii.30; N, 7.21.
Ethyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-2-thioxo-1,ii,3,iv-tetrahydro-pyrimidine-5-carboxylate 9b. White solid. Yield 61%. 1000.p. 235–237 °C (EtOH:HtwoO 2:1). NMR aneH (CDCl3, δ, ppm, 3JHH, Hz): 1.11 (t, 3H, CH3, J = 7.1 Hz,); 1.34 (s, 18H, t-Bu); ii.37 (south, 3H, CH3); 4.12 (q, 2H, CHii, J = 7.1 Hz,); five.24 (south, 1H, CH); five.35 (s, 1H, OH); seven.01 (due south, 2H, Ar); 7.38 (s, 1H, NH); 8.13 (southward, 1H, NH). NMRxiiiC (CDCliii, δ, ppm): 14.2; 18.2; 30.2; 3.3; 56.2; lx.3; 103.half dozen; 123.4; 128.4; 133.2; 136.2; 142.4; 153.8; 165.five. Elemental analysis found: C, 65.15; H, viii.08; N, 6.77; S, seven.82. Calculated for C22H32North2O3S: C, 65.31; H, 7.97; N, six.92; S, 7.92.
1-(iv-(3,v-Di-tert-butyl-4-hydroxyphenyl)-6-methyl-ii-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethan-1-one 9c. White solid. Yield 64%. m.p. 204–206 °C (EtOH:HtwoO four:ane). NMR 1H (DMSO-d6, δ, ppm, threeJHH, Hz): 1.41 (s, 18H, t-Bu); 1.48 (south, 3H, CHthree); v.26 (s, 1H, CH); 7.05 (south, 1H, OH); 7.36 (southward, 2H, Ar); 7.73(s, 1H, NH); 8.03 (due south, 1H, NH). NMRxiiiC (DMSO-dvi, δ, ppm): 19.4; 30.1; 30.2; 34.four; 56.8; 111.7; 123.7; 128.4; 132.2; 136.6; 141.6; 154.1; 195.8. Elemental analysis constitute: C, 67.44; H, viii.25; N, 7.36; S, viii.47 Calculated for C21HthirtyN2O2S: C, 67.34; H, 8.07; N, 7.48; South, 8.56.
3.3. Redox Backdrop
Cyclic voltammetry (CV) was carried out in the argon atmosphere in a three-electrode cell using an Ecotest-VA potentiostat (Moscow, Russia). The working electrode was a stationary platinum electrode Southward = of 3 mmtwo; the auxiliary electrode was a platinum plate (S = 18 mm2). The reference electrode was (Ag/AgCl/KCl), with a waterproof diaphragm. The potential sweep rate was 0.2 V·s–one. Et4NClO4 (99%, Acros) for the supporting electrolyte was twice recrystallized from the aqueous ethanol and dried for 48 h in vacuum at 50 °C. The concentration of the studied compounds was 5 mM.
3.4. Biological Action
Antimicrobial screening was performed past CO-ADD (The Community for Antimicrobial Drug Discovery), funded past the Wellcome Trust (London, United kingdom) and The Academy of Queensland (Brisbane, Australia). The antimicrobial activities were evaluated against cultures of Staphylococcus aureus ATCC 43300, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603, Acinetobacter baumannii ATCC 19606, and Pseudomonas aeruginosa ATCC 27853. Compounds were plated every bit a 2-fold dose response from 32 to 0.25 μg/mL (or 20 to 0.156 uM), with a maximum of 0.5% DMSO, final in analysis concentration. The growth inhibition of all bacteria was adamant measuring absorbance at 600 nm (OD600), using a Tecan M1000 Pro monochromator plate reader. The pct of growth inhibition was calculated for each well, using the negative control (media simply) and positive control (bacteria without inhibitors) on the same plate equally references. The minimum inhibitory concentration (MIC) was determined following the CLSI guidelines, identifying the lowest concentration at which full inhibition of the leaner has been detected. Full inhibition of growth has been divers at <20% growth (or >80% inhibition), and concentrations have only been selected if the next highest concentration displayed full inhibition (i.e., lxxx–100%) too (eliminating 'singlet' active concentration).
Growth inhibition of HEK293 cells was determined measuring fluorescence at ex:530/10 nm and em:590/10 nm (F560/590), after the add-on of resazurin (25 µg/mL concluding concentration) and incubation at 37 °C and 5% COii, for an boosted 3 h. The fluorescence was measured using a Tecan M1000 Pro monochromator plate reader. The percent of growth inhibition was calculated for each well, using the negative control (media only) and positive control (prison cell culture without inhibitors) on the aforementioned plate as references.
iv. Conclusions
In this study, the synthesis, redox properties and anibacterial activity of 9 2,half dozen-di-tert-buthylphenol derivatives linked to different heterocycles are described. For uracil and thymine, information technology is revealed by 2D-NMR spectroscopy that substitution takes identify at the N-1 atom. Electrochemical studies of obtained compounds prove, that the nature of the substituent in the 4th position of the phenolic ring strongly influences on the antioxidant activity. Compounds 2–5 with an electron-withdrawing linker between heterocycle and phenol showed a shift in the oxidation potential to the positive region, but its values are still comparable to those of BHT. Dihydropyrimidines 9a–c, in which the heterocycle was connected with phenol, directly showed lower value of oxidation potential and higher antioxidant abilities. Studies of antibacterial properties showed that N-(two-(3,5-di-tert-butyl-4-hydroxyphenyl)-ii-oxoethyl)isatin 4 is agile confronting Staphylococcus aureus in concentration 32 μg/mL, with a low toxicity against human cells. Thus, chemical compound 4 was institute to be the multipotent antioxidant.
Scheme of training of bromo-acetophenon 1.
Scheme of grooming of compounds two–vii.
Scheme of preparation of 3,four-dihydropirimidin-2(1H)-one 9a and thiones 9b–c.
Supplementary Materials
1H-NMR and 13C-NMR spectra of obtained compounds.
Author Contributions
O.V.P., concept, performing chemical synthesis and purification, spectroscopy experiments, writing manuscript. S.V.5., analyzing spectroscopy data, writing manuscript. Fifty.V.I., electrochemical experiments, analyzing data, writing manuscript. 5.N.K., concept, supervision, writing manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of involvement.
Footnotes
Sample Availability: Samples of the compounds ane–9a–c are available from the authors.
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