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Medicinal Chemistry, 2010, 6, 144-149
Targeting -Aminobutyric Acid (GABA) Carriers to the Brain: Potential Relevance as Antiepileptic Pro-Drugs Mohammad H. Semreena,*, Abdel-Nasser El-Shorbagia, Taleb H. Al-Tela and Izzeddin M.M. Alsalahatb a
College of Pharmacy, University of Sharjah, Sharjah-27272, UAE; bCollege of Pharmacy, Al-Isra University, P.O. Box 961582, Amman-Jordan Abstract: The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured.
Keywords: GABA, antiepileptic, pro-drugs, blood brain barrier, tetrahydro-2H-1,3,5-thiadiazine-2-thione. INTRODUCTION Epilepsy is considered one of the most common neurological disorders in the world. The aetiology of epilepsy remains unclear, but one of the most acceptable mechanisms of its genesis is the diminished production of the inhibitory neurotransmitter -aminobutyric acid (GABA), as observed in individuals suffering from this disorder [1-6]. GABA is of diminished or even entirely absent clinical use because of it is poor bioavailability as a result of its susceptibility to degradation by enzymes, and its insufficient lipophilicity to be absorbed from the gastrointestinal tract (GIT) or to cross the blood-brain-barrier (BBB) [7]. Therefore, GABA was targeted in order to enhance its physicochemical properties especially its lipophilicity through a prodrug strategy. The titled tetrahydro–2H-1,3,5-thiadiazine–2-thione (THTT) system has been found to be a promising prodrug system, as it can be both chemically and enzymatically cleaved, and consequently release the desired moieties to the brain [8-14]. Introducing GABA in the THTT system has been found to dramatically enhance its lipophilicity. This work has been designed to outline the presentation of the THTT system as a prodrug for GABA, and the synthesis of a series of derivatives of the THTT prodrug system as biodegradable molecules capable of releasing the bioactive GABA through enzymatic biotransformation. Also, preliminary studies to investigate the anticonvulsant activity of these derivatives and to evaluate the structure activity relationship of these compounds have been conducted.
*Address correspondence to this author at the College of Pharmacy, University of Sharjah, Sharjah-27272, UAE; Tel: +971-501614497; Fax: +971-6-5585812; E-mail:
[email protected] 1573-4064/10 $55.00+.00
SYNTHESIS OF 3,5-DISUBSTITUTED TETRAHYDRO-2H-1,3,5-THIADIAZINE-2-THIONE DERIVATIVES The target compounds were synthesized through a tandem process by the reaction of the appropriate alkylamine (1a-g) with carbon disulfide in the presence of sodium or potassium hydroxide (Scheme 1). Without workup, the resulting dithiocarbamate salts (2a-g) were added to formalin to give intermediates (Ia-g). The latter derivatives were poured in portions onto GABA to deliver compounds (3a-g). Spectral data of compounds (3a-d), are in accordance with the proposed structures. The IR spectra of compounds (3a-d), showed stretching frequencies around 3400-3350 cm1 (COOH), 3000-2900 cm-1 (CH), and 1700-1695, 1455-1445 cm-1 ( C=O and C=S, respectively). Salient features in the 1H NMR- spectra of 3a-g, are the chemical shifts of the methylene protons at C4 and C6 of the THTT ring, each of which appeared as a separate singlet or in some derivatives as a broad singlet integrating to four protons (see experimental) . The unambiguous elucidation of the structures of 3a-g was further verified from their 13C NMR spectra. In Vivo Studies The anticonvulsant activity (represented by the percentage of protection, as summarized in Table 1) of the new compounds was found to vary from 20% as in case of 2c, to 100% as in case of 3d and 3f. However, in case of 3f (cyclohexyl-substituted N3) no signs of convulsions were observed. Only mild jerks were observed. The 3,5-dibutyl analogue (3,5-dibutyl-tetrahydro-2H-1,3,5-thiadiazine-2-thione) previously described by El-Shorbagi [15-20] and coworkers to exclude any likely anticonvulsant activity of the other © 2010 Bentham Science Publishers Ltd.
Targeting -Aminobutyric Acid (GABA) Carriers to the Brain
Medicinal Chemistry, 2010, Vol. 6, No. 3
constituents of the carrier itself, was found inactive. However, compared to the control that received only the vehicle it was only found to delay PTZ-induced death in the tested animals. The anticonvulsant activity of these compounds can be attributed to the liberated GABA molecules in animals’ brains after undergoing enzymatic biotransformation. R
R N
H
CS2, KOH R
N
HCHO S
NH2
1a-g
CH2 OH
S
2a-g
Ia-g
S- K+
S
CH 2OH
R N
GABA, Buf f er
S
N
CO2 H
S
3a: R = CH3; 3b: R = C2H5; 3c: R = C3H7 3d: R = C4H9; 3e: R = C5H11; 3f: R = cyclohexyl 3g: R = benzyl
Scheme 1. Synthesis of THTT prodrugs.
Brain Bioavailablity Table 2 summarizes the brain concentrations of the new compounds after 15 minutes of the administration of compound 3a, and 1 hour after the administration of all the compounds 3a-g. Brain concentrations were found to be time dependent, as explained by compound 3a, in which, the brain concentration after one hour is higher than after 15 minutes. Also, the brain concentrations of the new compounds increase as the alkyl groups on N3 become bulkier. However, there are some slight variations in the case of compounds 3d and 3e, and 3f and 3g. Comparing the results summarized in Table 3 with the anticonvulsant activity shows that increasing the brain bioavailability of a compound does not necessarily mean enhancing the activity. This is clear in the case of, for example, 3d and 3e (which were found to have approximately the same brain concentration after the first hour), where the percentage of protection of 3d is 100% whereas it is 60% in the case of 3e. This can be attributed to the fact that increasing brain bioavailability might not be accompanied by more enhanced release of GABA from the compounds or by enhanced activity on GABA receptors. CONCLUSION In summary, we have synthesized various motifs of THTT carrying GABA as potential prodrugs for treatment of epilepsy. Furthermore, the alkyl groups introduced at N3 of the THTT ring play a prime role in the lipophilicity and transport of the prodrugs to animal brains. EXPERIMENTAL SECTION General GABA was purchased from Sigma Chemicals Company [St.Louis, USA]. Acetonitrile (HPLC grade) was available from Scharlau (Barcelona Spain). Water used in the mobile phase was deionized, distilled and filtered through a 0.45 m membrane pore filter (Sartorius, Germany) under vacuum before use, and potassium dihydrogen (Panreac, Barcelona, Spain) was of analytical grade. Pre-coated silica gel F-254
145
plates (Merck) were used for TLC. TLC spots were detected by UV and/or staining with iodine vapour. 1H NMR and 13C NMR spectra were obtained using a Bruker 300 and 75.46 MHz spectrometer in CDCl3, respectively, using TMS as internal standard and the chemical shifts were given in ppm. The HPLC instrument was a Merck-Hitachi chromatograph equipped with a pump (L-6200A), injector (Rheodyne 7725), and an UV-VIS detector (L-4000A). Peak area integration were performed using a chromatographic data system (PE NELSON 1022 HPLC System Manager Program, with a Vertex Reversed-Phase Hypersil C18 column (25 cm 4.6 mm i.d., 5m particle size as stationary phase). The mobile phase was a mixture of phosphate buffer (pH 4) and acetonitrile (60:40 V/V). The flow rate was 1.5 ml/min. The U.V detector wavelength was set at 285 nm and a range of 0.005 AUFS was used to give a reasonable retention time of 2.627 min. The preparation of standard solutions was carried out by weighing the required amount of product into 100 ml volumetric flasks. The substance was dissolved and diluted to volume with mobile phase. General Procedure for the Preparation of Compounds 3a-g Carbon disulfide (60 mmol) was added in portions to a stirred solution of appropriate amines 1a-g (10 mmol) and potassium hydroxide (20%, 10 mmol). Stirring was continued for about 2h at ambient temperature. To the resulting mixture, containing the dithiocarbamates 2a-g, the formalin solution (40%, 22 mmol) was added, and stirring was continued for another 3h. The resulting mixtures of Ia-g were added in portions within 5 minutes to a stirred solution of GABA (10 mmol) in phosphate buffer (pH 7.8, 20 ml), and stirring was continued for 1h at ambient temperature. Then, the reaction mixture was acidified with dilute hydrochloric acid (5%, ~35 ml) to pH 2, and stirring was continued for 20 minutes. The crude precipitate was filtered or the formed resinous substance was collected and extracted with chloroform, dried over anhydrous MgSO4, evaporated under reduced pressure, and crystallized from a methanol-chloroform mixture. 3-Methyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione (3a) The white solid product was crystallized from chloroform-methanol (9:1). Yield: 1.4 g (59 %), m. p. 102-103 oC. – 1H NMR (300 MHz, CDCl3): = 11.20 (s, 1H, COOH), 4.47 (s, 2H, methylene C-4), 4.44 (s, 2H, methylene C-6), 3.32 (s, 3H, methyl N-3), 2.70 (t, 2H, -CH2 at N-5), 2.22 (t, 2H, -CH2 at N-5), 1.68 (t, 2H, -CH2 at N-5). – 13C NMR (75 MHz, CDCl3): = 190.8 (C=S), 174.8 (COOH), 71.4 (C4 of THTT), 58.1 (C-6 of THTT), 49.5 (C of -CH2 at N-5), 39.2 (C of CH3 at N-3), 32.1 (C of -CH2 at N-5), 22.9 (C of -CH2 at N-5). – C8H14N2O2S2 (234.33): calcd. C 41.01, H 6.02, N 11.95; found C 41.32, H 6.41, N 11.65. 3-Ethyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione (3b) The white solid product was crystallized from chloroform-methanol (9:1). Yield: 2.0 g (82 %), m. p. 98-99 oC. –
146 Medicinal Chemistry, 2010, Vol. 6, No. 3
Table 1.
Semreen et al.
Anticonvulsant Activity of The Synthesized Compounds During The First Hour After PTZ Injection*
Compound
3a
3b
3c
3d
3e
3f
3g
Control
Placebo
3,5-dibutyl analogue
Effects
15 Min
30 Min
45 Min
60 Min.
% Protection
Death
0
1
1
0
60%
Convulsion
+
++
++
+
Jerks
+
++
++
++
Death
0
0
1
0
Convulsion
+
+
+
+
Jerks
+
++
++
+
Death
0
1
1
2
Convulsion
++
++
+++
++
Jerks
++
+++
+++
+++
Death
0
0
0
0
Convulsion
-
-
+
-
Jerks
-
+
++
+
Death
0
1
1
0
Convulsion
++
+++
++
++
Jerks
+++
+++
+++
+++
Death
0
0
0
0
Convulsion
-
-
-
-
Jerks
-
+
+
+
Death
0
0
1
0
Convulsion
+
+
+
-
Jerks
++
++
+
+
Death
5
0
0
0
Convulsion
+++
-
-
-
Jerks
+++
-
-
-
Death
0
1
4
0
Convulsion
+++
+++
+++
+++
Jerks
+++
+++
+++
+++
Death
0
1
1
3
Convulsion
++
+++
+++
+++
Jerks
++
+++
+++
+++
80%
20%
100%
60%
100%
80%
0%
0%
0%
*+++ Severe, ++ moderate,+ weak,- no convulsions. 1 H NMR (300 MHz, CDCl3): =11.15 (s, 1H, COOH), 4.88 (s, 4H, methylenes of C-4 & C-6 of THTT), 4.50 (q, 2H, CH2 at N-3), 3.20 (t, 2H, -CH2 at N-5), 2.78 (t, 2H, -CH 2 at N-5), 2.18 (m, 2H, -CH2 at N-5), 1.41 (t, 3H, -CH3 at N5). – C9H16N2O2S2 (248.36): calcd. C 43.53, H 6.49, N 11.28; found C 43.36, H 6.71, N 11.03.
3-Propyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione (3c) A white solid product was crystallized from chloroformmethanol (9:1). Yield: 1.97 g (76 %), m. p. 116-118 oC. – 1 H NMR (300 MHz, CDCl3): = 11.32 (s, 1H, of COOH), 4.82 (s, 4H, methylenes of C-4 & C-6 of THTT), 4.34 (dd, 2H, CH2 at N-3), 3.18 (t, 2H, -CH2 at N-5), 2.72 (t, 2H, -CH 2
Targeting -Aminobutyric Acid (GABA) Carriers to the Brain
Table 2.
Table 3.
Medicinal Chemistry, 2010, Vol. 6, No. 3
147
Brain Concentrations for Selected Compounds at Different Time Intervals
Compound
Injection Time
Concentration mg%
3a
15 min.
0.24
3a
1 hr.
1.83
3b
1hr.
1.95
3c
1 hr.
2.05
3d
1 hr.
2.73
3e
1 hr.
2.70
3f
1 hr.
3.00
3g
1 hr.
2.96
Calibration Curve of the HPLC Method of Compound 3a
Trial
Concentration mg %
Average Area
Slope
Intercept
r2
1
0.416
82697
182362
6890
0.9998
2
0.624
121648
3
0.832
157155
4
1.04
196798
5
1.25
234778
at N-5), 1.55-2.35 (m, 4H, -CH2 at N-3& -CH2 at N-5), 1.07 (t, 3H, -CH3 at N-3). – C10H18N2O2S2 (262.39): calcd. C 45.78, H 6.91, N 10.68; found C 45.57, H 7.20, N 10.46. 3-Butyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione ( 3d) A white solid product was crystallized from chloroformmethanol (9:1). Yield: 1.97 g (76 %), m. p. 101-102 oC. – 1 H NMR (300 MHz, CDCl3): = 10.52 (s, 1H, of COOH), 4.36 (s, 2H, methylene C-4), 4.32 (s, 2H, methylene C-6 of THTT), 3.97 (t, 2H, -CH2 of butyl at N-3), 2.84 (t, 2H, CH2 at N-5), 2.40 (t, 2H, -CH2 at N-5), 1.83 (m, 2H, -CH 2 at N-3), 1.62 (m, 2H, -CH2 at N-5), 1.28 (m, 2H, -CH2 at N-3), 0.92 (t, 3H, CH3 of butyl at N-3). – 13C NMR (75 MHz, CDCl3): = 191.3 (C=S), 178.2 (COOH), 70.0 (C-4 of ring THTT), 57.9 (C-6 of ring THTT), 52.2 (C of -CH2 at N-3), 49.6 (C of -CH2 at N-5), 28.7 (C of -CH2 at N-3), 22.4 (C of -CH2 at N-5), 20.1 (C of -CH2 at N-3), 13.9 (C of CH3 at N-3). – C11H20N2O2S2 (276.41): calcd. C 47.80, H 7.29, N 10.13; found C 48.00, H 7.53, N 9.89. 3-Pentyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione (3e) A white solid product was crystallized from chloroformmethanol (9:1). Yield: 2.5 g (84 %), m. p. 83-84 oC. – 1H NMR (300 MHz, CDCl3): = 10.60 (s, 1H, COOH), 4.80 (s, 4H, methylenes of C-4 & C-6 of THTT), 4.35 (dd, 2H, CH2 at N-3), 3.14 (t, 2H, -CH2 at N-5), 2.67 (t, 2H, -CH 2 at N-5), 1.20-2.35 (m, 8H, -(CH2)3- at N-3& -CH2 at N-5),
0.95 (t, 3H, -CH3 at N3). – C12H22N2O2S2 (290.44): calcd. C 49.63, H 7.63, N 9.65; found C 49.75, H 7.75, N 9.42. 3-Cyclohexyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5Thiadiazine-2-Thione (3f) A white solid product was crystallized from chloroformmethanol (9:1). Yield: 2.7 g (89 %), m. p. 135-136 oC. – 1H NMR (300 MHz, CDCl3): = 10.23 (s, 1H, COOH), 5.62 (m, 1H, methine of cyclohexyl at N-3), 4.37 (s, 2H, methylene C-4), 4.32 (s, 2H, methylene C-6 of THTT), 2.65 (t, 2H, -CH2 at N-5), 2.32 (t, 2H, -CH2 at N-5), 1.10-1.78 (m, 12H, -(CH2)5- of cyclohexyl at N-3& -CH2 at N-5). – 13C NMR (75 MHz, CDCl3): = 190.5 (C=S), 174.8 (COOH), 64.9 (C-4 of THTT), 58.0 (C-6 of THTT), 56.9 (C-1 of cyclohexyl at N-3), 48.9 (C of -CH2 at N-5), 31.7 (C of -CH 2 at N-5), 28.4 (C-2 of cyclohexyl at N-3), 25.8 (C-3 of cyclohexyl at N-3), 25.1 (C-4 of cyclohexyl at N-3), 22.9 (C of CH2 at N-5). – C13H22N2O2S2 (302.45): calcd. C 51.63, H 7.33, N 9.26; found C 51.77, H 7.61, N 9.00. 3-Benzyl-5-(3-Carboxypropyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione (3g) A white solid product was crystallized from chloroformmethanol (9:1). Yield: 2.7 g (87 %), m. p. 124-126 oC, – 1H NMR (300 MHz, CDCl3): = 10.45 (s, 1H, COOH), 7.35 (m, 5H, C6H5 of benzyl at N-3), 5.33 (s, 2H, CH2 of benzyl at N-3), 4.38 (s, 2H, methylene of C-4 of THTT), 4.25 (s, 2H, methylene of C-6 of THTT), 2.70 (t, 2H, -CH2 at N-5), 2.25 (t, 2H, -CH2 at N-5), 1.53 (m, 2H, -CH2 at N-5). – 13C
148 Medicinal Chemistry, 2010, Vol. 6, No. 3
Semreen et al.
NMR (75 MHz, CDCl3): = 192.9 (C=S), 178.2 (COOH), 135.3 (C-1 of C6H5-CH2 at N-3), 128.9 (C-2 of C6H5-CH2 at N-3), 128.6 (C-3 of C6H5-CH2 at N-3), 128.3 (C-4 of C6H5CH2 at N-3), 53.8 (C of C6H5-CH2 at N-3), 49.5 (C of -CH2 at N-5), 31.2 (C of -CH2 at N-5), 22.0 (C of -CH2 at N-5). – C14H18N2O2S2 (310.43): calcd. C 54.17, H 5.84, N 9.02; found C 54.02, H 6.11, N 8.75.
HPLC Conditions
Anticonvulsant Activity of the New Compounds
Five solutions at five different concentrations were prepared by dissolving the amount of 3a (as an example) in mobile phase. The final concentrations of solutions were 0.416, 0.624, 0.832, 1.04 and 1.25 mg% (Table 3). Before injecting solutions, the column was equilibrated for at least 30 min with the mobile phase flowing through the system, three determinations were carried out for each solution and peak areas were recorded. The correlation graph was constructed by plotting the peak areas obtained at the optimum wavelength of detection versus the injected amounts. The linearity of peak area response versus concentrations was studied from 0.416 to 1.25 mg %. A linear response was observed over the examined concentration range. Table 3 summarizes the correlation coefficient slope and intercept for compound 3a.
To evaluate the anticonvulsant activity of the newly synthesized compounds, Albino mice 50% male and 50% female weighing 25± 3 g, grown in the animal breeding facility at (Israa University) were used in this study. The animals were housed 10 per cage with free access to food and water ad lib, and maintained under a natural light/dark cycle and temperature 25± 2ºC. They were acclimatized to laboratory conditions before the experiment. The experiment was carried out between 9.00 am and 16.00 p.m. All animals were used once. The protocols were approved by the animal ethics regulations in the school. Ten groups comprising 5 animals each were used for studying the anticonvulsant activity of the new compounds using a lethal dose of the convulsing agent pentylenetetrazole (PTZ) (Sigma, St. Louise) in mice. To study the anticonvulsant activity of these compounds using PTZ model, group 1 received a lethal dose of PTZ alone (112 mg/kg i.m.) which was freshly prepared by dissolving it in saline. Group 2 received the vehicle alone (50% propylene glycol), one hour prior to the administration of PTZ. Groups 3-9 received the named 4a-g compounds (35mg/kg i.p.) one hour prior to the administration of PTZ. Group 10 received the 3,5-dibutyl analogue (with two butyl groups, one at N3, and another at N5 instead of GABA) the same dose as the other compounds, to investigate the effect of the carrier itself on the antiepileptic activity. All animals were observed for one hour for jerks, convulsion and or death. The end point was to survive up to one hour in order to calculate the percentage of protection for each compound, which is defined as the number of protected animals against PTZ-induced death divided by the number of all animals being tested for each compound [21]. Brain Bioavailability of the New Compounds In order to preliminarily evaluate the capability of the new compounds to cross the BBB according to their structures, and to correlate the PTZ- anticonvulsant activity of the new compounds with their brain bioavailability, eight groups of Albino mice (5 animals per group) kept under the same experimental conditions as in the PTZ-anticonvulsant activity study were used. Two groups were given compound 3a while the rest of the groups received one of the compounds 3b-g. The compounds were administered at 35 mg/kg i.p, the same dose used in PTZ- anticonvulsant activity study. Mice in group 1 were sacrificed by decapitation after 15 min, while mice in the other groups were all decapitated 1 hour after the administration of the compounds. The brains were isolated and homogenized and the homogenates were extracted with chloroform/methanol (2:1). The compounds concentrations were calculated using High Performance Liquid Chromatography (HPLC).
The mobile phase was a mixture of phosphate buffer, pH=4, and acetonitrile (60:40 V/V). The flow rate was 1.5 ml/min. The U.V detector wavelength was set at 285 nm and a range of 0.005 AUFS was used. An HPLC column with Hypersil reversed-phase C18 25cm x 4.6 I.d, 5m particle size was used.
ACKNOWLEDGEMENTS The authors are grateful to the college of graduate studies and research at University of Sharjah (UAE) and Al-Isra University, Amman-Jordan for funding this research project. REFERENCES [1] [2]
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Received: March 08, 2010
Revised: July 01, 2010
Accepted: July 08, 2010
Medicinal Chemistry, 2010, Vol. 6, No. 3 [17]
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