FABAD J. Pharm. Sci., 31, 23-29, 2006 RESEARCH ARTICLE
Synthesis of Some New Hydroxypyranone Derivatives and Evaluation of Their Anticonvulsant Activities
Summary
INTRODUCTION
About 0.5 to 1% of the world’s population is affected by epilepsy, which is one of the most common neuro- logical disorders and characterized by recurrent sei- zure attacks. The drugs that are widely used for treating epileptic seizures have failed to adequately control seizures and have unfavorable adverse effects such as ataxia, hepatotoxicity, gingival hyperplasia and megaloblastic anemia. The restrictive treatment of epileptic seizures in patients have led to researches
to discover new agents with more effective anticon- vulsant activity and which toxicity1,2.
The derivatives of hydroxypyranone exhibit a variety of biological activities, such as herbicidal3, antimicrobial4-8, pesticide and insecticide9,10, antitumor11,12 and tyrosinase inhibitory effect13,14. 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (kojic acid) and 3-hydroxy-2-methyl-4H-pyran-4-one (mal-
Synthesis of Some New Hydroxypyranone Derivatives and Evaluation of Their Anticonvulsant Activities
In this study, Mannich bases of hydroxypyranone derivatives were synthesized by starting from kojic acid. Their anticonvulsant activities were evaluated in in vivo studies. Mannich bases were prepared by the reaction of cyclic amine derivatives with allomaltol and formaline. The chemical structure of synthesized compounds 3a-e was proven by IR, 1H-NMR, mass spectra and elementary analysis data. Anticonvulsant activities of the compounds were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet) tests. Neurotoxicity was determined by rotorod toxicity test. All these tests were performed in mice according to procedures of the Antiepileptic Drug Development (ADD) program of the National Institutes of Health (NIH). According to the activity studies, compound 3a, which is carrying 4-[(2,3- dimethylphenyl)piperazin-1-yl]methyl at 2 position on the pyranone ring, showed activity against scMet at 300 mg/kg dose at 4 h. Only compound 3b was determined to be protective against MES at 300 mg/kg dose at 5 h in this series. None of the synthesized compounds was observed to have neurotoxicity.
Key Words: Hydroxypyranone derivatives, kojic acid, allomaltol, Mannich reaction, anticonvulsant activity.
Received : 26.02.2007 Revised : 20.06.2007 Accepted : 12.07.2007
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Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara Turkey Corresponding author e-mail: mutlud@hacettepe.edu.tr
metal ions15,16. Tris (maltol)aluminium(III) and -gallium(III) complexes have lipid solubility; therefore, they can cross the blood-brain barrier with consider- able facility17.
Maltol, kojic acid and allomaltol (5-hydroxy-2-methyl- 4H-pyran-4-one) have been reported to show the same anticonvulsant effect18,19. 2-Butyl-3-hydroxy- 4H-pyran-4-ones was the most potent protective of the pentylenetetrazole-induced convulsion among the 2-alkyl series. The increase in inhibitory effect of these compounds with increasing carbon number of the alkyl group might be due to enhancement of lipid solubility18. It is generally accepted that the lipid solubility of a drug is an important factor in connection with its transfer into the central spinal fluid and brain20. In our previous studies21, we have reported the anticonvulsant and antifungal activities of novel Mannich base derivatives possessing piperazine groups.
This study describes the synthesis of Mannich base derivatives possessing piperidine, piperazine and morpholine rings and investigates their anticonvulsant activity. Anticonvulsant activities of the synthesized compounds were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet) tests. Sei- zure assays and neurotoxicity were determined ac- cording to the phase I tests of the Antiepileptic Drug Development (ADD) program, which were developed by the National Institute of Neurological Disorders and Stroke (NINDS) and National Institutes of Health (NIH)21-27.
MATERIALS and METHODS Chemistry
All chemicals used in this study were supplied by Merck (Darmstadt, Germany) and Aldrich Chemical Co. (Steinheim, Germany). Melting points were de-
uncorrected. IR spectra were recorded on a Perkin Elmer FT-IR Spectrometer 1720 X (Beaconsfield, UK) as KBr disc (γ, cm-1). 1H-NMR spectra were obtained on a Bruker AC 80 MHz spectrophotometer and Bruker GMBH DPX-400 MHz High Performance Digital FT NMR spectrophotometer (Karlsruhe, Ger- many) using TMS as an internal standard (chemical shift in δ, ppm). Mass spectra were recorded on Sci- entific Instrument Service HPP7-M direct insertion probe spectrometer using Agilent 5973 network mass selective electron impact detector and Agilent 6890 network GC system. The elemental analyses were performed with a Leco CHNS-932 (St. Joseph, MI, USA) at The Scientific & Technological Research Council of Turkey-Ankara Testing and Analyses Lab- oratory (TÜB‹TAK-ATAL). The purity of the com- pounds was assessed by TLC on Kieselgel 60 F254 (Merck, Darmstadt, Germany).
Seven compounds were synthesized according to the procedures as shown below.
2-(Chloromethyl)-5-hydroxy-4H-pyran-4-one27 (1)
Kojic acid (25 g, 0.198 mol) was dissolved in distilled thionyl chloride (100 mL) and stirred for 1 h. The product formed, a yellow crystalline solid, was col- lected by filtration and washed with petroleum ether and then recrystallized from water to give colorless needles (23.5 g, 74%), mp 166-167°C (lit. value27 166- 168°C). IR (KBr disc) 3230 (O-H st), 1657 (C=O st),
1623, 1586, 1455 (C=C st), 1286, 1166 (C-O st), 767 cm-1 (C-Cl st). 1H-NMR (DMSO-d6, 60 MHz) δ
4.55 (2H; s; 2-CH2Cl), 6.45 (1H; s; H3), 8.00 (1H; s; H6), 9.0-9.3 (1H; broad; 5-OH).
5-Hydroxy-2-methyl-4H-pyran-4-one27 (2)
Chlorokojic acid (1) (20 g, 0.125 mol) was added to 100 mL of distilled water and heated to 50ºC with stirring. Zinc dust (16.29 g, 0.25 mol) was added followed by the dropwise addition of concentrated hydrochloric acid (37 mL) over 1 h with vigorous stirring maintaining the temperature between 70- 80ºC. The reaction mixture was left stirring for 2-3 h
at 70°C. The excess zinc was removed by hot filtration and the filtrate extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and con- centrated in vacuum to yield the crude product.
Recrystallization from isopropanol afforded allomaltol (2) as colorless plates (9.5 g, 60%): mp 152-153ºC (lit.
value27 152-153°C). IR (KBr disc) 3300-3100 (O-H st), 1640 (C=O st), 1587, 1384 (C=C st), 1223, 1150 cm-1
(C-O st). 1H-NMR (DMSO-d6, 60 MHz) δ 2.25 (3H; s;
2-CH3), 6.10 (1H; s; H3), 6.30-7.15 (broad, 1H, 5-OH), 7.80 (1H; s; H6).
General preparation of Mannich bases of allomaltol derivatives (3a-e)
Mannich bases were prepared by the reaction of substituted cyclic amine derivatives (0.01 mol) and allomaltol (0.01 mol) in methanol (15 mL) with 37%
formaline (1 mL). The reaction mixture was stirred vigorously for 15 to 25 min. The resulting precipitate was collected by filtration and washed with cold methanol. The crude product recrystallized from appropriate solvents.
2-{[4-(2,3-Dimethylphenyl)piperazin-1-yl]methyl}- 3-hydroxy-6-methyl-4H-pyran-4-one (3a)
It was synthesized by the general procedure using 1-(2,3-xylyl)piperazine, allomaltol and formaline.
Recrystallization from methanol gave a white crys- talline solid. IR (KBr disc) 1659 (C=O st), 1587 (C=C st) and 1219 cm-1 (C-O st). 1H-NMR δ (CDCl3, 400 MHz) 2.22 (3H; s; -CH3), 2.27 (3H; s; -CH3), 2.33 (3H;
s; 6-CH3), 2.80-2.90 (4H; m; piperazine), 2.95 (4H; t;
J= 4.66, piperazine), 3.75 (2H; s; -CH2-), 6.26 (1H; s;
H5), 6.92 (2H; d; J= 6.87, phenyl), 7.08 ppm (1H; t;
J= 7.72, phenyl). EI m/e 328 (M+), 329 (M++1), 189, 160, 148 (base peak), 132, 117, 105, 91, 77, 56, 43. Anal.
Cal. for C19H24N2O3 M.W.: 328 Cal. C: 69.49 H: 7.37 N: 8.53 Found C: 69.40 H: 8.03 N: 8.43.
2-{[4-(3-Chlorophenyl)piperazin-1-yl]methyl}-3- hydroxy-6-methyl-4H-pyran-4-one (3b)
It was synthesized by the general procedure using
1-(3-chlorophenyl)piperazine, allomaltol and forma- line. Recrystallization from chloroform gave a white crystalline solid. IR (KBr disc) 1630 (C=O st), 1488 (C=C st) and 1224 cm-1 (C-O st). 1H-NMR δ (DMSO- d6, 400 MHz) 2.27 (3H; s; 6-CH3), 2.57 (4H; t; J= 4.60, piperazine), 3.16 (4H; t; J= 4.56, piperazine), 3.55 (2H;
s; -CH2-), 6.24 (1H; s; H5), 6.77 (1H; d; J= 7.68, phenyl), 6.88 (1H; d; J= 8.34, phenyl), 6.92 (1H; s; phenyl), 7.20 ppm (1H; t; J= 8.10, phenyl). EI m/e 334 (M+), 335 (M++1), 264, 195, 179, 166, 154 (base peak), 140, 111, 85, 69, 56, 43. Cal. for C17H19ClN2O3 M.W.: 334.79 Cal. C: 60.98 H: 5.72 N: 8.36 Found C: 60.71 H: 5.24 N: 8.24.
3-Hydroxy-6-methyl-2-[(4-pyrimidin-2-ylpiperazin- 1-yl)methyl]-4H-pyran-4-one (3c)
It was synthesized by the general procedure using N-(2-pyrimidinyl)piperazine, allomaltol and forma- line. Recrystallization from chloroform/petroleum ether (40-60°C) gave a white powder. IR (KBr disc) 1621 (C=O st), 1587 (C=C st) and 1218 cm-1 (C-O st).
1H-NMR δ (CDCl3, 80 MHz) 2.30 (3H; s; 6-CH3), 2.60 (4H; t; piperazine), 3.60 (2H; s; -CH2-), 3.80 (4H; t;
piperazine), 6.20 (1H; s; H5), 6.40 (1H; t; pyrimidine), 8.25 ppm (2H; d; pyrimidine). EI m/e 302 (M+), 303 (M++1), 264, 177, 163 (base peak), 140, 122, 108, 96, 56, 43. Anal. Cal. for C15H18N4O3 M.W.: 302 Cal.
C: 59.59 H: 6.00 N: 18.53 Found C: 59.87 H: 5.87 N:
18.23.
2-(1,4'-Bipiperidin-1'-ylmethyl)-3-hydroxy-6-methyl- 4H-pyran-4-one (3d)
It was synthesized by the general procedure using 4-piperidinopiperidine, allomaltol and formaline.
Recrystallization from chloroform/petroleum ether (40-60ºC) gave an orange powder. IR (KBr disc) 1622 (C=O st), 1459 (C=C st) and 1198 cm-1 (C-O st).
1H-NMR δ (DMSO-d6, 400 MHz) 1.27-2.11 (11H; m;
piperidine), 2.17 (3H; s; 6-CH3), 2.34-2.79 (8H; m;
piperidine), 3.37 (2H; s; -CH2-), 6.13 ppm (1H; s; H5).
GC(MS) m/e 253, 235, 210 (base peak), 193, 158, 139, 111, 99, 86, 57. Anal. Cal. for C17H26N2O3 M.W.: 306 Cal. C: 66.64 H: 8.55 N: 9.14 Found C: 66.50 H: 7.99 N: 8.74.
FABAD J. Pharm. Sci., 31, 23-29, 2006
It was synthesized by the general procedure using morpholino, allomaltol and formaline. Recrystalliza- tion from methanol gave a white crystalline solid. IR (KBr disc) 1621 (C=O st), 1461 (C=C st) and 1200 cm-1 (C-O st). 1H-NMR δ (CDCl3, 80 MHz) 2.40 (3H;
s; 6-CH3), 2.60-3.00 (4H; t; morpholine), 3.80-4.00 (6H;
m; morpholine and -CH2-), 6.40 ppm (1H; s; H5).
GC(MS) m/e 151, 140 (base peak), 111, 86, 69, 56.
Anal. Cal. for C11H15NO4 M.W.: 225.24 Cal. C: 58.65 H: 6.71 N: 6.21 Found C: 58.35 H: 6.31 N: 6.03.
Anticonvulsant Activity
The compounds were tested for their anticonvulsant activity against MES- and scMet-induced seizures, and rotorod toxicity test was performed for neurolog- ical toxicity according to the phase I tests of the ADD program24. Stimulator (Grass S88, Astro-Med. Inc.
Grass Instrument Division, W. Warwick, RI, USA), constant current unit (Grass CCU1A, Grass Medical Instrument, Quincy, MA, USA), and corneal electrodes were used for the evaluation of anticonvulsant activity against MES test. All synthesized compounds were suspended in 30% aqueous PEG 400 and administered to the mice intraperitoneally in a volume of 0.01 ml/g body weight. Twelve Swiss albino male mice (20 ± 2 g) were used for each compound (mice were obtained from the Hacettepe University Animal Farm according to the NINDS-ADD program24 and used according to Hacettepe University’s `Laboratory Animals Ethics Committee’ decision (17.04.2002 date 2002/24-3 num- ber). Control animals received 30% aqueous PEG 400.
Pentetrazol (metrazol) was administer ed subcutane- ously (s.c.) on the back of the neck. The rotorod toxicity test was performed on a 1 inch diameter knurled wooden rod, rotating at 6 rpm (the rotorod used in Phase I test was made by Hacettepe University’s Technical Department).
Maximal Electroshock Seizure (MES) test
Maximal electroshock seizures were elicited with a 60-cycle alternating current of 50 mA intensity (5-7
electrodes. A drop of 0.9% saline was instilled into the eye prior to application of the electrodes in order to prevent the death of the animal. Abolition of the hind limb tonic extension component of the seizure was defined as protection.
Subcutaneous Pentetrazol (Metrazol) (ScMet) test
85 mg/kg of pentetrazol (produces seizures in more than 95% of mice) was administered as a 0.5% solution s.c. into the posterior midline. The animal was ob- served for 30 min to decide whether the failure of the threshold seizure (a single episode of clonic spasms of at least 5 sec duration) could be defined as protec- tion.
Neurotoxicity
The rotorod test was used to evaluate neurotoxicity.
The animal was placed on a 1 inch diameter knurled wooden rod rotating at 6 rpm. Normal mice remain on a rod rotating at this speed indefinitely. Neurologic toxicity was defined as the failure of the animal to remain on the rod for 1 min.
RESULTS and DISCUSSION Chemistry
Allomaltol, which was used as a starting material, was synthesized from commercially available kojic acid in accordance with previous studies27,28. Chlo- rokojic acid (1) was prepared with quite a significant yield (75%) by chlorination of kojic acid using neat thionyl chloride at room temperature. Reduction of chlorokojic acid with zinc dust in concentrated hy- drochloric acid resulted in the production of allomaltol (2)27,28. In the hydroxypyran form, only one enolic hydroxyl group is present and the position ortho
to this hydroxyl group is readily subject to aminomethylation in the Mannich reaction at room
temperature29,30.
In this study, the synthesis of 2-substituted-3-hydroxy-
FABAD J. Pharm. Sci., 31, 23-29, 2006
6-methyl-4H-pyran-4-one derivatives (3a-e) was pre- pared by the reaction of appropriate cyclic amine derivatives with allomaltol and formaldehyde at room temperature as shown in Scheme 1. Yields and the melting point properties of the synthesized com- pounds are presented in Table 1.
The structures of the synthesized compounds were confirmed by IR, 1H-NMR, mass spectra and elemen- tary analysis. All the spectral data of the compounds were in accordance with the assigned structures. In the IR spectra, the synthesized compounds have O-H stretching bands at 3400-3300 cm–1. All com- pounds were associated with C=O, C=C and C-O stretching bands at 1659-1621, 1587-1459 and 1224- 1198 cm–1, respectively. With 1H-NMR spectra, allo-
maltol derivatives showed methyl group protons as a singlet at 2.17-2.40 ppm. The methylene group protons of 3a-e appeared as a singlet at 3.37-3.80 ppm.
H5 protons of the 4H-pyran-4-one ring were found as a singlet peak in the region 6.13-7.20 ppm in accor- dance with literature21. EI mass spectra’s of 3a, 3b and 3c showed the molecular ion (M+) and (M++1) peaks of the compounds.
Anticonvulsant Activity
The anticonvulsant activity results of the synthesized compounds are shown in Table 2. According to the activity studies, chlorokojic acid (1) has anticonvulsant activity against MES seizures at 300 mg/kg dose at 5 and 4 h. Allomaltol (2) showed activity against scMet at 300 mg/kg at 4 h. Compound 3a, which is carrying 4-(2,3-dimethylphenyl)piperazinylmethyl at second position on the 4H-pyran-4-one ring, showed activity against scMet at 300 mg/kg dose at 4 h.
Compound 3b, carrying 4-(3-chlorophenyl)piperazine ring, was protective against MES at 300 mg/kg dose at 5 h. None of compounds 3c, 3d and 3e showed anticonvulsant activity. In our previous study21, de- rivatives of Mannich bases possessing piperazine ring were found to be protective against MES and scMet at different doses. In this study, when the piperazine ring (3a and 3b) was changed with piperidine (3d) and morpholine (3e) rings, Mannich bases were inac- tive. Neurotoxicity was not observed with any of the synthesized compounds that wer e administered to mice in the dose range of 30-300 mg/kg.
Acknowledgement
This research was supported by a grant from The Scientific & Technological Research Council of Turkey (TÜB‹TAK) (Project no: TBAG 2021).
Table 1. Yields and melting points of the synthesized compounds (3a-e)
Compound Number 3a 3b
3c 3d
3e
R Melting points (°C) 181-2 193-4
158-9 157-8
154-5
Yield (%) 70 57
80 40
40
Scheme 1. Schematic representation of the synthesized compounds.
Compound Number
1 2 3a 3b 3c 3d 3e
1/2 h
mg/kg 4 h
mg/kg 30 0/2 0/2 0/2 0/2 0/2 0/2 0/2
100 0/2 0/2 0/2 0/2 0/2 0/2 0/2
300 0/2 0/2 0/2 0/2 0/2 0/2 0/2 30
0/4 0/4 0/4 0/4 0/4 0/4 0/4
100 0/4 0/4 0/4 0/4 0/4 0/4 0/4
300 0/4 0/4 0/4 0/4 0/4 0/4 0/4 1/2 h
mg/kg 4 h
mg/kg 30 0/1 0/1 0/1 0/1 0/1 0/1 0/1
100 0/1 0/1 0/1 0/1 0/1 0/1 0/1
300 0/1 0/1 1/1 0/1 0/1 0/1 0/1 30
0/1 0/1 0/1 0/1 0/1 0/1 0/1
100 0/1 0/1 0/1 0/1 0/1 0/1 0/1
300 0/1 1/1 0/1 0/1 0/1 0/1 0/1 1/2 h
mg/kg 4 h
mg/kg 30 0/1 0/1 0/1 0/1 0/1 0/1 0/1
100 0/1 0/1 0/1 0/1 0/1 0/1 0/1
300 1/1 0/1 0/1 0/1 0/1 0/1 0/1 30
0/1 0/1 0/1 0/1 0/1 0/1 0/1
100 0/1 0/1 0/1 0/1 0/1 0/1 0/1
300 1/1 0/1 0/1 1/1 0/1 0/1 0/1
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