Acetylcholinesterase inhibitory and antioxidant activities of novel symmetric sulfamides derived from phenethylamines.

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Arch. Pharm. Chem. Life Sci. 2015, 348, 446–455

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Full Paper Acetylcholinesterase Inhibitory and Antioxidant Activities of Novel Symmetric Sulfamides Derived from Phenethylamines _ € ksu1 € mer3, and Su € leyman Go Kadir Aksu1, Fevzi Topal1, Ilhami Gulcin1,2, Ferhan Tu 1 2

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Department of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey Fetal Programming of Diseases Research Chair, Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia Department of Chemistry, Faculty of Science and Arts, Sutcu Imam University, Kahramanmaras, Turkey

The antioxidant and acetylcholinesterase inhibitory properties of novel symmetric sulfamides derived from phenethylamines were evaluated. Phenethylamines 8–11 were reacted with SO2Cl2 in the presence of Et3N to afford sulfamides in good yields. The synthesized sulfamides were converted to their phenolic derivatives with BBr3. We elucidated the antioxidant activity of novel symmetric sulfamides by using different bioanalytical assays. For this purpose, the radical scavenging activities of the novel symmetric sulfamides were assessed by DPPH•, ABTS•þ, DMPD•þ, and O2•– radical scavenging tests. In addition, the reducing abilities of the novel symmetric sulfamides were evaluated by Fe3þ-Fe2þ reducing, Cu2þ-Cuþ reducing, and [Fe3þ-(TPTZ)2]3þ-[Fe2þ-(TPTZ)2]2þ reducing activity tests. Also, the Fe2þ chelating activity by the pipyrdyl reagent and the acetylcholinesterase inhibitory activities of the novel symmetric sulfamides were studied. Especially, the novel phenolic and symmetric sulfamides 16–19 showed high antioxidant and acetylcholinesterase inhibitory properties. On the other hand, IC50 values were calculated for the DPPH•, ABTS•þ, DMPD•þ, and O2•–scavenging, the metal chelating, and the acetylcholinesterase inhibition effects of the novel symmetric sulfamides. Keywords: Acetylcholine esterase / Antioxidant activity / Enzyme inhibition / Phenethylamines / Sulfamide Received: February 3, 2015; Revised: March 13, 2015; Accepted: March 20, 2015 DOI 10.1002/ardp.201500035

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Additional supporting information may be found in the online version of this article at the publisher’s web-site.

Introduction € ksu, Department of Chemis€ leyman Go Correspondence: Prof. Su € rk University, 25240 Erzurum, Turkey. try, Faculty of Science, Atatu E-mail: [email protected] Fax: þ90-442-2360948 Abbreviations: DPPH•, 1,1-diphenyl-2-picrylhydrazyl radicals; DMPD•þ, N,N-dimethyl-p-phenylenediamine radicals; ABTS•þ, 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DTNB, 5,50 dithio-bis(2-nitro-benzoic)acid; TPTZ, 2,4,6-tripyridyl-s-triazine; BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; TBHQ, t-butylhydroquinone; PG, propyl gallate; FRAP, ferric reducing antioxidant power; IC50, the half maximal inhibitory concentration; O2•, superoxide anion radicals; EDTA, ethylenediaminetetraacetic acid; AChE, acetylcholinesterase enzyme; AChI, acetylcholiniodate; NBT, nitro blue tetrazolium.

Sulfamides are an important class of organic compounds that have attracted attention in synthetic organic chemistry and medicinal chemistry [1]. Some drugs such as doripenem (1) [2], quinagolide (2) [3], macitentan (3) [3], and famotidine (4) [4] bear sulfamide units in their structures. It has been reported that sulfamide 5, a derivative of trace amine phenethylamine, shows protein tyrosine kinase inhibitory [5], treatment of diabetes [6], HCV replication inhibitory [7], and endothelin receptor antagonists [8] activities. Recently, human carbonic anhydrases inhibition properties of some methoxylated derivatives of 5 have been reported by our group [9]. Compound 6 is a derivative of 5 and it has hormone-sensitive lipase inhibitory action for the

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Arch. Pharm. Chem. Life Sci. 2015, 348, 446–455 Acetylcholinesterase Inhibitory and Antioxidant Activities of Sulfamides

treatment of diabetes and related disorders [10]. Symmetric sulfamide 7 derived from phenethylamine has a wide range of beneficial biological activities such as antiprotozoal [11], anticonvulsant [12], antitrypanosomal [13], anxiolytic [14], and inhibition pattern in binding to carbonic anhydrase isoforms I, II, VII, XII, and XIV [15]. The synthesis [16], carbonic anhydrase [17–19], and acetylcholinesterase [20] inhibitory properties of some other sulfamides have also been reported by our group (Fig. 1). Oxidation process is the electron(s) transfer between two atoms and stands for a required part of aerobic life and our metabolism [21, 22]. Lipid oxidation is one of the most important factors limiting the shelf life and protection of many food and pharmaceutical products. It produces not only undesirable off-flavors, but also decreases the nutritional safety and quality of food products, which are unacceptable to consumers [23–25]. Among the methods employed to retard or inhibition of lipid oxidation, the one including the addition of antioxidants is the most effective solution [26–29]. Antioxidants are bioactive compounds that are commonly used to preserve the quality of food and pharmaceutical products by protecting them against oxidation rancidity [30, 31]. Moreover, they protect the human body from many chronic cardiovascular diseases, including cancers, and aging via capturing free radicals [32]. Antioxidant is a compound that prevents or retards the oxidation of substrates even if this compound is available in substantially lower concentration than the oxidized substrates [33]. Synthetic antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), t-butylhydroquinone (TBHQ), and propyl gallate (PG) are the most widely used synthetic antioxidants in the foods and pharmaceuticals additives to prevent oxidative deterioration of food products. There is a worldwide trend toward the use of safer antioxidants [34–36]. In recent decades, safety concerns over synthetic antioxidants have led to consumer

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interest in natural replacements. Additionally, it is very important to find out new sources for the synthesis of safer and inexpensive antioxidants. Thus, researchers are constantly looking for new natural antioxidants [37–39]. In this study, we report the synthesis and characterization of several novel symmetric sulfamides and their antioxidant, antiradical, metal binding, acetylcholinesterase inhibitory, and reducing activities which were spectrophotometrically determined by different bioanalytical methods.

Results and discussion Chemistry The synthesis of symmetric sulfamides can be achieved from the reaction of free amines with sulfuryl chloride (SO2Cl2). This synthetic methodology has been described for the synthesis of N,N 0 -bis(2-phenylethyl)-sulfamide (7) by Gavernet et al. [12]. A similar synthesis can also be carried out from the reaction of amines with sulfonyldiimidazole [40] and catechol sulfate [41]. In this study, the first synthetic methodology including the reaction of free amines with SO2Cl2 was chosen for the synthesis of symmetric sulfamides with a slight modification. In this context, free amines 8–11 were reacted with SO2Cl2 in methylene chloride (CH2Cl2) in the presence of triethyl amine (Et3N) at 0°C for 1 h then at room temperature (rt) for 3 h to give sulfamides 12–15 in high yields. To compare the biological activities of compounds 12–15 with their phenolic derivatives, compounds 12–15 were converted to their phenolic derivatives 16–19. In our previous studies, we synthesized a series of bromophenols [42, 43] and phenolic sulfonamides [44] from demethylation of aryl methyl ethers with boran tribromide (BBr3). Hence, this demethylation method was applied to 12–15 to give 16–19. The reaction of sulfamides 12–15 with BBr3 in CH2Cl2 at 0°C for 1 h then at rt

Figure 1. Some selected drugs 1–4 and biologically active sulfamides 5–7.


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Arch. Pharm. Chem. Life Sci. 2015, 348, 446–455 K. Aksu et al.

for 23 h under N2 afforded phenolic sulfamides 16–19 with the yields ranging from 67 to 74% (Scheme 1). The structures of all the synthesized compounds were characterized by 1H NMR, 13 C NMR, IR, and elemental analysis.

Antioxidant properties The human diet contains different compounds that possess antioxidant activities. Phenolic compounds are a class of chemicals consisting of a hydroxyl group (–OH) bonded directly to an aromatic hydrocarbon ring. They are secondary plant metabolites and naturally present in almost all plant materials, including food and pharmaceutical products of plant origin. Phenolic compounds are thought to be an integral part of both human and animal diets and frequently used for pharmacological applications [45–51]. The antioxidant capacities of novel symmetric sulfamides are determined by using several antioxidant methods. [Fe(CN)6]3þ [Fe(CN)6]2þ reduction method is the first antioxidant evaluation being used of novel symmetric sulfamides [52]. As can be seen in Table 1, novel symmetric sulfamides demonstrated effective ferric ions (Fe3þ) reducing ability and these differences were statistically very significant (p < 0.01). Increased [Fe(CN)6]2þ absorbance of the reaction mixture indicates increased reducing capacity due to an increase in the formation of the complex. Reducing ability of novel symmetric sulfamides and standard compounds exhibited the following order: 16 (2.291 0.049) > BHA (2.072 0.192) > BHT (1.923 0.274) > trolox (1.391 0.102) > a-tocopherol (0.848 0.159) > 17 (0.475 0.023) > 14 (0.199 0.055) > 19 (0.183 0.056) 13


(0.180 0.022) 18 (0.171 0.024) 15 (0.161 0.039) 12 (0.157 0.048). The results clearly demonstrated that novel symmetric sulfamides 16 showed the most powerful Fe3þ ability and changed yellow color of the test solution to green or blue depending on their reducing properties. Cupric ions (Cu2þ) are reducing assays based on reduction Cu2þ to Cuþ combined action of all antioxidants or reducing in aqueous–ethanolic medium (pH 7.0) in the presence of neocuproine yielding Cuþ complexes with maximum absorption peak at 450 nm [53]. This reducing method is costeffective, selective, rapid, stable, and suitable for antioxidants regardless of hydrophilicity or chemical type [54]. Cu2þ reducing capacity of novel symmetric sulfamides and standard compounds are shown in Table 1. Cupric ions reducing power of novel symmetric sulfamides and standard compounds at the same concentration (20 mg/mL) exhibited the following order: 16 (0.914 0.088) > BHT (0.908 0.094) > BHA (0.854 0.078) > trolox (0.780 0.080) 17 (0.770 0.034) > a-tocopherol (0.592 0.046) > 18 (0.490 0.021) > 19 (0.346 0.44) > 14 (0.254 0.056) > 13 (0.166 0.040) > 12 (0.140 0.025) 15 (0.136 0.046). Cu2þ reducing assays can be used for measurement of activity of antioxidants, which include thiol groups such as glutathione [53–55]. On the other hand, FRAP assay measures the antioxidant ability to reduce the ferric [Fe3þ-(TPTZ)2]3þ to the intensely blue colored ferrous complex [Fe2þ-(TPTZ)2]2þ in acidic medium [56, 57]. FRAP assay is one of the widely simple and convenient methods for determining the antioxidants activity [58]. This assay is conducted at acidic pH 3.6 to

Scheme 1. Synthesis of sulfamides and their phenolic derivatives. (i) SO2Cl2/Et3N, CH2Cl2, 0–25°C, 4 h; (ii) BBr3, CH2Cl2, 0–25°C, 24 h, then cold H2O.


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Table 1. Determination of reducing power of same concentration (20 mg/mL) of novel symmetric sulfamides (12–19) by FRAP methods, ferric ions (Fe3þ) reducing and cupric ions (Cu2þ) reducing capacity by CUPRAC method.a) Cu2þ-Cuþ reducing

Fe3þ-Fe2þreducing Compounds BHA BHT a-Tocopherol Trolox 12 13 14 15 16 17 18 19

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R2

0.9859 0.9588 0.9985 0.9973 0.9430 0.9986 0.9725 0.9430 0.9971 0.9525 0.9020 0.9386

2.072 1.923 0.848 1.391 0.157 0.180 0.199 0.161 2.291 0.475 0.171 0.183

0.192 0.274 0.159 0.102 0.048 0.022 0.055 0.039 0.049 0.023 0.024 0.056

Fe3þ-TPTZ reducing

l450

R2

0.9410 0.9482 0.9778 0.9932 0.9450 0.9281 0.9199 0.9317 0.9533 0.9403 0.9954 0.9556

0.854 0.908 0.592 0.780 0.140 0.166 0.254 0.136 0.914 0.770 0.490 0.346

0.078 0.094 0.046 0.080 0.025 0.040 0.056 0.046 0.088 0.034 0.021 0.440

l593

R2

0.9847 0.9707 0.9973 0.9971 0.9293 0.9320 0.9351 0.9334 0.9850 0.9691 0.9460 0.9374

1.994 1.343 1.255 1.611 0.510 0.514 0.592 0.522 2.048 1.285 0.569 0.553

0.030 0.137 0.052 0.046 0.015 0.012 0.035 0.070 0.103 0.042 0.016 0.013

The results are average of triplicate analysis. a) Expressed as absorbance values.

maintain iron solubility. Decreases observed in the results in terms of the reducing abilities of the symmetric sulfamides and standard compounds samples were as follows: 16 (2.048 0.103) > BHA (1.994 0.030) > trolox (1.611 0.046) > BHT (1.343 0.137) 17 (1.285 0.042) > a-tocopherol (1.255 0.052) > 14 (0.592 0.035) > 18 (0.569 0.016) 19 (0.553 0.013) > 15 (0.522 0.070) > 13 (0.514 0.012) 12 (0.510 0.015). These results emphasized that symmetric sulfamides 16 and 17 had notable Fe3þ reducing ability and electron donor properties for neutralizing free radicals. The antioxidant activity of phenolic compounds depends on the number and position of the hydroxyl groups (–OH) bound to the aromatic ring, the binding site and mutual position of –OH in the aromatic ring, and the type of substituents [50, 54]. It was reported that phenolic compounds are not active antioxidants unless substitution at either the ortho- or para- position has increased the electron density at the hydroxyl group and lowered the oxygen–hydrogen bond energy [59, 60]. The novel sulfamide 16 had symmetric neighboring two hydroxyl groups. Thereby, this symmetric sulfamide is expected to show strong reducing activity. The presence of different substituents in the phenol backbone structure modulates their antioxidant property, in particular their hydrogen-donating capacity. In addition, the presence of a carbonyl group such as aromatic acid, ester, or lactone enhanced its antioxidant activity [54]. Also, it is well known that steric and electronic effects are responsible for the antioxidant activities and stoichiometric factors of the chain-breaking phenolic antioxidants [61]. The antioxidant activity of a molecule also increases when its carbonyl group is separated from the aromatic ring. For instance, cinnamic acid is more effective as an antioxidant than the corresponding benzoic acid. Steric hindrance of the phenolic hydroxyls by a neighboring

inert group such as methoxy groups enhanced its antioxidant activity [51, 62]. Radical scavenging activities spectrophotometrically determine the scavenging capacities and antioxidant capacity of pure compounds [63, 64]. The radical scavenging properties of novel symmetric sulfamides were investigated by DPPH•, ABTS•þ, DMPD•þ, and O2• scavenging assays. DPPH, a stable N-centered free radial, has been well used to employ the ability of free radical scavenging properties or hydrogen donation of compounds and medicinal/pharmaceutical materials [65, 66]. This is a fast and simple radical scavenging method. In this study, DPPH• scavenging assay was used for the primary screening of novel symmetric sulfamides free radical scavenging activity [67, 68]. Consequently, novel symmetric sulfamides in particular symmetric sulfamides 16 and 17 exhibit a remarkable DPPH free radical scavenging activity. As can seen in Table 2, IC50 values of DPPH• scavenging effects of symmetric sulfamides 16–19 and standard radical scavengers increased in the following order: 16 (8.34 mg/mL) > 18 (29.37 mg/mL) > 17 (40.76 mg/mL) > 19 (62.14 mg/mL). A lower IC50 value indicates a powerful DPPH• scavenging activity. On the other hand, BHA, BHT, a-tocopherol, and trolox demonstrated the IC50 values of 10.82, 24.75, 14.74, and 7.01 mg/mL, respectively. Additionally, IC50 values of pro-compounds 12–15 of phenolic symmetric sulfamides 16–19 are in the range of 342.10–693.00 mg/mL. These results clearly showed that novel symmetric sulfamides 16–19 had notable DPPH• scavenging ability and electron donor properties for neutralizing free radicals. In ABTS•þ scavenging assay, ABTS is oxidized by oxidants like K2S2O8 and MnO2 to its radical cation (ABTS•þ), which is intensely colored and has the antioxidant capacity measured as the ability of pure compounds to decrease the color reacting directly with the ABTS•þ. ABTS•þ radicals are more


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Table 2. Determination of half maximal concentrations (IC50) of novel symmetric sulfamides and standards for radical scavenging AChE inhibition, Fe2þ chelating, DPPH•, ABTS•þ, DMPD•þ, and O2• scavenging assays.

Compounds BHA BHT a-Tocopherol Trolox 12 13 14 15 16 17 18 19 Tacrined) EDTAe)

AChE inhibitiona) IC50

Ki

– – – – 2.17 3.75 4.34 3.19 3.76 1.96 2.11 2.33 252.45

– – – – 0.62 5.38 4.25 2.87 2.13 0.59 1.15 2.12 71.18

Fe2þ chelatingb)

DPPH• scavengingb)

ABTS•þ scavengingb)

DMPD•þ scavengingb)

O2• scavengingb)

86.63 25.67 38.60 99.01 19.80 18.23 8.25 18.73 17.70 18.66 18.24 18.24 – 8.25

10.82 24.75 14.74 7.01 602.14 693.00 346.50 342.10 8.34 40.76 29.37 62.14 – –

11.73 11.80 12.58 11.97 49.01 57.71 49.50 57.75 5.97 11.69 11.67 7.87 – –

26.65 c) c) 10.19 69.30 77.00 86.62 69.30 21.00 18.23 28.87 23.31 – –

15.06 33.00 49.50 46.51 33.01 40.76 34.65 53.31 16.92 26.20 13.32 24.75 – –

The results are average of triplicate analysis. a) They were determined as nM. b) They were determined as mg/mL. c) Hydrophobic antioxidants such as a-tocopherol or BHT did not show activity in this assay. d) Tacrine was used as positive control for AChE inhibition. e) EDTA was used as positive control for metal chelating activity. reactive than DPPH radicals and applicable for both hydrophilic and lipophilic compounds [69, 70]. As seen in Table 2, the results indicate important ABTS•þ scavenging due to the scavenging ability of novel symmetric sulfamides 16–19. IC50 values of ABTS•þ scavenging of novel symmetric sulfamides 16–19 increased by the following order: 16 (5.97 mg/mL) > 19 (7.87 mg/mL) > 18 (11.67 mg/mL) 17 (11.69 mg/mL). In addition, IC50 value of pro-compounds 12–15 of phenolic symmetric sulfamides 16–19 was found ranging 49.01– 57.75 mg/mL. Also, BHA (11.73 mg/mL), BHT (11.80 mg/mL), a-tocopherol (12.58 mg/mL), and trolox (11.97 mg/mL) were used as positive controls for ABTS•þ scavenging activity. DMPD•þ scavenging assay is another frequently used method for radical scavenging activity and antioxidant capacity of pure compounds [71, 72]. Antioxidant substances are able to transfer a hydrogen atom to DMPD•þ, turn off color of the solution, and provide decolorization (DMPDþ). As shown in Table 2, novel symmetric sulfamides 16–19 exhibited a marked DMPD•þ scavenging activity. IC50 value of DMPD•þ scavenging activity of novel symmetric sulfamides 16–19 was found to be 18.23 mg/mL for symmetric sulfamide 17, 21.00 mg/mL for symmetric sulfamide 16, 23.31 mg/mL for symmetric sulfamide 19, and 28.87 mg/mL for symmetric sulfamide 18. On the other hand, this value (IC50) was found as 10.10 mg/mL for trolox and 26.65 mg/mL for BHA, respectively. There was a significant decrease (p < 0.05) control value and DMPD•þ scavenging capacity of novel symmetric sulfamides 16–19. Also, IC50 value of pro-compounds 12–15 of phenolic symmetric sulfamides (16–19) was found ranging

69.30–86.62 mg/mL. It was reported that the main drawback of the DMPD•þ scavenging method is that its reproducibility and sensitivity dramatically decreased when hydrophobic antioxidants such as BHT or a-tocopherol were used. Because of this reason, both the positive controls were not used in DMPD•þ scavenging assay [55]. In superoxide anion radical (O2•) scavenging method, O2• reduces nitro blue tetrazolium (NBT) to the yellow dye (NBT2þ) to produce the blue formazan, which is spectrophotometrically measured at 560 nm [73]. Novel symmetric sulfamides 16–19 had distinctive inhibition of O2• generation. As seen in Table 2, IC50 values belonging to inhibition of O2• generation of novel symmetric sulfamides 12–19 were found to be 33.01, 40.76, 34.65, 53.31, 16.92, 26.20, 13.32, and 24.75 mg/mL, respectively. The most effective O2• scavenging activity was observed in symmetric sulfamide 18 and had higher O2• scavenging activity than that all of tested reference compounds. On the other hand, BHA, BHT, a-tocopherol, and trolox exhibited IC50 values of 15.06, 33.00, 49.50, and 46.51 mg/mL in O2• scavenging activity, respectively. Iron and copper are the most important elements for the living organisms, whereas excessive amounts of both metal ions are potentially dangerous [74]. Fe2þ had high reactivity that can stimulate lipid peroxidation and accelerate lipid peroxidation [75, 76]. Therefore, the Fe2þ chelating activity is considered to be an important antioxidant property of materials. In this study, the Fe2þ chelating ability was determined by the reduction of absorbance at 562 nm [77, 78]. Novel symmetric sulfamides 12–19 had efficient chelating


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effect on ferrous ions (Fe2þ). IC50 values of metal chelating effect of novel symmetric sulfamides 12–19 increased in the following order: 14 (8.25 mg/mL) > 16 (17.70 mg/mL) 13 (18.23 mg/mL) 18 (18.24 mg/mL) ¼ 19 (18.24 mg/mL) 17 (18.66 mg/mL) 15 (18.73 mg/mL) 12 (19.80 mg/mL). These new synthesized symmetric sulfamides 12–19 had more effective IC50 values of Fe2þ chelating activity than that of standard antioxidants like BHA (86.63 mg/mL), BHT (25.67 mg/ mL), a-tocopherol (38.60 mg/mL), and trolox (99.01 mg/mL) but lower than that of EDTA (8.25 mg/mL). In this assay, novel symmetric sulfamides 12–19 disrupted the formation of the Fe2þ-ferrozine complex. It suggests that novel symmetric sulfamides 12–19 have chelating activity and are able to capture Fe2þ before ferrozine. AChE was also highly inhibited by novel symmetric sulfamides (12–19) at the low nanomolar inhibition with Ki values in range of 0.59–5.38 nM (Table 2). The most powerful inhibition was observed by symmetric sulfamide 12 with a Ki value of 0.59 nM. Additionally, all the other newly synthesized symmetric sulfamides reported here were highly efficient inhibition constants against AChE. On the other hand, tacrine, which is the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease, demonstrated Ki value of 71.18 nM.

Conclusion In summary, starting from dopamine-related compounds, a series of symmetric sulfamides 12–15 and their phenolic derivatives 16–19 were synthesized. The synthesized compounds were studied for their antioxidant and acetylcholinesterase inhibitory activities. Symmetric sulfamides 12–15, especially their phenolic derivatives 16–19, were found to have high acetylcholinesterase inhibition and antioxidant activities in different bioanalytical assays including reducing power, DPPH•, ABTS•þ, DMPD•þ, and O2•- radical scavenging, and Fe2þ-chelating activities. Based on the discussion above, novel symmetric sulfamides 12–15 and their phenolic derivatives 16–19 can be used for minimizing or preventing lipid oxidation in food and pharmaceutical products, retarding the formation of toxic oxidation products, maintaining nutritional quality, and prolonging the shelf life of pharmaceuticals.

Experimental General information

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Me4Si as the internal standard. Elemental analyses were performed on a Leco CHNS-932 apparatus. All column chromatography was performed on silica gel (60-mesh, Merck). PLC is preparative thick-layer chromatography: 1 mm of silica gel 60 PF (Merck) on glass plates.

Chemistry General procedure for the synthesis of sulfamides: Synthesis of N,N0 -bis[2-(3,4-dimethoxyphenyl)ethyl]sulfamide (12) 3,4-Dimethoxyphenethyl amine (8) (0.50 g, 2.76 mmol) was dissolved in CH2Cl2 (15 mL). After the solution was cooled 0°C, NEt3 (0.34 g, 3.31 mmol) was added to this solution. To this solution was added a cooled solution of SO2Cl2 (0.19 g, 1.38 mmol) in CH2Cl2 (10 mL) dropwise over 20 min. The reaction mixture was stirred at 0°C for 1 h. Then at rt for 3 h. The reaction mixture was cooled to 0°C and a solution 0.1 N HCl (40 mL) was added to this solution. Organic layer was separated and H2O layer was extracted with CH2Cl2 (2 30 mL). Combined organic layers were dried over Na2SO4 and CH2Cl2 was evaporated. The column chromatography of the residue on silica gel (50 g) with 25% EtOAc/hexane yielded N,N0 -bis[2-(3,4dimethoxyphenyl)ethyl]-sulfamide (12) [79] (0.85 g, 73%). Yellow solid. mp: 83–84°C. IR (CH2Cl2, cm1) 3403, 2928, 1526, 1452, 1310, 1255, 1186. 1H NMR (400 MHz, CDCl3) d 7.00 (d, 2H, J ¼ 7.9 Hz, 2Ar-H), 6.43 (d, 2H, J ¼ 2.2 Hz, 2Ar-H), 6.42 (dd, 2H, J ¼ 2.2, J ¼ 10.6 Hz, 2Ar-H), 4.21 (t, 2H, J ¼ 5.9 Hz, 2NH), 3.782 (s, 6H, 2OCH3), 3.779 (s, 6H, 2OCH3), 3.14 (q, 4H, J ¼ 6.5 Hz, 2CH2), 2.74 (t, 4H, J ¼ 6.7 Hz, 2CH2). 13C NMR (100 MHz, CDCl3) d 159.9 (2C), 158.4 (2C), 131.0 (2CH), 118.8 (2C), 104.2 (2CH), 98.7 (2CH), 55.4 (2OCH3), 55.3 (2OCH3), 43.2 (2CH2), 29.9 (2CH2). Anal. calcd. for (C20H28N2O6S): C 56.59; H 6.65; N 6.60; S 7.55. Found: C 56.60; H 6.63; N 6.57; S 7.57.

N,N0 -Bis[2-(2,4-dimethoxyphenyl)ethyl]-sulfamide (13) The general procedure for the synthesis of 12 was applied to amine 9 to give symmetric sulfamide 13. 83% yield. Brown solid, mp: 91–92°C. IR (CH2Cl2, cm1) 3301, 2943, 1419, 1357, 1236, 1108. 1H NMR (400 MHz, CDCl3) d 6.80 (d, 2H, J ¼ 7.9 Hz, 2Ar-H), 6.70–6.73 (m, 2H, 2Ar-H), 6.70 (s, 2H, 2Ar-H), 4.23 (t, 2H, J ¼ 6.2 Hz, 2NH), 3.87 (s, 6H, 2OCH3), 3.85 (s, 6H, 2OCH3), 3.21 (q, 4H, J ¼ 6.7 Hz, 2CH2), 2.77 (t, 4H, J ¼ 6.8 Hz, 2CH2). 13C NMR (100 MHz, CDCl3) d 149.2 (2C), 147.9 (2C), 130.4 (2C), 120.7 (2CH), 111.9 (2CH), 111.5 (2CH), 55.94 (2OCH3), 55.91 (2OCH3), 44.3 (2CH2), 35.3 (2CH2). Anal. calcd. for (C20H28N2O6S): C 56.59; H 6.65; N 6.60; S 7.55. Found: C 56.61; H 6.67; N 6.58; S 7.54.

N,N0 -Bis[2-(2-methoxyphenyl)ethyl]-sulfamide (14)

All chemicals and solvents are commercially available and they were used without purification or after distillation and treatment with drying agents. Melting points are uncorrected and they were determined on a capillary melting apparatus (BUCHI 530). IR spectra were obtained from solutions in 0.1 mm cells with a Perkin-Elmer spectrophotometer. The 1H and 13C NMR spectra were recorded on a 400 (100)-MHz Varian and 400 (100)-MHz Bruker spectrometer; d in ppm,

The general procedure given for the synthesis of 12 was applied to amine 10 to give symmetric sulfamide 14. 77% yield. White solid; mp: 83–85°C. IR (CH2Cl2, cm1) 3379, 2967, 1552, 1508, 1455, 1392, 1236, 1107. 1H NMR (400 MHz, CDCl3) d 7.21 (td, 2H, J ¼ 1.7, J ¼ 8.0Hz, Ar-H), 7.10 (dd, 2H, J ¼ 1.7, J ¼ 8.0Hz, Ar-H), 6.89 (t, 2H, J ¼ 7.3 Hz, Ar-H), 6.85 (d, 2H, J ¼ 8.3 Hz, Ar-H), 4.24 (t, 2H, J ¼ 5.9 Hz, NH), 3.81 (s, 6H,


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2OCH3), 3.17 (q, 4H, J ¼ 6.5 Hz, 2CH2), 2.87 (t, 4H, J ¼ 6.6 Hz, 2CH2). 13C NMR (100 MHz, CDCl3) d 157.5 (2C), 130.7 (2CH), 128.2 (2CH), 126.5 (2C), 120.8 (2CH), 110.5 (2CH), 55.3 (2OCH3), 43.0 (2CH2), 30.5 (2CH2). Anal. calcd. for (C18H24N2O4S): C 59.32; H 6.64; N 7.69; S 8.80. Found: C 59.36; H 6.68; N 7.67; S 8.76.

N,N0 -Bis[2-(4-methoxyphenyl)ethyl]-sulfamide (15) The general procedure for the synthesis of 12 was applied to amine 11 to give symmetric sulfamide 15. 78% yield. White solid, mp: 102–104°C. IR (CH2Cl2, cm1) 3157, 2894, 1503, 1431, 1376, 1235, 1142. 1H NMR (400 MHz, CDCl3) d 7.08 (A part of AB, d, 4H, J ¼ 8.1 Hz, Ar-H), 6.83 (B part of AB, d, 4H, J ¼ 8.0 Hz, Ar-H), 4.08 (bs, 2H, NH), 3.77 (s, 6H, 2OCH3), 3.15 (t, 4H, J ¼ 6.8 Hz, 2CH2), 2.74 (t, 4H, J ¼ 6.8 Hz, 2CH2). 13C NMR (100 MHz, CDCl3) d 158.5 (2C), 130.4 (2C), 130.0 (2CH), 129.8 (2CH), 55.3 (2OCH3), 44.4 (2CH2), 34.8 (2CH2). Anal. calcd. for (C18H24N2O4S): C 59.32; H 6.64; N 7.69; S 8.80. Found: C 59.34; H 6.65; N 7.66; S 8.83.

General procedure for the synthesis of phenolic sulfamides: N,N0 -bis[2-(3,4-dihydroxyphenyl)ethyl]sulfamide (16) N,N0 -Bis[2-(3,4-dimethoxyphenyl)ethyl]-sulfamide (12) (0.5 g, 1.18 mmol) was dissolved in CH2Cl2 (15 mL). This solution was cooled to 0°C and then a solution of BBr3 (4.72 g, 18.85 mmol) in CH2Cl2 (5 mL) was added dropwise under N2(g) atmosphere over 10 min. The reaction mixture was stirred under N2(g) atmosphere, at 0°C for 1 h, then at rt for 23 h. The mixture was poured to a separation funnel containing ice (20 g) and then the organic layer was extracted. The water phase was extracted with EtOAc (2 30 mL). After the combined organic phases were dried over Na2SO4, the solvent was evaporated. The residue was chromatographed by TLC with 3% MeOH–CH2Cl2. Phenolic symmetric sulfamide (16) was synthesized as yellow oil (0.30 g, 69%). IR (CH2Cl2, cm1) 3563, 3408, 3016, 1621, 1546, 1413, 1298, 1101. 1H NMR (400 MHz, acetone-d6) d 7.86 (bs, 4H, 4OH), 6.74–6.76 (m, 2H, Ar-H), 6.74 (s, 2H, Ar-H), 6.57 (d, 2H, J ¼ 7.2 Hz, Ar-H), 5.82 (t, 2H, J ¼ 5.8 Hz, 2NH), 3.10–3.16 (m, 4H, 2CH2), 2.71 (t, 4H, J ¼ 7.5 Hz, 2CH2). 13C NMR (100 MHz, acetone-d6) d 145.8 (2C), 144.4 (2C), 131.7 (2C), 120.9 (2CH), 116.7 (2CH), 116.2 (2CH), 45.5 (2CH2), 36.0 (2CH2). Anal. calcd. for (C16H20N2O6S): C 52.16; H 5.47; N 7.60; S 8.70. Found: C 52.14; H 5.44; N 7.57; S 8.73. Phenolic symmetric sulfamides 17–19 were also synthesized by the same procedure with yields of 74, 67, and 71%, respectively.

N,N0 -Bis[2-(2,4-dihydroxyphenyl)ethyl]-sulfamide (17)


44.2 (2CH2), 30.7 (2CH2). Anal. calcd. for (C16H20N2O6S): C 52.17; H 5.47; N 7.60; S 8.70. Found: C 52.15; H 5.49; N 7.62; S 8.68.

N,N0 -Bis[2-(2-hydroxyphenyl)ethyl]-sulfamide (18)

Yellow oil. IR (CH2Cl2, cm1) 3592, 3428, 2952, 1579, 1536, 1417, 1344, 1221, 1166. 1H NMR (400 MHz, acetone-d6) d 8.21 (s, 2H, OH), 6.99 (d, 2H, J ¼ 7.4 Hz, Ar-H), 6.90 (t, 2H, J ¼ 7.7 Hz, Ar-H), 6.70 (d, 2H, J ¼ 8.0 Hz, Ar-H), 6.64 (t, 2H, J ¼ 7.5 Hz, Ar-H), 5.71 (bs, 2H, NH), 3.02–3.09 (m, 4H, 2CH2), 2.74 (t, 4H, J ¼ 7.5 Hz, 2CH2). 13C NMR (100 MHz, acetone-d6) d 156.1 (2C), 131.6 (2CH), 128.4 (2CH), 126.4 (2C), 120.5 (2CH), 115.9 (2CH), 43.9 (2CH2), 31.3 (2CH2). Anal. calcd. for (C16H20N2O4S): C 57.12; H 5.99; N 8.33; S 9.53. Found: C 57.10; H 6.02; N 8.35; S 9.52.

N,N0 -Bis[2-(4-hydroxyphenyl)ethyl]-sulfamide (19)

Yellow oil. IR (CH2Cl2, cm1) 3576, 3369, 2972, 1561, 1504, 1417, 1328, 1293, 1140. 1H NMR (400 MHz, acetone-d6) d 8.28 (bs, 2H, OH), 7.07 (A part of AB, d, 2H, J ¼ 8.4 Hz, Ar-H), 6.77 (B part of AB, d, 2H, J ¼ 8.4 Hz, Ar-H), 5.87 (t, 2H, J ¼ 5.7 Hz, NH), 3.12–3.14 (m, 4H, 2CH2), 2.76 (t, 4H, J ¼ 7.6 Hz, 2CH2). 13C NMR (100 MHz, acetone-d6) d 156.8 (2C), 130.7 (2C), 130.6 (2CH), 116.1 (2CH), 45.5 (2CH2), 35.8 (2CH2). Anal. calcd. for (C16H20N2O4S): C 57.12; H 5.99; N 8.33; S 9.53. Found: C 57.09; H 6.01; N 8.35; S 9.52.

Determination of antioxidant activity In order to measure antioxidant activities of novel symmetric sulfamides, DPPH•, ABTS•þ, DMPD•þ, O2• scavenging, metal chelating, and acetylcholinesterase inhibitory effects of novel symmetric sulfamides were used. The antioxidant activities were determined by the following nine bioanalytical assays.

Fe3þ-Fe2þ reducing assay For determination of Fe3þ reducing ability of novel symmetric sulfamides Fe3þ(CN)6-Fe2þ(CN)6 reduction method was used [80, 81]. Briefly, different concentrations of novel symmetric sulfamides (10–30 mg/mL) in 0.75 mL of deionized H2O were added with 1.25 mL of phosphate buffer (0.2 M, pH 6.6) and 1.25 mL of potassium ferricyanide [K3Fe(CN)6] (1%). Then, the solution was incubated at 50°C during 20 min. After incubation period, 1.25 mL of trichloroacetic acid was added (10%). Lastly, 0.5 mL of FeCl3 (0.1%) was transferred to this mixture and the absorbance value was measured at 700 nm in a spectrophotometer [82, 83].

CUPRAC assay

Yellow oil. IR (CH2Cl2, cm ) 3512, 3369, 2900, 1587, 1517, 1351, 1202, 1136. 1H NMR (400 MHz, acetone-d6) d 8.27 (bs, 2H, 2OH), 8.08 (bs, 2H, 2OH), 6.93 (d, 2H, J ¼ 8.1 Hz, Ar-H), 6.41 (d, 2H, J ¼ 2.3 Hz, Ar-H), 6.30 (dd, 2H, J ¼ 2.3, J ¼ 8.1 Hz, Ar-H), 5.79 (t, 2H, J ¼ 5.9 Hz, 2NH), 3.13–3.19 (m, 4H, 2CH2), 2.79 (t, 4H, J ¼ 7.5 Hz, 2CH2). 13C NMR (100 MHz, acetone-d6) d 157.9 (2C), 156.9 (2C), 132.0 (2CH), 117.3 (2C), 107.6 (2CH), 103.5 (2CH),

This assay is based on utilizing the Cu2þ–neocuproine reagent as the chromogenic oxidizing agent. To the mixture of 1 mL of Cu2þ–neocuproine (7.5 103 M) and CH3COONH4 (1 M) buffer solutions were transferred to a test tube, which contains different concentrations of novel symmetric sulfamides (10–30 mg/mL). Total volume was completed with distilled H2O to 2 mL and shaken vigorously. Absorbance of samples was recorded at 450 nm after 30 min [53, 84].


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FRAP assay 3þ

3þ

[Fe -(TPTZ)2] reducing values of novel symmetric sulfamides are estimated by measuring the absorbance increase at 593 nm and relating it to a ferrous ions standard solution or to an antioxidant standard solution. The change in absorbance is proportional to the combined [Fe3þ-(TPTZ)2]3þ reducing value of novel symmetric sulfamides [71, 72].

ABTS•þ scavenging assay ABTS radical cation was generated by the interaction of ABTS (7 mM/L) and K2S2O8 (2.45 mM/L) [85] described previously [86, 87]. This solution was diluted with methanol until the absorbance in the samples reached 0.750 0.05 at 734 nm. Then, 1 mL of ABTS•þ solution was supplemented to 3 mL of novel symmetric sulfamides and control solutions. The extent of decolorization is calculated as percentage reduction of absorbance.

DMPD•þ scavenging assay

DMPD•þ scavenging ability of novel symmetric sulfamides was performed according to Fogliano et al. [88] and reported previously [57]. The scavenging capability of DMPD•þ radical of the sample was monitored in spectrophotometer at 505 nm [89].

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different concentrations and 50 mL AChE (5.32 103 U) solution were mixed and incubated for 10 min at 25°C. Then 50 mL of DTNB (0.5 mM) was transferred. Then the reaction was initiated by the addition of 50 mL of AChI. The hydrolysis of AChI was recorded spectrophotometrically by the formation of yellow 5-thio-2-nitrobenzoate anion as the result of the reaction of DTNB with thiocholine at a wavelength of 412 nm [19]. We are greatly indebted to Ataturk University (BAP 2014/67) for financial support of this work. Also, I.G. would like to extend his sincere appreciation to the Research Chairs Program at King Saud University for funding this research. The authors have declared no conflict of interest.

References

The inhibition effects of novel symmetric sulfamides on AChE activities were measured by Ellman’s method [94, 95]. AChI and 5,50 -dithio-bis(2-nitro-benzoic)acid (DTNB) were used as substrate for this enzymatic reaction. To this end, 100 mL of Tris-HCl buffer (1 M, pH 8.0) and 10 mL of sample solution at

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DPPH• scavenging assay In this assay, the antioxidants were able to reduce the stable radical DPPH to the yellow colored DPPH2 [90, 91]. DPPH• scavenging assay was detailed described previously [92, 93].

O2• scavenging assay Superoxide radicals scavenging of novel symmetric sulfamides were performed according to the method of Beauchamp and Fridovich [94] with slight modification [55]. They are generated in riboflavin–methionine–illuminate system and may reduce NBT, a chemical compound composed of two tetrazole moieties, into formazan. Novel symmetric sulfamides were added to the reaction mixture, in which O2• was scavenged, thereby inhibiting the NBT reduction [68].

Metal chelating assay Ferrous ions (Fe2þ) chelating activities of novel symmetric sulfamides were evaluated according to the method described previously [37]. The different concentrations (10– 30 mg/mL) of novel symmetric sulfamides in 0.25 mL ethanol, 0.25 mL FeSO4 solution (2 mM), 1 mL Tris-HCl buffer solution (pH 7.4), 1 mL ferrozine solution (0.2% in 0.2 M HCl), and 2.5 mL ethanol solution were placed into a test tube, respectively. The absorbance was measured at 562 nm.

AChE inhibitory assay

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Synthesis and carbonic anhydrase inhibitory effects of novel sulfamides derived from 1-aminoindanes and anilines.

Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones.

Alkaloids from the bulbs of Lycoris longituba and their neuroprotective and acetylcholinesterase inhibitory activities.

Antioxidant and anti-acetylcholinesterase activities of extracts and secondary metabolites from Acacia cyanophylla.

Antioxidant activities of a peptide derived from chicken dark meat.

Alkaloids from the roots of Stichoneuron caudatum and their acetylcholinesterase inhibitory activities.

Chemical constituents from Sonneratia ovata Backer and their in vitro cytotoxicity and acetylcholinesterase inhibitory activities.

Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives.

Antioxidant and α-glucosidase inhibitory activities of Achillea tenorii.

Antioxidant, 5-lipoxygenase inhibitory and cytotoxic activities of compounds isolated from the Ferula lutea flowers.

Antioxidant and tyrosinase inhibitory activities of flavonoids from Trifolium nigrescens Subsp. petrisavi.

Evaluation of the Antioxidant Activities and Tyrosinase Inhibitory Property from Mycelium Culture Extracts.

Enzyme Inhibitory Properties, Antioxidant Activities, and Phytochemical Profile of Three Medicinal Plants from Turkey.

Phytochemical compositions of extract from peel of hawthorn fruit, and its antioxidant capacity, cell growth inhibition, and acetylcholinesterase inhibitory activity.

Production of novel vinegar having antioxidant and anti-fatigue activities from Salicornia herbacea L.

Inhibitory effects of a novel cationic dodecapeptide [CL(14-25)] derived from cyanate lyase of rice on endotoxic activities of LPSs from Escherichia coli and periodontopathic Aggregatibacter actinomycetemcomitans.

Oligostilbenoids with acetylcholinesterase inhibitory activity from Dipterocarpus alatus.

Ex vivo digestion of carp muscle tissue--ACE inhibitory and antioxidant activities of the obtained hydrolysates.

In vitro antioxidant and cholinesterase inhibitory activities of methanolic fruit extract of Phyllanthus acidus.

Acetylcholinesterase inhibitory activity of Haplophyton cimicidum.

Antioxidant activities and oxidative stress inhibitory effects of ethanol extracts from Cornus officinalis on raw 264.7 cells.

New phenolic compounds from Coreopsis tinctoria Nutt. and their antioxidant and angiotensin i-converting enzyme inhibitory activities.

Phenolic composition, antioxidant and enzyme inhibitory activities of Eryngium bornmuelleri leaf.

Antioxidant and nitric oxide production inhibitory activities of galacturonyl hydroxamic acid.