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Article

Synthesis and Pharmacological Evaluation of Novel Benzenesulfonamide Derivatives as Potential Anticonvulsant Agents

by
Zhiming Wang
†,
Jinping Li
†,
Xiao-Dong Zeng
,
Xian-Ming Hu
,
Xiaoju Zhou
* and
Xuechuan Hong
*
State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 Donghu Road, Wuhan 430071, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2015, 20(9), 17585-17600; https://doi.org/10.3390/molecules200917585
Submission received: 30 July 2015 / Revised: 17 September 2015 / Accepted: 17 September 2015 / Published: 23 September 2015
(This article belongs to the Section Medicinal Chemistry)
Browse Figures
Versions Notes

Abstract

:
A novel series of benzenesulfonamide derivatives containing 4-aminobenzenesul-fonamide and α-amides branched valproic acid or 2,2-dimethylcyclopropanecarboxylic acid moieties were synthesized and screened for their anticonvulsant activities in mice maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) test. The activity experimental study showed that 2,2-dipropyl-N1-(4-sulfamoylphenyl)malonamide (18b) had the lowest median effective dose (ED50) of 16.36 mg/kg in MES test, and 2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12c) had the lowest ED50 of 22.50 mg/kg in scPTZ test, which resulted in the protective indexe (PI) of 24.8 and 20.4, respectively. These promising data suggest the new compounds have good potential as new class of anticonvulsant agents with high effectiveness and low toxicity for the treatment of epilepsy.

1. Introduction

Epilepsy is a common neurological disorder that affects approximately 50 million people around the world [1,2,3]. In spite of the appearance of several novel antiepileptic drugs (AEDs) during the last two decades [4,5,6,7], it is still depressing that about 30% of epileptic patients fail to respond to the existing AEDs [8,9,10], which makes it necessary to focus on the development of active and safe AEDs accommodating wider range of people.
The clinical utilization of Valproic acid (VPA), one of the most widely used AEDs, is limited by its side effects such as teratogenicity and life-threatening hepatotoxicity [11,12,13]. The formation of hepatotoxic metabolites with a terminal double bond, 4-ene-VPA, is possibly the main cause of the hepatotoxicity [14,15]. In order to searching for new nonteratogenic and nonhepatotoxic compounds, numerous analogues and derivatives of VPA have been investigated. TMCA (2, Figure 1), a cyclic analogue of VPA, is found to be inactive at the rat anticonvulsant maximal electroshock seizure (MES) (ED50 > 150 mg/kg) model and can prevent its biotransformation to hepatotoxic metabolites [16,17]. Further studies have revealed that amide derivatives of 2, TMCD (5), especially N-methoxy TMCD (MTMCD, 6) and TMC-urea (7) are broad-spectrum anticonvulsants with a much wider safety margin than VPA [18]. In 2008, Jakob reported the synthesis and high potency of TMCD-benzenesulfonamide (3, ED50 = 26 mg/kg) along with a wide protective index (PI = TD50/ED50 >19) in the rat-MES test [19]. Recently, it was reported that α-fluoronated TMCD (4) was 120 times more potent than VPA in the rat-scMet test (ED50 = 6 mg/kg) with a remarkable protective index (PI = 20) [20]. These developments prompted us to focus on systematic structural modifications in the α position. In the current study, we introduced amid groups to the benzenesulfonamide system in order to get novel anticonvulsant agents. In view of the difficulty of synthesis, the 2,2,3,3-tetramethylcyclopropane fragment was replaced by 2,2-dimethylcyclopropane group, which has been proven to be a safe and effective structure in our group’s early work [21,22,23,24,25,26]. Herein, a series of benzenesulfonamide derivatives containing 4-amino-benzenesulfonamide and α-amides branched valproic acid or 2,2-dimethylcyclopropanecarboxylic acid moieties were synthesized and their pharmacological activities as potential anticonvulsant agents were evaluated in mice maximal MES and subcutaneous pentylenetetrazole (scPTZ) tests in this paper.
Molecules 20 17585 g001 550
Figure 1. Structure of AEDs and designed compounds.
Figure 1. Structure of AEDs and designed compounds.
Molecules 20 17585 g001

2. Results and Discussion

2.1. Chemistry

The general synthetic route for compound 12 is shown in Scheme 1. Compound 8, used as the starting material, was reacted with SOCl2 in anhydrous DCM to obtain compound 9. The coupling reaction of compound 9 and sulfonamide in the presenve of TEA resulted in the formation of compound 10 in 80% yield. Compound 11 was then obtained by hydrolysis of compound 10 in a 1 mol/L NaOH in EtOH–water (1:1) solution for 12 h. Amidation of compound 11 with a variety of amines in the EDCI/HOBt system gave the corresponding final products 12a–n in good yields. The structures of all new compounds were characterized by 1H-NMR, 13C-NMR and MS. The spectrums were shown in supplementary materials.
Molecules 20 17585 g003 550
Scheme 1. Synthetic route for the synthesis of compounds 12a–n. Reagents and conditions: (a) SOCl2, DCM, refluxed, 2 h; (b) TEA, acetone, r.t, 4 h; (c) NaOH, EtOH, r.t, 12 h; and (d) EDCI, HOBt, DCM/THF, r.t, 12 h (r.t. means room temperature).
Scheme 1. Synthetic route for the synthesis of compounds 12a–n. Reagents and conditions: (a) SOCl2, DCM, refluxed, 2 h; (b) TEA, acetone, r.t, 4 h; (c) NaOH, EtOH, r.t, 12 h; and (d) EDCI, HOBt, DCM/THF, r.t, 12 h (r.t. means room temperature).
Molecules 20 17585 g003
The synthetic route of compounds 18a–c is listed in Scheme 2. It was very similar to that of compounds 12a–n. However, all anilines and secondary amines failed to react with compound 17. It may be attributed to the steric hindrance of the double propyl branch.
Molecules 20 17585 g004 550
Scheme 2. Synthetic route for the synthesis of compounds 18a–c. Reagents and conditions: (a) NaOH, EtOH, r.t, 12 h; (b) SOCl2, DCM, refluxed, 2 h; (c) TEA, acetone, r.t, 4 h; (d) NaOH, EtOH, r.t, 12 h; and (e) EDCI, HOBt, DCM/THF, r.t, 12 h (r.t. means room temperature).
Scheme 2. Synthetic route for the synthesis of compounds 18a–c. Reagents and conditions: (a) NaOH, EtOH, r.t, 12 h; (b) SOCl2, DCM, refluxed, 2 h; (c) TEA, acetone, r.t, 4 h; (d) NaOH, EtOH, r.t, 12 h; and (e) EDCI, HOBt, DCM/THF, r.t, 12 h (r.t. means room temperature).
Molecules 20 17585 g004

2.2. Pharmacological Evaluation

Chemical diversity and different biological mechanism of anticonvulsant drugs make it difficult to find a common method to identify the candidates. When it comes to develop novel anticonvulsant agents, it is necessary to apply conventional screening or structure modification of these tested compounds. Early identification of anticonvulsant agents is usually conducted via in vivo screening such as MES test and scPTZ test [27,28,29].
In the present study, 22 new synthesized compounds were evaluated following the standard procedure (NIH anticonvulsant drug development program). Those compounds were administrated intraperitoneally (i.p.) to male Kunming mice weighting 18–22 g. In the initial evaluation, the compounds were given at dose of 300 mg/kg, 100 mg/kg and 30 mg/kg. The observations were taken at two time intervals, namely 0.5 h and 4 h. The acute neurotoxicity was measured by the rotarod test. The results are summarized in Table 1.
Table
Table 1. Anticonvulsant activity and neurotoxicity of compounds administered intraperitoneally.
Table 1. Anticonvulsant activity and neurotoxicity of compounds administered intraperitoneally.
CompoundsIntraperitioneal Injection into Mice aClogP b
MES cscPTZ dNeurotoxocity e
No.R0.5 h4 h0.5 h4 h0.5 h4 h
10-OEt100- f300-300-1.633
11-OH100---300-0.865
12a-NHC(CH3)3100-----1.484
12b-N(CH2CH3)2100300--300-1.735
12c-NH23010030100300-−0.019
12d-NHCH330300100300--0.247
12e Molecules 20 17585 i001100-----1.305
12f Molecules 20 17585 i002300---300-3.223
12g Molecules 20 17585 i003300300----0.797
12h Molecules 20 17585 i004100300300---2.503
12i Molecules 20 17585 i005100-----2.604
12j Molecules 20 17585 i006100-----1.591
12k Molecules 20 17585 i007100-300-300-1.834
12l Molecules 20 17585 i008------1.032
12m Molecules 20 17585 i009300-----3.071
12n Molecules 20 17585 i010100300----1.021
16-OEt300---300-2.815
17-OH100-300-300-2.046
18a Molecules 20 17585 i011100300----2.203
18b-NH23030--300-1.163
18c Molecules 20 17585 i012100100----2.487
Phenytoin g3030--100100
Ethosuximide h--100300--
a: 30 mg/kg, 100 mg/kg, and 300 mg/kg of doses were administered i.p. The data in the table indicate the minimal dose whereby bioactivity was demonstrated. The animals were examined at 0.5 h and 4.0 h after injection was administered; b: Clog P was calculated using software ChemDraw Ultra (version 6.0.1; PerkinElmer Informatics, Waltham, MA, USA); c: Maximal electroshock test; d: Subcutaneous pentylenetetrazole test; e: Neurotoxocity screening; f: A dash indicates the absence of anticonvulsant activity and neurotoxicity at the maximum dose administered (300 mg/kg); g: Data from Reference [30]; h: Data from Reference [31].
The initial evaluation of all these compounds, with the exception of 12l, showed anticonvulsant activities in the mice i.p. MES screening. Among 2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide derivatives (12a–12n), the most active analogs were 12c and 12d, which showed anticonvulsant activities at 0.5 h after administrated intraperitoneally (i.p.) at a dose of 30 mg/kg to the male Kunming mice. Furthermore, compound 12c was active at 4 h at a dose of 100 mg/kg and had a longer duration, while compound 12d did not show any improvements. The compounds containing aromatic amines substituents such as 12h and 12i acted much better than 12f and 12n, which indicated that substituents with the phenyl moiety had significant influence on the anticonvulsant activity. When the substituents at the carboxyl position were alkyl amines, the order of anticonvulsant activity against the MES test was found to be 12d > 12e = 12n > 12k = 12a. It is noteworthy that the anticonvulsant activity of those compounds was decreased when the alkyl moiety possesses more carbons. A double bond was introduced to the branch in compounds 12n and 18a in order to obtain a short-duration anticonvulsant agent like secobarbital, which also contained a carbon–carbon double bond within the molecular structure [32]. Unexpectedly, both compounds 12n and 18a showed the anticonvulsant activity at 4 h after administrated with a dose of 300 mg/kg. Speaking of the performance of compounds 12c and 18b, both containing the same amino-group, compound 18b showed anticonvulsant activity at 4 h after administrated with a dose of 30 mg/kg, while compound 12c showed anticonvulsant activity with a dose of 100 mg/kg, which may be attributed to the lipophilicity. Meanwhile, when compounds 18c and 12e were compared, a similar activity was obtained.
In the scPTZ test, only six compounds exhibited protection against induced seizure at 300 mg/kg or less. Compounds 10, 12h, 12k and 17 showed anticonvulsant activity at 300 mg/kg after 0.5 h, while compound 12c was more active at 30 mg/kg after 0.5 h. Compound 12c was still active after 4 h at a dose of 100 mg/kg. The result indicated that compound 12c had a rather quick onset and was more active than the positive control drug ethosuximide in the scPTZ screen.
All the tested compounds maintained balance well in the neurotoxicity test at 100 mg/kg or less. However, compounds 10, 11, 12b, 12c, 12f, 12k, 16, 17 and 18b revealed neurotoxicity at a dose of 300 mg/kg after 0.5 h and turned out to be non-toxic after 4 h. All the most active molecules, namely 12c, 12d and 18b, showed anticonvulsant potencies in lower doses than neurotoxic properties. No relation between the activity and the neurotoxocity was found. In other words, better activity did not mean more neurotoxocity.
Crossing the blood–brain barrier (BBB) is an important factor influencing anticonvulsant activity. It is believed that ClogP (calculated LogP) values between 1 and 2 is sufficient for crossing BBB and the lipophilicity of the titled compound is very important in the central nervous system drug penetrating through BBB [33]. The ClogP (calculated LogP) values of the tested compounds were also listed in Table 1. The above data did not show an obvious correlation between ClogP values and in vivo anticonvulsant activities. The most activity compounds, 12c and 12d, showed relatively lower ClogP of −0.019 and 0.247. These values suggested a low concentration of those compounds in brain.
There are two possible reasons for the existence of anticonvulsant activity. The designed compounds meet a general structural model of AEDs as shown in Figure 2 [34]. At first, the dimethylcyclopropane group or the double propyl branch can act as hydrophobic group to enable the compounds to penetrate through the BBB. At the same time, the amide groups act as hydrogen binding domain, while amino as an electron donor group. On the other hand, these compounds may act as carbonic anhydrase inhibitor.
Molecules 20 17585 g002 550
Figure 2. Pharmacophoric structure of designed compounds.
Figure 2. Pharmacophoric structure of designed compounds.
Molecules 20 17585 g002
In view of the excellent performance of compounds 12c, 12d and 18b in the initial screening, they were selected for Phase-II screening. The resulting results for these three molecules were shown in Table 2. Approximated time of peak effects (TPE) of compounds 12c, 12d and 18b were 1 h, 1 h and 2 h, respectively. The quantitative evaluation of pharmacological parameters (ED50 and TD50) was performed at TPE after administrated intraperitoneally. Compound 18b, the most active compound, showed an ED50 value of 16.36 mg/kg among the tested compounds in the MES screening. Compound 12d exhibited the lowest toxicity with a TD50 value >500 mg/kg. Compound 12c, which turned out to be seven times more active than that of valproate, revealed the best activity in the scPTZ test with an ED50 value of 22.50 mg/kg. All these three compounds mentioned above possessed higher PI than that of standard drugs (e.g., Phenytoin and valproate). Consequently, the higher anticonvulsant activity of compound 18b (PI = 24.8) in the MES test and compound 12c (PI = 20.4) in scPTZ test as compared to VPA and its substantially wider safety margin than VPA and Phenytoin were observed. These observations indicated this benzenesulfonamide derivative containing 4-aminobenzenesulfonamide and the α-amide branched valproic acid or 2,2-dimethylcyclopropanecarboxylic acid moiety was a potential candidate as a new AED.
Table
Table 2. Quantitative anticonvulsant data in mice dosed intraperitoneally.
Table 2. Quantitative anticonvulsant data in mice dosed intraperitoneally.
CompoundED50 aTD50 bPI c
MESscPTZMESscPTZ
12c24.47 (20.05–29.83) d22.50 (16.25–31.14)499.2 (455.3–547.4)20.422.19
12d25.25 (18.14–35.14)ND e>500>19.80ND e
18b16.36 (14.17–18.89)ND e406.7 (337.7–489.7)24.85ND e
phenytoin f9.5 (8.1–10.4)>30065.56.9<0.22
valproate f2721494261.62.9
a: Dose in milligrams per kilogram body mass; b: Minimal toxicity which was determined by rotarod test 30 min after the test drug was administered; c: Protection index (TD50/ED50); d: Data in parentheses are the 95% confidence limits; e: Not determined; f: Data from Reference [33].
The acute toxicity of compounds 12c, 12d and 18b were measured and the results were reported in Table 3 and Table 4. In the preliminary test, all compounds dosed intragastric administration did not show acute toxicity to kill mice at 2000 mg/kg. Unfortunately, when these compounds were administrated intraperitoneally, some mice died at 500 mg/kg or 2000 mg/kg. The LD50 values of the tested agents administered intraperitoneally, along with the data on the standard drug (phenytoin), are listed in Table 4. Compound 12c showed a LD50 of 762.7 mg/kg; compound 12d, the least toxic compound, showed a LD50 of 922.0 mg/kg, while the LD50 value of phenytoin was 100 mg/kg. These results proved that the newly synthesized compounds were safer than the standard drug. When comparing 12c with 18b, it was self-evident that lower LD50 came with lower ED50.
Table
Table 3. The acute toxicity of compounds in preliminary test.
Table 3. The acute toxicity of compounds in preliminary test.
CompoundDose aAdministration Route
i.g bi.p c
12c20000/5 d4/5
500ND e1/5
50ND0/5
12d20000/55/5
500ND1/5
50ND0/5
18b20000/55/5
500ND2/5
50ND0/5
a: Dose in milligrams per kilogram body mass; b: Intragastric injection; c: Intraperitoneal injection; d: Number of animals protected/number of animals tested; e: Not determined.
Table
Table 4. The acute toxicity of compounds in intrapertioneal injection.
Table 4. The acute toxicity of compounds in intrapertioneal injection.
CompoundLD50 a
12c762.7 (656.8–885.6)
12d922.0 (601.1–1414)
18b638.0 (475.0–857.0)
phenytoin100 (94.3–101.2)
a: Dose in milligrams per kilogram body mass.

3. Experimental Section

3.1. General Information

All commercially available solvents and reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. 1H- and 13C-NMR spectra were recorded on Bruker AV400 MHz spectrometers (Bruker Biospin, Rheinstetten, Germany) in deuteriochloroform (CDCl3) unless otherwise stated. All 1H chemical shifts are reported in ppm (δ) relative to TMS (0.00); 13C shifts are reported in ppm (δ) relative to CDCl3 (77.0). Data are reported in the following order: chemical shifts are given (δ); multiplicities are indicated as br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), app (apparent); coupling constants, J, are reported (Hz); integration is provided. Uncalibrated melting points were taken on XT-4 apparatus (Yuhua Instruments Co., Ltd., Gongyi, Henan, China). Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminum sheets (Merck KGaA, Darmstadt, Germany) with F-254 indicator. Visualization was accomplished by UV light, or with solutions of K2CO3/KMnO4 in water. Purification by chromatography was performed using 200–300 mesh SiO2 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, Shandong, China) with compressed air as a source of positive pressure. The mass spectra were obtained on Applied Biosystem/MDS-SCIEX API 2000 (AB Sciex Pte. Ltd., Framingham, MA, USA) with Agilent HPLCs, and MicrOTOF-Q orthogonal-accelerated TOF mass spectrometer (Bruker Daltonics, Bremen, Gremany) with an ESI source. Solvents for reactions and chromatography were reagent grade and used as received. “Brine” refers to a saturated aqueous solution of NaCl.

3.2. Synthesis

3.2.1. Ethyl 1-(Chlorocarbonyl)-2,2dimethylcyclopropanecarboxylate 10

Compound 8 (1.86 g) was dissolved in SO2Cl2 (10 mL) before the mixture was heated to reflux for 2 h. Reaction completion was monitored by TLC analysis. Then, this mixture was cooled to room temperature and concentrated. The resulting oil was dissolved in dry acetone (10 mL) and was transferred dropwise to a solution of sulfonamide (1.7 g ) in dry acetone (20 mL) in the presence of 2 Et3N (mL) and catalytic amount of DMAP. The mixture was completed in 4 h at room temperature. Then, the reaction mixture was diluted with ethyl acetate (30 mL), the organic layer was washed with 1 mol/L HCl (10 mL × 2), water (10 mL × 2) and brine (10 mL) subsequently. The organic phase was dried over MgSO4 and concentrated under vacuum. The obtained crude product was purified by column chromatography (EtOAc:Petroleum ether = 1:1) to give the titled compound 10 as a white solid. Yield: 90%; mp: 138–140 °C; 1H-NMR (400 MHz, DMSO) δ 10.40 (s, -CONH, 1H), 7.86–7.66 (m, 4H, ArH), 7.25 (s, 2H, SO2NH2), 4.21–4.00 (m, 2H, -CH2CH3), 1.38 (d, J = 4.8 Hz, 1H, Cpr-CH), 1.37 (d, J = 4.8 Hz, 1H, Cpr-CH), 1.33 (s, 3H, Me), 1.18 (t, J = 7.1 Hz, 3H, -CH2CH3), 1.12 (s, 3H, Me). 13C-NMR (101 MHz, MeOD) δ 171.4, 168.3, 143.4, 139.8, 128.2, 120.67, 62.8, 42.8, 31.7, 26.5, 23.3, 20.4, 14.5. HRMS-ESI Calcd. for C15H21N2O5S [M + H]+: 341.1171; Found: 341.1433.

3.2.2. 2,2-Dimethyl-1-(4-sulfamoylphenylcarbamoyl)cyclopropanecarboxylic Acid 11

1 mol/L sodium hydroxide (12 mL) was added dropwise to a solution of compound 10 (3.4 g) in ethanol (20 mL). The resulting mixture was stirred at room temperature for 18 h. EtOH was removed under reduced pressure and the mixture was extracted with ethyl acetate (10 mL × 2). The remaining aqueous layer was acidified to pH 2 by 3 mol/L HCl, extracted with ethyl acetate (10 mL × 2). The organic layer was concentrated to give a pale yellow oil and further crystallized by ethyl ether to give compound 11 as a white solid. Yield: 88%; mp: 180–183 °C; 1H-NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 10.41 (s, 1H), 7.95–7.62 (m, 4H), 7.24 (s, 2H), 1.35 (d, J = 4.5 Hz, 1H), 1.33 (s, 3H), 1.31 (d, J = 4.5 Hz, 1H), 1.10 (s, 3H).13C-NMR (101 MHz, MeOD) δ 173.3, 168.8, 143.4, 139.7, 128.2, 120.6, 42.5, 31.7, 26.3, 23.0, 20.6. HRMS-ESI Calcd. for C13H16N2NaO5S [M + Na]+: 335.0672; Found: 335.0826.

3.2.3. General Produce for the Synthesis of Compounds 12a–n

Compound 11 (0.62 g) and HOBt (0.27 g) were dissolved in anhydrous tetrahydrofuran (10 mL) and was transferred to a stirred solution of EDCI (0.4 g) in dicolormethane (10 mL). After 0.5 h, a suitable amine (2 mmol) in tetrahydrofuran (5 mL) was added, the reaction was monitored by TLC analysis and completed in 12–24 h. The solvents were evaporated under vacuum to give a yellow oil, which was chromatographed (Petroleum ether–EtOAc system) to give compounds 12a–n as white solids.
N-tert-Butyl-2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12a): Yield: 70%; mp: 212–215 °C; 1H-NMR (400 MHz, DMSO) δ 10.33 (s, 1H, CONH), 7.76 (s, 4H, ArH), 7.59 (s, 1H, NH), 7.27 (s, 2H, SO2NH2), 1.47 (d, J = 5.5 Hz, 1H, Cpr-CH), 1.40 (d, J = 5.3 Hz, 1H, Cpr-CH), 1.27 (s, 9H, Me), 1.10 (s, 3H, Me), 1.06 (s, 3H, Me ).13C-NMR (101 MHz, MeOD) δ 169.8, 169.7, 142.8, 140.2, 128.2, 120.8, 52.7, 44.6, 28.8, 28.0, 23.3, 21.8, 21.6. MS-ESI [M + H]+ 368.2. HRMS-ESI Calcd. for C17H25N3NaO4S [M + Na]+: 390.1463; Found: 390.1567.
N,N-Diethyl-2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12b): Yield: 75%; mp: 156–158 °C; 1H-NMR (400 MHz, DMSO) δ 9.83 (s, 1H, CONH), 7.79 (d, J = 8.9 Hz, 2H, ArH), 7.73 (d, J = 8.9 Hz, 2H, ArH), 7.25 (s, 2H, SO2NH2), 3.32 (m, 4H, -CH2CH3), 1.37 (d, J = 4.9 Hz, 1H, Cpr-CH), 1.16 (s, 3H, Me), 1.14 (d, J = 5.0 Hz, 1H, Cpr-CH), 1.10 (s, 3H, Me), 1.05 (t, J = 6.9 Hz, 3H, Me), 1.00 (t, J = 7.0 Hz, 3H, Me).13C-NMR (101 MHz, MeOD) δ 170.5, 168.1, 143.0, 140.1, 128.4, 128.3, 120.6, 43.8, 43.1, 41.2, 28.0, 25.4, 24.1, 21.5, 14.1, 12.8. MS-ESI [M + H]+: 368.2. HRMS-ESI Calcd. for C17H25N3NaO4S [M + Na]+: 390.1463; Found: 390.1561.
2,2-Dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12c): Yield: 60%; mp: 197–200 °C; 1H-NMR (400 MHz, DMSO) δ 10.60 (s, 1H, CONH), 7.76 (s, 4H, ArH), 7.54 (d, J = 5.2 Hz, 2H, NH2), 7.26 (s, 2H, SO2NH2), 1.46 (d, J = 5.5 Hz, 1H, Cpr-CH), 1.44 (d, J = 5.5 Hz, 1H, Cpr-CH), 1.15 (s, 3H, Me), 1.08 (s, 3H, Me).13C-NMR (101 MHz, MeOD) δ 173.7, 169.0, 142.9, 140.0, 128.3, 120.8, 43.6, 28.7, 24.3, 23.4, 21.7, 21.6. MS-ESI [M + H]+: 312.1. HRMS-ESI Calcd. for C13H17N3NaO4S [M + Na]+: 334.0837; Found: 334.1000.
N,2,2-Trimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12d): Yield: 80%; mp: 217–220 °C; 1H-NMR (400 MHz, DMSO) δ 10.56 (s, 1H, CONH), 8.02 (d, J = 4.6 Hz, 1H, NH), 7.76 (s, 4H, ArH), 7.27 (s, 2H, SO2NH2), 2.65 (d, J = 4.6 Hz, 3H, Me), 1.44 (s, 2H, Cpr-CH), 1.08 (s, 6H, Me). 13C-NMR (101 MHz, MeOD) δ 171.8, 168.6, 142.9, 134.0, 128.3, 120.6, 43.9, 28.6, 26.7, 22.9, 21.9, 21.3. MS-ESI [M + H]+: 326.1. HRMS-ESI Calcd. for C14H19N3NaO4S [M + Na]+: 348.0994; Found: 348.1202.
2,2-Dimethyl-N-propyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12e): Yield: 70%; mp: 180–183 °C; 1H-NMR (400 MHz, DMSO) δ 10.53 (s, 1H, CONH), 8.09 (t, J = 5.7 Hz, 1H, NH), 7.76 (s, 4H, ArH), 7.27 (s, 2H, SO2NH2), 3.19–2.95 (m, 2H, CH2), 1.47(d, J = 7.2 Hz, 1H, Cpr-CH), 1.45 (m, 2H, CH2), 1.42 (d, J = 7.2 Hz, 1H, Cpr-CH), 1.09 (s, 3H, Me), 1.08 (s, 3H, Me), 0.83 (t, J = 7.4 Hz, 3H, Me).13C-NMR (101 MHz, MeOD) δ 176.0, 174.2, 142.8, 140.1, 128.2, 121.4, 59.0, 42.5, 40.9, 23.5, 19.5, 14.6, 11.8. MS-ESI [M + H]+: 354.1. HRMS-ESI Calcd. for C16H23N3NaO4S [M + Na]+ : 376.1307; Found: 376.1458.
N-(4-Bromophenyl)-2,2-dimethyl-N-(4-sulfamoylpheny-l)cyclopropane-1,1-dicarboxamide (12f): Yield: 50%; mp: 199–201 °C; 1H-NMR (400 MHz, DMSO) δ 10.24 (s, 1H, CONH), 10.05 (s, 1H, NH), 7.78 (q, J = 9.1 Hz, 4H, ArH), 7.61 (d, J = 8.9 Hz, 2H, ArH), 7.52 (t, J = 8.7 Hz, 2H, ArH), 7.28 (s, 2H, SO2NH2), 1.59 (s, 2H, Cpr-CH), 1.17 (s, 6H, Me). 13C-NMR (101 MHz, DMSO) δ 166.7, 141.1, 139.0, 137.5, 131.5, 126.6, 122.2, 119.6, 115.7, 43.4, 27.0, 22.8, 21.4, 21.2. MS-ESI [M + H]+: 467.0. HRMS-ESI Calcd. for C19H20BrN3NaO4S [M + Na]+: 488.0256, 490.0235; Found: 488.0389, 490.0376.
2,2-Dimethyl-1-(morpholine-4-carbonyl)-N-(4-sulfamoylphenyl)cyclopropanecarboxamide (12g): Yield: 65%; mp: 170–173 °C;1H-NMR (400 MHz, DMSO) δ 9.93 (s, 1H, CONH), 7.78 (m, 4H, ArH), 7.27 (s, 2H, SO2NH2), 3.53 (m, 8H, CH2), 1.39 (d, J = 5.1 Hz, 1H, Cpr-CH), 1.16 (s, 3H, Me), 1.14 (d, J = 5.1 Hz, 1H, Cpr-CH), 1.12 (s, 3H, Me).13C-NMR (101 MHz, MeOD) δ 169.6, 168.1, 143.0, 140.2, 128.2, 127.1, 120.8, 66.8, 43.0, 27.9, 25.4, 23.9, 21.7, 15.5. MS-ESI [M + H]+: 382.1. HRMS-ESI Calcd. for C17H23N3NaO5S [M + Na]+: 404.1256; Found: 404.1285.
N-(4-Fluorophenyl)-2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12h): Yield: 60%; mp: 200–203 °C;1H-NMR (400 MHz, DMSO) δ 10.27 (s, 1H, CONH), 9.99 (s, 1H, NH), 7.88–7.70 (m, 4H, ArH), 7.70–7.55 (m, 2H, ArH), 7.28 (s, 2H, SO2NH2), 7.17 (dd, J = 12.3, 5.5 Hz, 2H, ArH), 1.59 (s, 2H, Cpr-CH), 1.17 (s, 3H, Me), 1.15 (s, 3H, Me).13C-NMR (101 MHz, MeOD) δ 169.2, 169.0, 162.3, 159.9, 142.7, 140.2, 135.2, 128.2, 124.0, 124.0, 121.0, 116.5, 116.3, 44.7, 29.2, 23.5, 22.0, 21.6. MS-ESI [M + H]+: 406.1. HRMS-ESI Calcd. for C17H23N3NaO5S [M + Na]+: 404.1256; Found: 404.1285.
2,2-Dimethyl-N-(4-sulfamoylphenyl)-N-p-tolylcyclopropane-1,1-dicarboxamide (12i): Yield: 70%; mp: 134–136 °C;1H-NMR (400 MHz, DMSO) δ 10.31 (s, 1H, CONH), 9.85 (s, 1H, NH), 7.78 (q, J = 9.0 Hz, 4H, ArH), 7.49 (d, J = 8.3 Hz, 2H, ArH), 7.27 (s, 2H, SO2NH2), 7.13 (d, J = 8.2 Hz, 2H, ArH), 2.26 (s, 3H, Me), 1.60 (d, J = 5.7 Hz, 1H, Cpr-CH), 1.58 (d, J = 5.7 Hz, 1H, Cpr-CH), 1.16 (s, 3H, Me), 1.14 (s, 3H, Me).13C-NMR (101 MHz, MeOD) δ 169.1, 169.0, 142.7, 140.2, 137.9, 130.7, 129.9, 128.2, 123.2, 121.0, 44.8, 29.3, 23.6, 21.9, 21.7. MS-ESI [M + H]+: 402.1. HRMS-ESI Calcd. for C20H23N3NaO4S [M + Na]+: 424.1307; Found: 424.1422.
2,2-Dimethyl-1-(piperidine-1-carbonyl)-N-(4-sulfamoylpenyl)cyclopropanecarboxamide (12j): Yield: 50%; mp: 207–209 °C; 1H-NMR (400 MHz, DMSO) δ 9.79 (s, 1H, CONH), 7.76 (d, 8.9 Hz, 2H, ArH), 7.56 (d, 8.9 Hz, 2H, ArH), 7.25 (s, 2H, SO2NH2), 3.75 (s, 1H, CH2), 3.51 (s, 2H, CH2), 3.38 (s, 1H, CH2), 1.44 (m, 6H, CH2), 1.40 (d, J = 4.9 Hz, 1H, Cpr-CH), 1.15 (s, 3H, Me), 1.11 (s, 3H, Me), 1.09 (d, J = 5.0 Hz, 1H, Cpr-CH).13C-NMR (101 MHz, MeOD) δ 169.5, 168.1, 143.0, 140.1, 128.2, 120.6, 43.0, 30.7, 28.2, 27.6, 26.8, 25.6, 25.3, 24.0, 21.5. MS-ESI [M + H]+: 380.1. HRMS-ESI Calcd. for C18H25N3NaO4S [M + Na]+: 402.1463; Found: 402.1567.
N-Butyl-2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12k): Yield: 57%; mp: 170–172 °C; 1H-NMR (400 MHz, DMSO) δ 10.53 (s, 1H, CONH), 8.08 (t, J = 5.6 Hz, 1H, NH), 7.75 (s, 4H, ArH), 7.26 (s, 2H, SO2NH2), 3.25– 2.98 (m, 2H, CH2), 1.45 (s, 2H, Cpr-CH), 1.40 (m, 2H, CH2), 1.26 (m, 2H, CH2), 1.09 (s, 3H, Me), 1.08 (s, 3H, Me), 0.86 (t, J = 7.3 Hz, 3H, Me).13C-NMR (101 MHz, MeOD) δ 171.1, 168.8, 142.8, 140.0, 128.3, 120.6, 44.0, 40.7, 32.5, 28.4, 23.0, 22.0, 21.4, 21.2, 14.1. MS-ESI [M + H]+: 368.1. HRMS-ESI Calcd. for C17H25N3NaO4S [M + Na]+: 390.1463; Found: 390.1566.
2,2-Dimethyl-1-(pyrrolidine-1-carbonyl)-N-(4-sulfamoylphenyl)cyclopropanecarboxamide (12l): Yield: 39%; mp: 225–227 °C; 1H-NMR (400 MHz, DMSO) δ 9.88 (s, 1H, CONH), 7.76 (q, J = 9.0 Hz, 4H, ArH), 7.27 (s, 2H, SO2NH2), 3.53 (m, 2H, CH2), 3.35 (m, 2H, CH2), 1.92–1.78 (m, 2H, CH2), 1.78–1.64 (m, 2H, CH2), 1.39 (d, J = 5.0 Hz, 1H, Cpr-CH), 1.22 (d, J = 5.0 Hz, 1H, Cpr-CH), 1.15 (s, 3H, Me), 1.12 (s, 3H, Me). MS-ESI [M + H]+: 366.1. HRMS-ESI Calcd. for C17H23N3NaO4S [M + Na]+: 388.1307; Found: 388.1356.
N-(4-Chlorophenyl)-2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12m): Yield: 70%; mp: 210–213 °C;1H-NMR (400 MHz, DMSO) δ 10.26 (s, 1H, CONH), 10.07 (s, 1H, NH), 7.78 (m, 4H, ArH), 7.67 (d, J = 8.8 Hz, 2H, ArH), 7.38 (d, J = 8.8 Hz, 2H, ArH), 7.28 (s, 2H, SO2NH2), 1.59 (s, 2H, Cpr-CH), 1.16 (d, J = 3.0 Hz, 6H, Me). 13C-NMR (101 MHz, MeOD) δ 169.1, 169.0, 142.7, 140.2, 137.9, 130.7, 129.9, 128.2, 123.2, 121.0, 44.8, 29.3, 23.6, 21.9, 21.7. MS-ESI [M + H]+: 422.0. HRMS-ESI Calcd. for C19H20ClN3NaO4S [M + Na]+: 444.0761; Found: 444.0884.
N-Allyl-2,2-dimethyl-N-(4-sulfamoylphenyl)cyclopropane-1,1-dicarboxamide (12n): Yield: 80%; mp: 179–181 °C; 1H-NMR (400 MHz, DMSO) δ 10.46 (s, 1H, CONH), 8.23 (t, J = 5.7 Hz, 1H, NH), 7.76 (s, 4H, ArH), 7.27 (s, 2H, SO2NH2), 5.92– 5.67 (m, 1H, CH), 5.29– 4.96 (m, 3H, Me), 3.77 (m, 3H, Me), 1.49 (d, J = 5.5 Hz, 1H, Cpr-CH), 1.45 (d, J = 5.5 Hz, 1H, Cpr-CH), 1.10 (s, 3H, Me), 1.09 (s, 3H, Me). 13C-NMR (101 MHz, MeOD) δ 170.9, 168.8, 142.8, 140.0, 135.2, 128.3, 120.7, 116.6, 44.0, 43.2, 28.5, 23.1, 21.9, 21.5. MS-ESI [M + H]+: 352.1. HRMS-ESI Calcd. for C16H21N3NaO4S [M + Na]+: 374.1150; Found: 374.1182.

3.2.4. Ethyl 2-Propyl-2-(4-sulfamoylphenylcarbamoyl)pentanoate 16

Ethyl 2-propyl-2-(4-sulfamoylphenylcarbamoyl)pentanoate (16): Yield: 50%; mp: 112–115 °C; 1H-NMR (400 MHz, DMSO) δ 9.82 (s, 1H, CONH), 7.85–7.67 (m, 4H, ArH), 7.27 (s, 2H, SO2NH2), 4.15 (q, J = 7.1 Hz, 2H, CH2), 1.93–1.79 (m, 4H, CH2), 1.18 (m, 4H, CH2), 1.17 (t, J = 7.1 Hz, 3H, CH2CH3), 0.89 (t, J = 7.2 Hz, 6H, Me). 13C-NMR (101 MHz, MeOD) δ 175.2, 172.4, 142.8, 140.2, 128.2, 121.6, 121.5, 62.7, 60.1, 38.6, 19.2, 14.7, 14.5. HRMS-ESI Calcd. for C17H27N2O5S [M + H]+: 371.1641; Found: 371.1610.

3.2.5. 2-Propyl-2-(4-sulfamoylphenylcarbamoyl)pentanoic Acid 17

2-Propyl-2-(4-sulfamoylphenylcarbamoyl)pentanoic acid (17): Yield: 50%; mp: 78–80 °C; 1H-NMR (400 MHz, DMSO) δ 9.96 (s, 1H, CONH), 7.80 (d, J = 9.0 Hz, 2H, ArH), 7.75 (d, J = 9.0 Hz, 2H, ArH), 7.27 (s, 2H, SO2NH2), 1.96–1.75 (m, 4H, CH2), 1.29–1.05 (m, 4H, CH2), 0.88 (t, J = 7.2 Hz, 6H, Me). 13C-NMR (101 MHz, MeOD) δ 177.9, 173.1, 142.6, 140.2, 128.3, 121.4, 59.7, 40.0, 19.5, 14.6. HRMS-ESI Calcd. for C15H23N2O5S [M + H]+: 343.1322; Found: 343.1296.

3.2.6. General Produce for the Synthesis of Compounds 18a–c

The synthesis of compounds 18a–c was similar to the synthesis of compounds 12a–n.
N1-Allyl-2,2-dipropyl-N3-(4-sulfamoylphenyl)malonamide (18a): Yield: 60%; mp: 189–192 °C; 1H-NMR (400 MHz, DMSO) δ 10.86 (s, 1H, CONH), 8.32 (t, J = 5.7 Hz, 1H, NH), 7.85–7.77 (m, 2H, ArH), 7.77–7.73 (m, 2H, ArH), 7.27 (s, 2H, SO2NH2), 5.90–5.72 (m, 1H, CH), 5.19–4.99 (m, 2H, CH2), 3.78 (t, J = 5.3 Hz, 2H, CH=CH2), 1.98–1.79 (m, 4H, CH2), 1.18–1.04 (m, 4H, CH2), 0.85 (t, J = 7.3 Hz, 6H, Me). 13C-NMR (101 MHz, MeOD) δ 175.9, 174.2, 142.8, 140.1, 128.2, 121.3, 58.9, 40.9, 40.4, 32.5, 21.2, 19.5, 14.6, 14.2. MS-ESI [M + H]+: 382.2. HRMS-ESI Calcd. for C18H28N3O4S [M + H]+: 382.1801; Found:382.1769.
2,2-Dipropyl-N1-(4-sulfamoylphenyl)malonamide (18b): Yield: 60%; mp: 202–205 °C; 1H-NMR (400 MHz, DMSO) δ 11.15 (s, 1H, CONH), 7.85–7.70 (m, 4H, ArH), 7.65 (s, 1H, NH), 7.50 (s, 1H, NH), 7.27 (s, 2H, SO2NH2), 1.93–1.65 (m, 4H, CH2), 1.21–1.03 (m, 4H, CH2), 0.84 (m, 6H, Me). 13C-NMR (101 MHz, MeOD) δ 179.2, 173.9, 142.8, 140.1, 128.2, 121.3, 59.0, 41.0, 19.5, 14.6. MS-ESI [M + H]+: 342.1. HRMS-ESI Calcd. for C15H24N3O4S [M + H]+: 342.1488; Found: 342.1460.
N1,2,2-Tripropyl-N3-(4-sulfamoylphenyl)malonamide (18c): Yield: 55%; mp: 189–192 °C; 1H-NMR (400 MHz, DMSO) δ 11.14 (s, 1H, CONH), 8.18 (t, J = 5.5 Hz, 1H, NH), 7.95–7.71 (m, 4H, ArH), 7.32 (s, 2H, SO2NH2), 3.20 (m, 2H, CH2), 2.02–1.80 (m, 4H), 1.55–1.39 (m, 2H, CH2), 1.31 (m, 4H, CH2), 1.21–1.08 (m, 4H, CH2), 0.91 (m, 9H, Me). 13C-NMR (101 MHz, MeOD) δ 175.9, 174.1, 142.8, 140.1, 135.5, 128.2, 121.4, 116.4, 59.1, 42.9, 40.7, 19.5, 14.6. MS-ESI [M + H]+: 384.2. HRMS-ESI Calcd. for C18H28N3O4S [M + H]+: 382.1801.; Found: 382.1786.

3.3. Pharmacology

3.3.1. Preparation of the Compounds for Testing

All the tested compounds were suspended in 5% carboxymethyl cellulose sodium in sterilizedphysiological saline solution. The pentylenetetrazol was prepared by dissolution of pentylenetetrazol in sterilized physiological saline to make a 0.8% solution.

3.3.2. MES Test

Kunming mice (18–22 g) purchased from Wuhan University Laboratory Animal Center were used in the MES test. After 0.5 h and 4 h of intraperitoneal (i.p.) administration of drugs at doses of 300 mg/kg, 100 mg/kg and 30 mg/kg, the mice were stimulated by an electrical stimulus (50 mA, 60 Hz, 0.2 s) through ear electrodes. Because the aim in this work was to find more effective and safer anticonvulsant drugs, the high, middle and low doses of drugs were chosen according to the effective dose of the drugs used clinically and reported previously by our group [21,22,24,25]. The procedure may cause the mice immediate hindlimb tonic extension. Protection against seizure was defined as the absence of hindlimb tonic extension. The duration of tonic seizures was analyzed over 5 min [35].

3.3.3. scPTZ Test

After 0.5 h and 4 h of i.p. administration of drugs, the pentylenetetrazol solution was injected subcutaneously. Protection against pentylenetetrazol induced seizure was defined as the abolition of a threshold. All animals were observed for 30 min [36].

3.3.4. Neurotoxicity Screening

The neurotoxicity of compounds was measured according to standardized rotorod test. Trained mice were placed on an accelerating rotarod (diameter 3.2 cm) rotating at 10 rpm after drug administration. Neurotoxicity was defined as the inability of the mice to keep balance on the rotarod fpr at least 1 min

3.3.5. Calculation of ClogP

ClogP was calculated by using ChemDraw-Ultra software (Version 6.0.1; PerkinElmer Informatics, Waltham, MA, USA).

3.3.6. Quntification Studies

For the determination of the median effective dose (ED50), groups of 10 mice were given a range of i.p. doses (160 mg/kg, 80 mg/kg, 40 mg/kg, 20 mg/kg, and 10 mg/kg) of the tested compounds. Similarly, for the determination of median toxic dose (TD50), mice were given a range of i.p. doses (100 mg/kg, 300 mg/kg, 500 mg/kg, 700 mg/kg, and 900 mg/kg) of the tested compounds. These data were subjected to Graphpad prism 5 to calculate the ED50, TD50 and the 95% confidence interval.

4. Conclusions

A novel series of benzenesulfonamide derivatives containing 4-aminobenzenesulfonamide and α-amides branched valproic acid or 2,2-dimethylcyclopropanecarboxylic acid moieties were synthesized in good yields and screened for their anticonvulsant activities in MES and scPTZ test. Compounds 12c, 12d and 18b showed outstanding anticonvulsant activities in the MES test or scPTZ test. The highest activity in the MES test was observed for compound 18b with an ED50 value of 16.36 mg/kg. The most active compound in the scPTZ test was compound 12c, which was seven times more active than that of valproate. Meanwhile, these three compounds have lower toxicity compared to phenytoin. The least toxic compound was compound 12d, with a LD50 value of 992.0 mg/kg, which was nine times more than that of phenytoin. All three of these compounds exhibited better protective index than phenytoin and valproate, which indicated they can be used as lead compounds for future investigation to discover more effective and safer anticonvulsant drugs.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/20/09/17585/s1.

Acknowledgments

This work was partially supported by the National Mega Project on Major Drug Development (2011ZX09401-302), International S & T Cooperation Program of China (2015DFA30440, 2014DFB30020), NSFC (No.81402882, 21102107, 81273363, 81373254, 81301268 and 21390402), NSFHP (2014CFB704), the National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2012ZX10004801-003-011), the Applied Basic Research Program of Wuhan Municipal Bureau of Science and Technology (2015060101010031), and the Fundamental Research Funds for the Central Universities.

Author Contributions

Xuechuan Hong and Xiaoju Zhou conceived, designed the study and revised the paper. Zhiming Wang and Jinping Li performed the experiments, analyzed the data and wrote the manuscript. Xiaodong Zeng contributed to the synthesis of the compounds. Xianming Hu supervised the project. All authors contributed to this study, read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds are available from the authors.

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MDPI and ACS Style

Wang, Z.; Li, J.; Zeng, X.-D.; Hu, X.-M.; Zhou, X.; Hong, X. Synthesis and Pharmacological Evaluation of Novel Benzenesulfonamide Derivatives as Potential Anticonvulsant Agents. Molecules 2015, 20, 17585-17600. https://doi.org/10.3390/molecules200917585

AMA Style

Wang Z, Li J, Zeng X-D, Hu X-M, Zhou X, Hong X. Synthesis and Pharmacological Evaluation of Novel Benzenesulfonamide Derivatives as Potential Anticonvulsant Agents. Molecules. 2015; 20(9):17585-17600. https://doi.org/10.3390/molecules200917585

Chicago/Turabian Style

Wang, Zhiming, Jinping Li, Xiao-Dong Zeng, Xian-Ming Hu, Xiaoju Zhou, and Xuechuan Hong. 2015. "Synthesis and Pharmacological Evaluation of Novel Benzenesulfonamide Derivatives as Potential Anticonvulsant Agents" Molecules 20, no. 9: 17585-17600. https://doi.org/10.3390/molecules200917585

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