|Year : 2012 | Volume
| Issue : 1 | Page : 22-30
Potent anti-inflammatory and analgesic activities of new derivatives of chalcone, pyridine, pyrazole, and isoxazole incorporated into 5,6,7,8-tetrahydronaphthalene
Nehal A. Hamdy1, Gehan M. Kamel2
1 Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt
2 Pharmacology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
|Date of Submission||22-Jan-2012|
|Date of Acceptance||14-Mar-2012|
|Date of Web Publication||18-Jul-2014|
Nehal A. Hamdy
Applied Organic Chemistry Department, National Research Centre, Dokki, 12622 Cairo
Source of Support: None, Conflict of Interest: None
Synthesis of new series of 5,6,7,8-tetrahydronaphthalene derivatives conjugated with chalcone, pyridine, pyrazole and isoxazole functionalities hoping to circumvent the unwanted ulcerogenic and other side effects of the already used nonsteroidal anti-inflammatory drugs.
Most currently used nonsteroidal anti-inflammatory drugs (NSAIDs) suffer from limitation in their therapeutic uses, since they cause gastrointestinal and renal side effects related to inhibition of cyclooxygenase1 (Cox1) in tissues where prostaglandins exert physiological effects.
Reaction of 2-acetyl tetralin (1) with some aromatic aldehydes in the presence of malononitrile yielded 2-amino-3-cyanopyridine derivatives 2a–c. Condensation of compound 1 with aromatic aldehydes afforded the chalcone derivatives 3a–c. Then, compound 3a reacted with hydrazine hydrate or phenyl hydrazine and yielded pyrazoline derivatives 4 or 5, respectively. Also, the reaction of compound 3c with hydroxylamine hydrochloride afforded the isoxazole derivative 6. Anti-inflammatory properties of the synthesized compounds were evaluated in vivo utilizing formalin induced paw edema method in rats, analgesic activities were tested via both hot plate and writhing methods.
Derivatives 2c and 3c revealed promising results when the anti-inflammatory, analgesic, and ulcerogenic activities of the synthesized compounds were evaluated. All of the compounds induced significant central and peripheral analgesia. The derivatives 2a, 2c, 3a, 3b, 3c, 5, and 6 showed higher activity than the standard ibuprofen.
Keywords: analgesic activity, anti-inflammatory, isoxazole, pyrazoline, pyridine, tetralin
|How to cite this article:|
Hamdy NA, Kamel GM. Potent anti-inflammatory and analgesic activities of new derivatives of chalcone, pyridine, pyrazole, and isoxazole incorporated into 5,6,7,8-tetrahydronaphthalene. Egypt Pharmaceut J 2012;11:22-30
|How to cite this URL:|
Hamdy NA, Kamel GM. Potent anti-inflammatory and analgesic activities of new derivatives of chalcone, pyridine, pyrazole, and isoxazole incorporated into 5,6,7,8-tetrahydronaphthalene. Egypt Pharmaceut J [serial online] 2012 [cited 2019 Aug 24];11:22-30. Available from: http://www.epj.eg.net/text.asp?2012/11/1/22/136966
| Introduction|| |
Importance of the pyridine ring in the chemistry of biological systems has been acknowledged because of its presence in many natural products of therapeutic importance that are involved in the oxidation–reduction process. The potent biological activity of various vitamins and drugs 1–4 is primarily ascribed to the presence of the pyridine ring in their molecular makeup. In contrast, cyanopyridine derivatives have promising antimicrobial 5, 6, anticancer 7, 8, anti-inflammatory, analgesic, antipyretic 9, and colon tumor cell growth inhibitory 10 activities. Recently, some new heterocyclic compounds containing pyridine moiety were reported as anticancer and anti-inflammatory agents 11,12.
α,β-Unsaturated ketones are useful key intermediates 13,14 bearing the well-known chalcone pharmacophore. Chalcones can be isolated from several plants and are precursors of flavones and anthocyan compounds. Some of them exhibit antioxidant and anticancer properties. In fact, the pharmacological properties of chalcones are due to the presence of both α,β-unsaturation 15 and an aromatic ring. The pyrazole unit is the core structure in a number of natural products 16. Many pyrazole derivatives are known to exhibit a wide range of biological properties such as antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial, hypoglycemic, sedative-hypnotic 17, 18, and anticoagulant 19 activities. In particular, pyrazoles are important in medicinal chemistry 20 and were reported to have non-nucleoside HIV-1 reverse transcriptase inhibitor 21 and antimicrobial activities 22. It was also reported that 5-substituted pyrazoles are presently undergoing pharmacological study as antagonists of cannabinoid receptors 1. It was proved that they are useful for the treatment of obesity 23. Moreover, many pyrazole derivatives have been reported as adenosine receptor antagonists having high affinity and selectivity 24. Furthermore, isoxazoles possess analgesic and anti-inflammatory activities 25.
In view of the above-mentioned facts and in continuation of our search for various biologically active molecules 26–29, we report here the synthesis of some new 3-cyano pyridine, chalcone, pyrazole, and isoxazole derivatives in addition to evaluation of their preliminary anti-inflammatory and analgesic activities.
| Subjects and methods|| |
All melting points were uncorrected and measured using an Electro-thermal IA 9100 apparatus (Shimadzu, Japan). Microanalytical data were obtained using a Vario El-Mentar apparatus (Shimadzu) at the National Research Centre, Cairo, Egypt. Infrared (IR) spectra were recorded using a Biorad FTS 155 FT-IR spectrophotometer (ICB-IR Service Centre, Pozzuoli, Naples, Italy) and recorded as potassium bromide pellets on a Perkin-Elmer 1650 Spectrophotometer at the National Research Centre (Cairo, Egypt). 1H NMR experiments were conducted in DMSO at the ICB-NMR Service Centre (Pozzuoli, Naples, Italy), and shifts were referenced to TMS on a Bruker Avance-400 operating at 400 MHz. 1H NMR spectra were determined in DMSO-d 6 at 300 MHz (1H NMR) and 75 MHz (13C NMR) and determined on a JEOL-Ex-300 NMR spectrometer. Chemical shifts were expressed as parts per million (ppm) (δ values) against TMS as an internal reference (Faculty of Science, Cairo University, Cairo, Egypt). Mass spectra were obtained using an ion-trap MS instrument in electron impact mode at 70 eV (ICB-IR Service Centre) and determined on a Shimadzu GCMS-QP-1000EX mass spectrometer at 70 eV (Cairo University, Cairo, Egypt). Compound 1 was prepared according to a method reported previously 30.
General procedure for the preparation of compounds (2a–c)
A mixture of compound 1 (1.74 g, 0.01 mol), the appropriate aldehyde (2-chloro-5-nitrobenzaldehyde, 2-naphthaldehyde, or p-isopropyl benzaldehyde) (0.01 mol), malononitrile (0.66 g, 0.01 mol), and ammonium acetate (6.16 g, 0.08 mol) in n-butanol (30 ml) was refluxed for 6 h. The reaction mixture was concentrated, allowed to cool, and the separated product was filtered off, washed several times with diethyl ether, and recrystallized from the proper solvent to yield compounds 2a–c, respectively.
2-Amino-4-(2-chloro-5-nitrophenyl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridine-3-carbonitrile (2a)
Yield (74%); m.p. 250–252°C (EtOH/DMF); IR spectrum (KBr, &ngr;, cm−1): 3354, 3227 (NH2), 2930 (CH, alicyclic), 2217 (CN), 1632 (C=N), 1526, 1345 (NO2); 1H NMR (DMSO-d 6 , δppm): 1.73 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.74 (m, 4H, 2CH2 of tetrahydronaphthalene), 6.94 (s, 2H, NH2, exchangeable with D2O), 7.15 (d, J=8.4 Hz, 1H, Ar–H), 7.25 (s, 1H, Ar–H), 7.80 (d, J=7.6 Hz, 1H, Ar–H), 7.93–7.97 (m, 2H, Ar–H), 8.34–8.37 (m, 2H, Ar–H); 13C NMR (DMSO-d 6 ): δ (ppm): 22.52, 22.62, 28.70, 28.80 (4CH2), 127.70 (CN),109.19, 115.93, 120.75, 124.38, 125.46, 129.18, 131.17, 134.28, 136.90, 137.41, 138.53, 139.40, 146.25, 150.50, 159.17 (aromatic-C). MS m/z (%): 404 (M+, 100), 406 (35.35); Anal. calcd (%) for C22H17ClN4O2 (404.85): required C, 65.27; H, 4.23; N, 13.84; found C, 65.05; H, 4.43; N, 13.65.
2-Amino-4-(naphthalen-2-yl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridine-3-carbonitrile (2b)
Yield (78%); m.p. 200–202°C (CHCl3); IR spectrum (KBr, &ngr;, cm−1): 3361, 3212 (NH2), 2932 (CH, alicyclic), 2202 (CN); 1H NMR (DMSO-d 6 , δppm): 1.75 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.77 (m, 4H, 2CH2 of tetrahydronaphthalene), 6.92 (s, 2H, NH2, exchangeable with D2O), 7.12–8.08 (m, 11H, Ar–H); 13C NMR (DMSO-d 6 ): δ (ppm): 22.5, 29.5 (4CH2-tetralin), 113.7 (CN), 109.2, 114.7, 122.5, 125.6, 126.2, 127.7, 128.3, 128.4, 129.1, 129.4, 133.1, 134.4, 135.3, 135.7, 136.2, 154.4, 156.2, 161.9 (aromatic-C). MS m/z (%): 375 (M+, 42), 368 (80), 128 (100); Anal. calcd (%) for C26H21N3 (375.17): required C, 83.17; H, 5.64; N, 11.19; found C, 83.39; H, 5.44; N, 11.02.
2-Amino-4-(4-isopropylphenyl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridine-3-carbonitrile (2c)
Yield (80%); m.p. 210–212°C (EtOH); IR spectrum (KBr, &ngr;, cm−1): 3324, 3194 (NH2), 2935 (CH, alicyclic), 2207 (CN); 1H NMR (DMSO-d 6 , δppm): 1.23 (d, J=6.3 Hz, 6H, 2CH3), 1.74 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.76 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.98 (m, 1H, CH), 6.74 (s, 2H, NH2, exchangeable with D2O); 6.92–8.28 (m, 8H, Ar–H); 13C NMR (DMSO-d 6 ): δ (ppm): 22.5, 29.5 (4CH2-tetralin), 113.7 (CN), 109.2, 111.4, 114.7, 119.4, 121.4, 121.9, 122.5, 128.4, 128.4, 128.6, 129.1, 129.4, 135.3, 135.5, 136.2, 136.6, 154.4, 156.2, 161.9 (aromatic-C). MS m/z (%): 367 (M+, 100); Anal. calcd (%) for C25H25N3 (367.49): required C, 81.71; H, 6.86; N, 11.43; found C, 81.64; H, 6.63; N, 11.29.
General procedure for the preparation of compounds (3a, b)
To a mixture of compound 1 (4.9 g, 0.028 mol) and 2-chloro-5-nitrobenzaldehyde or 2-naphthaldehyde (0.028 mol) in ethanol (30 ml) was added NaOH solution (15 ml, 30%) dropwise within 15 min. The reaction mixture was stirred for 3 h and left overnight at room temperature. The formed solid was collected and recrystallized from ethanol to yield compounds 3a, b, respectively.
(E)3-(2-Chloro-5-nitrophenyl)-1-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (3a)
Yield (69%); m.p. 118–120°C; IR spectrum (KBr, &ngr;, cm−1): 2934 (CH, alicyclic), 1666 (C=O), 1524, 1347 (NO2); 1H NMR (DMSO-d 6 , δppm): 1.78 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.80 (m, 4H, 2CH2 of tetrahydronaphthalene), 7.23 (d, J=7.8 Hz, 1H, Ar–H), 7.84 (d, J=8.7 Hz, 1H, COCH=), 7.90–7.97 (m, 3H, Ar–H), 8.15–8.25 (m, 2H, Ar–H, =CH), 8.9 (d, J=2.7 Hz, 1H, Ar–H); 13C NMR (DMSO-d 6 ): δ (ppm): 22.5, 29.5 (4CH2-tetralin), 121.5, 121.6, 122.5, 124.1, 128.2, 128.4, 129.1, 129.4, 132.1, 135.3, 136.2, 139.1, 145.4, 148.3 (aromatic-C), 189.0 (CO). MS m/z (%): 341 (M+, 40), 343 (13), 159 (50), 136 (100); Anal. calcd (%) for C19H16ClNO3 (341.79): required C, 66.77; H, 4.72; N, 4.10; found C, 66.96; H, 4.54; N, 4.31.
(E)-3-(Naphthalen-2-yl)-1-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (3b)
Yield (76%); m.p. 154–156°C; IR spectrum (KBr, &ngr;, cm−1): 2942 (CH, alicyclic), 1651 (C=O), 1606 (C=C); 1H NMR (DMSO-d 6 , δppm): 1.78 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.81 (m, 4H, 2CH2 of tetrahydronaphthalene), 7.25 (d, J=7.8 Hz, 1H, Ar–H), 7.56–8.32 (m, 11H, 9Ar–H, COCH=, =CH); 13C NMR (DMSO-d 6 ): δ (ppm): 22.5, 29.5 (4CH2-tetralin), 121.2, 122.5, 125.6, 126.2, 127.7, 128.4, 128.6, 129.1, 129.4, 133.1, 134.4, 135.3, 135.7, 136.2, 145.4 (aromatic-C), 189.0 (CO). MS m/z (%): 312 (M+, 100); Anal. calcd (%) for C23H20O (312.4): required C, 88.43; H, 6.45; found C, 88.25; H, 6.24.
(E)-3-(1-H-Indol-3-yl)-1-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (3c)
A mixture of compound 1 (1.74 g, 0.01 mol) and 3-formyl indole (1.452 g, 0.01 mol) was dissolved in ethylene glycol (10 ml) containing piperidine (0.5 ml). The solution was then heated at 175–180°C for 10 min. After cooling, 5 ml of water and 0.5 ml of acetic acid were added. The crystals that deposited were filtered off and recrystallized from ethanol to yield compound 3c. Yield (74%); m.p. 208–210°C; IR spectrum (KBr, &ngr;, cm−1): 3218 (NH), 2934 (CH, alicyclic), 1657 (C=O); 1H NMR (DMSO-d 6 , δppm): 1.76 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.78 (m, 4H, 2CH2 of tetrahydronaphthalene), 6.94–8.07 (m, 10H, 8Ar–H, =CH, COCH=), 11.69 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d 6 ): δ (ppm): 22.5, 29.5 (4CH2-tetralin), 111.4, 119.4, 121.2, 121.4, 121.9, 122.5, 128.4, 128.6, 128.9, 129.1, 129.4, 135.5, 135.6, 136.2, 145.4 (aromatic-C), 189.0 (CO). MS m/z (%): 301 (M+, 100); Anal. calcd (%) for C21H19NO (301.15): required C, 83.69; H, 6.35; N, 4.65; found C, 83.87; H, 6.15; N, 4.56.
1-(5-(2-Chloro-5-nitrophenyl)-4,5-dihydro-1-(5, 6, 7, 8-tetrahydronaphthalen-7-yl)-1H-pyrazole-1-yl)ethane (4)
A solution of compound 3a (0.683 g, 0.02 mol) and hydrazine hydrate (1 g, 0.03 mol) in acetic acid (30 ml) was heated under reflux for 5 h. The reaction mixture was cooled and poured onto ice water. The precipitated product was filtered off, washed, and recrystallized from chloroform to yield compound 4. Yield (69%); m.p. 180–182°C; IR spectrum (KBr, &ngr;, cm−1): 2936 (CH, alicyclic), 1660 (C=O); 1H NMR (DMSO-d 6 , δppm): 1.72 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.35 (s, 3H, COCH3), 2.73 (m, 4H, 2CH2 of tetrahydronaphthalene), 3.15 (dd, J=5.1,18.0 Hz, 1H, CH of pyrazoline ring >CHHa), 3.93 (dd, J=12.0,18.0 Hz, 1H, CH of pyrazoline ring >CHbH), 5.79 (dd, J=5.4, 12.0 Hz, 1H, CH of pyrazoline ring >CHcAr), 7.12 (d, J=7.8 Hz, 1H, Ar–H), 7.44 (s, 1H, Ar–H), 7.50 (d, J=8.1 Hz, 1H, Ar–H), 7.80 (d, J=9 Hz, 2H, Ar–H), 8.15 (dd, J=2.7, 8.7Hz, 1H, Ar–H); 13C NMR (DMSO-d 6 ): δ (ppm): 23.5 (CH3), 22.5, 29.5 (4CH2-tetralin), 122.5, 127.4, 128.4, 129.1, 129.4, 131.2, 131.6, 133.3, 134.6, 144.3, 145.3, 151.2 (aromatic-C), 168.0 (CO). MS m/z (%): 399 (M++2, 33); 397 (M+, 100); Anal. calcd (%) for C21H20ClN3O3 (397.12): required C, 63.40; H, 5.07; N, 10.56; found C, 63.21; H, 5.13; N, 10.72.
5-(2-Chloro-5-nitrophenyl)-4,5-dihydro-3-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)-1-phenyl-1H-pyrazole (5)
A solution of compound 3a (0.673 g, 0.02 mol) and phenyl hydrazine (2.16 g, 0.02 mol) in absolute ethanol (50 ml) and triethylamine (0.5) was refluxed for 6 h. The formed precipitate was filtered off and recrystallized from ethanol to afford compound 5. Yield (67%); m.p. 268–270°C; IR spectrum (KBr, &ngr;, cm−1): 2942 (CH, alicyclic), 1596 (C=N); 1H NMR (DMSO-d 6 , δppm): 1.77 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.78 (m, 4H, 2CH2 of tetrahydronaphthalene), 3.16 (dd, J=6.0, 17.4 Hz, 1H, CH pyrazoline ring >CHHa), 4.03 (dd, J=12.3, 17.4 Hz, 1H, CH of pyrazoline ring >CHbH), 5.71 (dd, J=6.0, 12.3 Hz, 1H, CH pyrazoline ring >CHcAr), 6.76 (t, J=7.5 Hz, 1H, Ar–H), 6.94 (d, J=7.8 Hz, 1H, Ar–H), 7.09–7.28 (m, 3H, Ar–H), 7.42 (s, 1H, Ar–H), 7.49 (d, J=7.8 Hz, 1H, Ar–H), 7.93 (d, J=9.6 Hz, 1H, Ar–H), 8.13–8.29 (m, 4H, Ar–H); 13C NMR (DMSO-d 6 ): δ (ppm): 22.5, 29.5 (4CH2-tetralin), 116.7, 120.3, 122.5, 125.5, 127.4, 128.4, 129.4, 129.5, 129.7, 131.2, 131.6, 133.3, 134.6, 135.3, 136.2, 143.4, 144.3, 145.3, 151.2 (aromatic-C). MS m/z (%): 433 (M++2, 22), 432 (M++1, 19), 431 (M+, 66), 77 (100); Anal. calcd (%) for C25H22ClN3O2 (431.14): required C, 69.52; H, 5.13; N, 9.73; found C, 69.42; H, 5.37; N, 9.65.
3-(4,5-Dihydro-3-(5, 6, 7, 8-tetrahydronaphthalene-7-yl)-isoxazol-5-yl)-1H-indole (6)
A solution of compound 3c (3.01 g, 0.01 mol) and hydroxylamine hydrochloride (0.7 g, 0.01 mol) in pyridine (40 ml) was refluxed for 8 h. The cooled reaction mixture was acidified with ice-cold dilute hydrochloric acid. The separated solid was filtered off, dried, and recrystallized from ethanol to afford compound 6. Yield (69%); m.p. 190–192°C (EtOH); IR spectrum (KBr, &ngr;, cm−1): 3412 (NH), 2949 (CH, alicyclic), 1610 (C=C); 1H NMR (DMSO-d 6 , δppm): 1.74 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.74 (m, 4H, 2CH2 of tetrahydronaphthalene), 3.53 (dd, J=9.3, 16.8 Hz, 1H, CH of isoxazoline ring >CHHa), 3.73 (dd, J=10.8, 16.8 Hz, 1H, CH of isoxazoline ring >CHbH ), 5.93 (dd, J=9.3, 10.8 Hz, 1H, CH of isoxazoline ring >CHcAr), 6.95–7.15 (m, 3H, Ar–H), 7.37–7.47 (m, 5H, Ar–H), 11.2 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d 6 ): δ (ppm): 22.44, 22.46, 28.64, 28.94 (4CH2), 39.22, 39.50 (CHCH2), 111.70, 113.83, 118.67, 121.34, 123.34, 123.93, 125.20, 126.85, 126.95, 129.94, 136.79, 137.10, 138.74, 156.22 (aromatic-C). MS m/z (%): 316 (M+, 40), 225 (100); Anal. calcd (%) for C21H20N2O (316.16): required C, 79.72; H, 6.37; N, 8.85; found C, 79.54; H, 6.44; N, 8.65.
Adult male mice (20–25 g) were used for studying the analgesic activity. Adult male Wister albino rats (150–200 g) were used to study the anti-inflammatory activity. The animals (five per cage) were maintained under standard laboratory conditions (light period of 12 h/day and temperature 27±2°C) with access to food and water ad libitum. The experimental procedures were carried out in strict compliance with the Institutional Animal Ethics Committee regulations. All experiments were performed in the morning according to the guidelines for the care of laboratory animals 31.
Anti-inflammatory activity screening for the prepared compounds was determined in vivo by the standard formalin-induced paw edema method in rats 32. Wister albino rats of either sex weighing 150–200 g were divided into 11 groups of five animals each. Thickness of the left hind paw of each rat was measured (mm) using a vernier caliper before any drug administration (0 h). The control group received DMSO. Ibuprofen was given orally (50 mg/kg) as reference standard. The tested compounds 2a–c, 3a–c, and 4–6 dissolved in DMSO were administered orally (100 mg/kg) to the rest of the groups 1 h before induction of inflammation. Paw edema was induced by subcutaneous injection of 2.5% formalin solution (0.1 ml/rat) into the right hind paw of each rat. Paw thickness of each rat was measured after 30 min and 1, 2, and 3 h following formalin injection. Edema thickness (mm) was calculated by subtracting the zero-hour reading from each time reading. The anti-inflammatory activity was expressed as percentage inhibition of edema thickness in treated animals in comparison with the control group [Table 1]:
|Table 1: Anti-inflammatory activity of the tested compounds (100 mg/kg, orally) against formalin-induced paw edema|
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where V c and V t are the thickness of edema for the control and drug-treated animal groups, respectively.
The hot-plate method: Analgesic activity of the tested compounds was determined by the hot-plate method as reported before 33. A total number of 55 mice were divided into 11 groups of five animals each. The first group was administered DMSO orally (0.2 ml/mice) and kept as negative control. Ibuprofen was given as standard drug (50 mg/kg) to the second group, and the tested compounds 2a–c, 3a–c, and 4–6 dissolved in DMSO were administered at a dose of 100 mg/kg body weight to the rest of the groups. Each animal was placed individually on a hot plate and maintained at 55°C. The time taken by the animals to lick the hind paw or jump out of the plate was taken as the reaction time, which was measured at 0, 30, 60, and 120 min. A cut off period of 30 s was considered as maximal latency to avoid paw injury 34. The pain inhibition percentage (PIP) 35 was calculated according to the following formula:
where T c and T t are the latency for the control and drug-treated animal groups.
The acetic acid-induced writhing test: This test was conducted using the method described by Collier et al. 36. Muscle contractions were induced in 11 groups of mice (five animals per group) by intraperitoneal injection of 0.6% solution of acetic acid (10 ml/kg). Thirty minutes before this administration, the animals in the first group were treated orally with DMSO (0.2 ml/mice) and they served as negative controls. Ibuprofen as the reference standard (50 mg/kg) and the tested compounds (2a–c, 3a–c, and 4–6) dissolved in DMSO were administered orally (100 mg/kg) to the animals of the rest of the groups. Immediately after administration of acetic acid the animals were placed in glass cages, and the number of ‘stretching’ per animal was recorded during the course of the next 15 min. Writhing movement was accepted as contraction of the abdominal muscles accompanied by stretching of hind limbs. There was significant reduction in the number of writhes in the drug-treated animals as compared with vehicle-treated animals. This was considered a positive analgesic response, and the percentage inhibition of writhing was calculated according to the method described by Collier et al. 36.
Ulcerogenic liability: Ulcerogenic liability was determined in albino rats according to the reported standard methods 37. Rats were divided into 11 groups of five animals each. The animals were fasted 18 h before drug administration. Animals in the first group were treated orally with 2 ml of DMSO aqueous suspension (1% w/v) and considered as the control group; ibuprofen was administered (50 mg/kg body weight) as a reference standard to the second group. The tested compounds 2a–c, 3a–c, and 4–6 were administered in the form of DMSO aqueous suspensions (100 mg/kg body weight) to the rest of the groups. Treatment was continued once daily for three successive days in all groups. An hour after the last dose, the animals were killed by cervical dislocation and the stomach was removed, opened along the greater curvature, and rinsed with saline. The gastric mucosa was examined with a magnifying lens (×10) for the presence of lesions in the form of hemorrhages or linear breaks and erosions. The ulcer index was calculated [Table 3] and the degree of ulcerogenic effect was expressed in terms of:
- percentage incidence of ulcer divided by 10;
- average number of ulcers per stomach; and
- average severity of ulcers.
The ulcer index is the value that resulted from the sum of the above three values.
Results of anti-inflammatory and analgesic activities were represented as mean±SE. The significant difference between the groups was tested using one-way analysis of variance, followed by Dunnett’s test at P less than 0.05.
| Results and discussion|| |
The general synthesis of the 3-cyano-2-aminopyridine derivatives 2a–c is illustrated in Scheme 1. [Additional file 1] We used the in-solution one-pot synthesis. In this respect, 2-acetyl tetralin (1) was reacted with the appropriate aldehyde (2-chloro-5-nitrobenzaldehyde, 2-naphthaldehyde, or 4-isopropyl benzaldehyde) in the presence of malononitrile and excess ammonium acetate in n-butanol. The respective pyridine derivatives 2a–c were obtained. 1H NMR spectra of these compounds showed singlet signals at δ 6.94, 6.92, and 6.74 ppm, respectively, which corresponded to the NH2 group in addition to the signals due to the aromatic protons. Mass spectra of the synthesized compounds showed molecular ion peaks [M+] corresponding to the molecular weights of the target compounds. The chlorine containing derivative 2a showed molecular ion peaks for [M+] and [M++2] at a ratio of 3 : 1 because of the isotopic nature of the chlorine atom. Infrared spectra of all compounds showed bands at 3194–3361 cm−1 region due to NH stretching vibrations of the amino group, in addition to a band around 2200 cm−1 (CN, stretching).
2-Acetyl-5, 6, 7, 8-tetrahydronaphthalene (1) also condensed with aromatic aldehydes (2-chlorobenzaldehyde, or 2-naphthaldehyde) in ethanolic sodium hydroxide under Claisen–Schmidt conditions to yield 1-[2-(5, 6, 7, 8-tetrahydronaphthyl)]-3-aryl propenones 3a, b [Scheme 1]. The structures of 3a and b were confirmed by their IR, 1H NMR, 13C NMR, and mass spectra. IR spectra showed absorption bands at 1666–1651 cm−1 (C=O) and 1612–1606 cm−1 (C=C). Mass spectra showed ion peaks [M+] corresponding to their molecular weights. 1H NMR spectra of 3a and b showed signals at δ 7.23–8.32 ppm corresponding to the aromatic protons, in addition to the ethylene protons.
In contrast, condensation of compound 1 with 3-formyl indole takes place in ethylene glycol in the presence of piperidine on heating to 180°C for 20 min, according to the reported method 38, to yield 3c.IR spectrum showed absorption bands at 3218 cm−1 (NH) and 1657 cm−1 (C=O). Its mass spectrum showed molecular ion peak [M+] corresponding to the molecular weight, which is also the base peak; 1H NMR showed multiplet signals at δ 6.94–8.07 ppm corresponding to aromatic protons in addition to the ethylene protons and singlet signal at δ 11.6 ppm for NH.
Reaction of 3a with hydrazine hydrate in boiling acetic acid led to the formation of 1-acetyl-5-(2-chloro-5-nitrophenyl)-3-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)-4,5-dihydro-1H-pyrazole (4) [Scheme 2]. [Additional file 2] Structure of 4 was assigned on the basis of its spectral data and elemental analysis. For example, IR spectrum revealed the carbonyl absorption band at 1660 cm−1, whereas its 1H NMR spectrum revealed singlet signal at δ 2.35 ppm for COCH3, δ 3.15, 3.93 ppm (d, d for unsymmetrical 2H of pyrazoline ring), and 5.79 (d, d for 1H of pyrazoline ring), in addition to the aromatic protons in the region δ 7.12–8.15 ppm. Its mass spectrum showed the molecular ion peak [M+] as the base peak at m/z (397).
Meanwhile, reaction of the same compound 3a with phenyl hydrazine in absolute ethanol in the presence of a few drops of triethylamine yielded 5-(2-chloro-5-nitrophenyl)-1-phenyl-3-(5, 6, 7, 8-tetrahydronaphthlen-2-yl)-4,5-dihydro-1H-pyrazole (5). Its structure was confirmed on the basis of the disappearance of the carbonyl group in the IR spectrum. Its 1H NMR spectrum revealed signals at δ 3.16, 4.03 ppm (d, d for unsymmetrical 2H of pyrazoline ring), and 5.71 (d, d for 1H of pyrazoline ring), in addition to the aromatic protons in the region δ 6.76–8.29 ppm. In addition, the mass spectrum showed molecular ion peak [M+] at m/z (431).
Moreover, the reaction of chalcone 3c with hydroxylamine hydrochloride in boiling pyridine yielded 3-[2-(5, 6, 7, 8-tetrahydronaphthyl)-5-indolyl]-4,5-dihydroisoxazoline (6). Its IR spectrum showed absorption bands characteristic for the C=N and NH, whereas its 1H NMR spectrum showed the absence of the ethylenic protons present in chalcone 3c.
The newly synthesized pyridine compounds 2a–c (100 mg/kg, orally) exhibited significant anti-inflammatory activity in formalin-induced rat paw edema. 2-Amino-4-(4-isopropylphenyl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridine-3-carbonitrile (2c) exhibited the highest activity among this series [Table 1]. It showed 73.68% edema inhibition 3 h after formalin injection compared with 91.23% for the standard ibuprofen after the same period of time. Cyanopyridine derivatives were previously found to influence the inflammatory mediators nitric oxide (NO), tumor necrosis factor-α (TNF-α), prostaglandin E-2 (PGE-2), cycloxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) 28,39.
Chalcone derivatives 3a and 3c showed enhanced anti-inflammatory activity, with maximum edema inhibition percentage of 61.40 and 73.68, respectively, 3 h after formalin injection, whereas 3b showed complete loss of activity. This result was in agreement with the previous report that showed the presence of a reactive α,β-unsaturated ketone group in the propenone side chain as being responsible for the anti-inflammatory and analgesic activities 15. In addition, it was also reported that the value of the correlation coefficient of in-vitro COX-2 inhibition versus the in-vivo anti-inflammatory activity for these compounds is 0.61, which indicates that COX-2 inhibition may not be the sole mechanism by which these compounds act as anti-inflammatory agents and that other mechanisms such as inhibition of the lipoxygenase and hemeoxygenase-1 might be included 15. Other chalcone derivatives were found to have related dual COX-1/2- and 5/15-LOX-inhibiting effects 40.
The reaction of 3a with hydrazine hydrate to yield 1-(5-(2-chloro-5-nitrophenyl)-4,5-dihydro-1-(5, 6, 7, 8-tetrahydronaphthalen-7-yl)-1H-pyrazole-1-yl)ethane (4) greatly diminished its anti-inflammatory activity from 61.40% for the parent compound 3a to 22.81% for the obtained pyrazoline derivative 4. However. the reaction of 3a with phenyl hydrazine hydrate to obtain 5-(2-chloro-5-nitrophenyl)-4,5-dihydro-3-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)-1-phenyl-1H-pyrazole (5) did not alter its recorded potency but strongly affected its kinetic manner by enhancement of metabolism and/or excretion. The pyrazoline derivative 5 exerted its maximum activity with 56.60% inhibition of edema 30 min after formalin injection, which decreased stepwise to 35.09% after 3 h. According to the activity relationship, it could be suggested that the attachment of a phenyl group to the pyrazoline moiety could improve the anti-inflammatory and analgesic activities of the derivatives 4 and 5. Similar findings were recorded in the previous studies of different pyrazoline analogs bearing phenyl groups 41,42. Despite its moderate activity at 30 min, compound 5 might have a poor kinetic pattern, resulting in an abrupt decrease in its activity.
The analgesic activity of the synthesized compounds was evaluated by hot-plate and acetic acid writhing methods as central 34 and peripheral 36 antinociceptive methods, respectively. From the obtained results [Table 2] and [Table 3] it could be concluded that all of the tested compounds showed significant activity (P<0.05). Results obtained by the pyridines 2a–c revealed that (2-amino-4-(2-chloro-5-nitrophenyl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl) pyridine-3-carbonitrile) 2a showed the highest analgesic activity using both hot-plate and acetic acid writhing methods. The peak of its analgesic activity against thermal stimuli was demonstrated 1 h after oral dosing with PIP 311.84%, which is superior to the value of 221.45% exerted by the standard ibuprofen 3 h after dosing. Therefore, despite this promising activity of compound 2a, the activity was not sustained on the same potency for a long time as it decreased to 98.38 and 60.25% (2 and 3 h after dosing), which is expected to be because of its rapid metabolism and/or excretion of the compound. Other previous studies have indicated that tetralin-2-aminopyridine carbonitrile derivatives exert significant pain perception in the hot-plate test rather than in writhing response 43.
|Table 2: Analgesic activity of the tested compounds following oral administration (100 mg/kg, orally) in mice using hot-plate method|
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|Table 3: Analgesic activity of the tested compounds (100 mg/kg, orally) on acetic acid writhing abdominal contractions|
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The synthetic derivative 2-amino-4-(4-isopropylphenyl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridine-3-carbonitrile (2c) showed moderate analgesic activity using the hot-plate method with PIP 167.302 and 153.89% after 30 min and 1 h, respectively. These activities abruptly decreased afterward, in the same manner as that of compound 2a, indicating a similar kinetic profile for these two pyridine derivatives. It also exerted considerable activity in reducing numbers of abdominal contractions (74.06%) in the writhing test. The lowest analgesic activity of these tested pyridine series following either thermal or chemical stimulus was recorded for 2-amino-4-(naphthalen-2-yl)-6-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridine-3-carbonitrile 2b, with PIP 72.492 and 67.49%, respectively, revealing that introduction of a naphthalene moiety in the amino pyridine nucleus greatly diminishes its analgesic activity.
Chalcone derivatives 3a–c showed analgesic activity, with the highest activity for 3b, and their PIP ranged from 320.64 to 382.02% 30 min–3 h after administration (orally). This was followed by 3c with the highest PIP at 323.301% 2 h after dosing. These recorded activities were significantly (P<0.05) higher than the 221.45% obtained by the standard ibuprofen 3 h after administration. Meanwhile, compound 3a exhibited maximum activity of 293.968% 30 min after treatment, followed by abrupt decrease to 61.83% within 3 h. In the acetic acid writhing test, all of the prepared chalcones significantly inhibited the number of abdominal contractions, with the highest activity for compound 3b at 90.17%, followed by 3a at 89.05%, and finally for 3c at 76.86%. Thus, it is clear that the analgesic activity of these chalcones is mediated by both central and peripheral mechanisms. The exact mechanism of the recorded analgesic activity is not a point of this study. However, the previous findings demonstrated that the antinociceptive mechanism of the chalcone series is varied according to their chemical structures. In this regard, it was found that different chalcone analogs were found to be potent cyclooxygenase inhibitors 44 and others exhibited anti-inflammatory activity through 1,2 lipoxygenase inhibition 45. Furthermore, chalcone derivatives containing he flurophenyl group act through selective inhibition of COX-2. However, replacing the flurophenyl group by the isopropylphenyl group in the same compound resulted in an optimal combination of in-vitro COX-1/2 and 5/15-LOX inhibitory effects 40. Some phenylsulfonyl urenyl chalcone derivatives exert their antinociceptive responses through dual inhibition of COX-2 and 5-LOX activities 46.
Results of new pyrazoline derivatives 1-(5-(2-chloro-5-nitrophenyl)-4,5-dihydro-1-(5, 6, 7, 8-tetrahydronaphthalen-7-yl)-1H-pyrazole-1-yl)ethane (4) and 5-(2-chloro-5-nitrophenyl)-4,5-dihydro-3-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)-1-phenyl-1H-pyrazole (5) obtained by the hot-plate test revealed that compound 5 demonstrated better analgesic activity (P<0.05) compared with standard ibuprofen along the different time intervals, with maximum effect (323.30%) 2 h after dosing. However, mild activity was recorded for compound 4, with PIP 74.434–61.514%. Similar findings obtained using the acetic acid writhing test as higher inhibition of writhing response (78.863%) were recorded for compound 5 as compared with compound 4 (64.44%). Depending on the structure–activity relationship, it could be predicted that substitution of a phenyl group at position 1 of the pyrazole nucleus of compound 5 increases its antinociceptive activity. Similar suggestions were reported previously by Tabarelli et al. 47, and the authors suggested that some pyrazole derivatives involved antinociceptive activity through opioid mechanisms. Hence, our synthesized pyrazole derivatives showed analgesic activity using both the hot-plate and acetic acid writhing tests; hence, it was safe to decide that their pain perception inhibitory effects were through both central and peripheral mechanisms. A similar investigation was recorded for other benzimidazole–pyrazole series 48. Other earlier preliminary findings evaluated some of the previously synthesized 4,5-dihydro-1H-pyrazole derivatives as promising antinociceptive agents using both the acetic acid writhing model and the hot-plate test 49,50.
The synthesized isoxazole derivative 3-(4,5-dihydro-3-(5, 6, 7, 8-tetrahydronaphthalen-7-yl)-isoxazol-5-yl)-1H-indole (6) exhibited a promising analgesic activity that was higher than that of the parent compound 3c using both hot-plate and writhing tests. Thus, it can be deduced that the reaction of the chalcone derivative (E)-3-(1-H-indol-3-yl)-1-(5, 6, 7, 8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (3c) with hydroxylamine hydrochloride improves its analgesic activity. The latency time was significantly (P<0.05) prolonged against thermal stimulus 2 and 3 h after treatment (with 393.53 and 335.96% PIP, respectively), compared with ibuprofen (169.903 and 221.45%, respectively). However, the analgesic activity demonstrated 82.68% reduction in writhing response compared with ibuprofen (91.26%). Analgesic activities recorded for other isoxazole derivatives were found to be varied according to their mechanisms 51 depending on their chemical structures and the substituted groups even in the same compound. In this regard, 4,5-phenyl-4-isoxazolines exhibited potent analgesic activity, and most of these compounds were nonselective COX-2 inhibitors. However, those with methylsulfonyl or flourine substituents at the para position of the phenyl group were potent and selective COX-2 inhibitors 25.
In the same manner, 3,4-diarylisoxazole analogs of valdecoxib [4-(5-methyl-3-phenylisoxazol-4-yl)-benzensulfonamide] were found to be selective (COX-2) inhibitors. However, the removal of the sulfonamide group resulted in selective COX-1 inhibitors 52. Further studies are needed to determine the exact mechanism of the newly synthesized isoxazole compound 6.
The ulcerogenic liability for the tested compounds in each series was determined in albino rats according to previously reported methods 37. The obtained data revealed that all of the tested compounds possessed less ulcerogenic potentialities (ulcer indexes of 10.14±0.45–13.5±0.47) compared with that of the standard drug ibuprofen (ulcer index of 20.96±0.88) [Table 4]. The obtained results of the tested pyridine derivatives were consistent with the results obtained by Fathalla et al. 43, which indicated that similar tetrahydronaphthalene compounds exhibited reduced gastric ulcerogenic activities compared with indomethacin. The lowest ulcerogenic activity among all of the tested compounds was recorded for compound 2c, which belongs to the pyridine series. Reduced ulcerogenic activity recorded for the tested pyrazole derivatives 4 and 5 might be attributed to their phenolic moiety, which is responsible for the reduced ulcerogenic activity of other related compounds.
| Conclusion|| |
New 3-cyano pyridine and chalcone derivatives were synthesized. Chalcone derivatives of 3 were converted to pyrazole and isoxazole derivatives 4–6. Maximum anti-inflammatory activities were recorded for 2c and 3c. However, promising analgesic activity was established by the hot-plate method for most of the tested compounds, with higher activity for 2a, 2c, 3b, 3c, 5, and 6 compared with standard ibuprofen. Interestingly, compounds 3b–c, 5, and 6 possessed more pronounced activities compared with standard ibuprofen. In addition, these derivatives showed pronounced analgesia by the writhing test, with the highest activity for 2a, 3a, and 3b. All of the tested compounds showed reduced ulcerogenic potentialities.
| Acknowledgements|| |
This work was supported by the National Research Centre, Dokki, Cairo, Egypt. The authors are also grateful to Istituto di Chimica Biomolecolare Consiglio Nazionale delle Ricerche Via Campi Flegrei, Pozzuoli, Naples, Italy, for facilities and support. The authors are especially grateful to Dr Guido Cimino, Dr Margrita Givengi, and Dr Maria Letizia Ciavatta for their valuable help.
| References|| |
|1.||Joule J, Mills K, Smith G Heterocyclic chemistry. 19953rd ed London CRC Press |
|2.||Roth HJ, Kleeman AK Pharmaceutical chemistry: drug synthesis. 1988 London Prentice Hall |
|3.||Henry GD. De novo synthesis of substituted pyridines. Tetrahedron. 2004;60:6043–6061 |
|4.||Li AH, Moro S, Forsyth N, Melman N, Ji XD, Jacobson KA. Synthesis, CoMFA analysis and receptor docking of 3,5-diacyl-2, 4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists. J Med Chem. 1999;42:706–721 |
|5.||Altundas A, Ayvaz S, Logoglu E. Synthesis and evaluation of a series of aminocyanopyridines as antimicrobial agents. Med Chem Res. 2011;20:1–8 |
|6.||Amr AEGE, Mohamed AM, Ibrahim AA. Synthesis of some new chiral tricyclic and macrocyclic pyridine derivatives as antimicrobial agents. Z Naturforsch. 2003;58:861–868 |
|7.||Thompson PE, Manganiello V, Degerman E. Re-discovering PDE3 inhibitors - new opportunities for a long neglected target. Curr Top Med Chem. 2007;7:421–436 |
|8.||Abadi AH, Ibrahim TM, Abouzid KM, Lehmann J, Tinsley HN, Gary BD, et al. Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors. Bioorg Med Chem. 2009;17:5974–5982 |
|9.||Manna F, Chimenti F, Bolasco A, Bizzarri B, Filippelli W, Filippelli A, et al. Anti-inflammatory, analgesic and antipyretic 4,6-disubstituted 3-cyano- 2-aminopyridines. Eur J Med Chem. 1999;34:245–254 |
|10.||Abadi AH, Abouel Ella DA, Lehmann J, Tinsley HN, Gary BD, Piazza GA, et al. Discovery of colon tumor cell growth inhibitory agents through a combinatorial approach. Eur J Med Chem. 2010;45:90–97 |
|11.||Abo Ghalia MH, Amr AEGE, Abdalah MM. Synthesis of some new (Nα -dipicolinoyl)-bis-L-leucyl-DL-norvalyl linear tetra and cyclic octa bridged peptides as new antiinflammatory agents. Z Naturforsch. 2003;58:903–910 |
|12.||Abo Ghalia M, Amr A. Synthesis and investigation of a new cyclo (Nα- dipicolinoyl) pentapeptide of a breast and CNS cytotoxic activity and an ionophoric specificity. Amino Acids. 2004;26:283–289 |
|13.||Marzinzik AL, Felder ER. Key intermediates in combinatorial chemistry: access to various heterocycles from α,β-unsaturated ketones on the solid phase. J Org Chem. 1998;63:723–727 |
|14.||Srikanth GSC, Castle SL. Advances in radical conjugate additions. Tetrahedron. 2005;61:10377–10441 |
|15.||Furusawa M, Tanaka T, Ito T, Nishikawa A, Yamazaki N, Nakaya K, et al. Antioxidant activity of hydroxyflavonoids. J Health Sci. 2005;51:376–378 |
|16.||Elguero JKatritzky AP, Rees CW, Scriven EFV. Pyrazoles. Comprehensive heterocyclic chemistry II: a review of the literature 1982–1995. 19961st ed. Oxford Pergamon:1–75 |
|17.||Cottineau B, Toto P, Marot C, Pipaud A, Chenault J. Synthesis and hypoglycemic evaluation of substituted pyrazole-4-carboxylic acids. Bioorg Med Chem Lett. 2002;12:2105–2108 |
|18.||Lee KY, Kim JM, Kim JN. Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis—Hillman adducts. Tetrahedron Lett. 2003;44:6737–6740 |
|19.||Jia ZJ, Wu Y, Huang W, Zhang P, Song Y, Woolfrey J, et al. 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 3: design, synthesis and SAR of orally bioavailable benzamidine-P4 inhibitors. Bioorg Med Chem Lett. 2004;14:1229–1234 |
|20.||Lyga JW, Patera RM, Plummer MJ, Halling BP, Yuhas DA. Synthesis, mechanism of action and QSAR of herbicidal 3-substituted-2-aryl-4,5,6,7-tetrahydroindazoles. Pest Sci. 1994;42:29–36 |
|21.||Genin MJ, Biles C, Kesier BJ, Poppe SM, Tarpley WG, Yagi Y, et al. Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives. J Med Chem. 2000;43:1034–1040 |
|22.||Chandrakantha B, Isloor AM, Shetty P, Isloor S, Malladi S, Fun HK. Synthesis, characterization and antimicrobial activity of novel ethyl 1-(N-substituted)-5-phenyl-1 H-pyrazole-4-carboxylate derivatives. Med Chem Res. 2011 [Article in Press] |
|23.||Alekseeva OO, Mahadevan A, Wiley JL, Martin BR, Razdan RK. Synthesis of novel 5-substituted pyrazole derivatives as cannabinoid antagonists. Tetrahedron Lett. 2005;46:2159–2161 |
|24.||El Zein E, Kalla R, Li X, Perry T, Parkhill E, Palle V, et al. Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists. Bioorg Med Chem Lett. 2006;16:302–306 |
|25.||Habeeb AG, Praveen Rao PN, Knaus EE. Design and synthesis of 4,5-diphenyl-4-isoxazolines: novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity. J Med Chem. 2001;44:2921–2927 |
|26.||Hamdy NA, Gamal El Deen AM, Abdel Aziza HA, Fakhra IMI. Modulationof carcinogen metabolizingenzymes by new fused heterocycles pendant to 5,6,7,8-tetrahydronaphthalene derivatives. Eur J Med Chem. 2010;45:463–470 |
|27.||Abdel Aziz HA, Gamal Eldeen AM, Hamdy NA, Fakhr IM. Immunomodulatory and anticancer activities of some novel 2-substituted-6-bromo-3-methylthiazolo[3,2-a]benzimidazole derivatives. Arch Pharm. 2009;342:230–237 |
|28.||Hamdy NA, Gamal El Deen AM. New pyridone, thioxopyridine, pyrazolopyridine and pyridine derivatives that modulate inflammatory mediators in stimulated RAW 264.7 murine macrophage. Eur J Med Chem. 2009;44:4547–4556 |
|29.||Abdel Aziz HA, Hamdy NA, Gamal El Deen AM, Fakhr IM. Synthesis of new 2-substituted 6-bromo-3-methylthiazolo[3,2-alpha]-benzimidazole derivatives and their biological activities. Z Naturforsch. 2011;66C:7–16 |
|30.||Allinger NL, Jones ES. Synthesis of some functionally substituted benzocyclanones. J Org Chem. 1962;27:70–76 |
|31.||Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983;16:109–110 |
|32.||Crunkhorn P, Meacock SC. Mediators of the inflammation induced in the rat paw by carrageenin. Br J Pharmacol. 1971;42:392–402 |
|33.||Vogel HG Drug discovery and evaluation: pharmacological assays. 1998 Berlin Springer |
|34.||Tao YM, Li QL, Zhang CF, Xu XJ, Chen J, Ju YW, et al. LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential. Eur J Pharmacol. 2008;584:306–311 |
|35.||Yin W, Wang TS, Yin FZ, Cai BC. Analgesic and anti-inflammatory properties of brucine and brucine N-oxide extracted from seeds of Strychnos nux-vomica. J Ethnopharmacol. 2003;88:205–214 |
|36.||Collier HO, Dinneen LC, Johnson CA, Schneider C. The abdominal constriction response and its suppression by analgesic drugs in the mouse. Br J Pharmacol Chemother. 1968;32:295–310 |
|37.||Barsoum FF, Hosni HM, Girgis AS. Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties. Bioorg Med Chem. 2006;14:3929–3937 |
|38.||Tsukerman SV, Nikitchenko VM, Bugai AI, Lavrushin VF. Synthesis of chalcone analogs and derivatives of 2-pyrazoline form 3-formylindole. Chem Heterocycl Comp. 1969;5:268–272 |
|39.||Manna F, Chimenti F, Bolasco A, Filipelli A, Palla A, Filippelli W, et al. Anti-inflammatory, analgesic and antipyretic 4,6-disubstituted 3-cyanopyridine-2-ones and 3-cyano-2-aminopyridines. Eur J Med Chem. 1992;27:627–632 |
|40.||Rao PN, Chen QH, Knaus EE. Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases. J Med Chem. 2006;49:1668–1683 |
|41.||Amir M, Kumar H, Khan SA. Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents. Bioorg Med Chem Lett. 2008;18:918–922 |
|42.||Khode S, Maddi V, Aragade P, Palkar M, Ronad PK, Mamledesai S, et al. Synthesis and pharmacological evaluation of a novel series of 5-(substituted) aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents. Eur J Med Chem. 2008;21:1–7 |
|43.||Fathalla OA, Anwar MM, Haiba ME, Nofal SM. Synthesis of novel tetrahydronaphthalen-2-yl heterocycles for analgesic, anti-inflammatory and antipyretic evaluation. Acta Pol Pharm. 2009;66:259–270 |
|44.||Lin CN, Lee TH, Hsu MF, Wang JP, Ko FN, Teng CM. 2º,5º-Dihydroxychalcone as a potent chemical mediator and cyclooxygenase inhibitor. J Pharm Pharmacol. 1997;49:530–536 |
|45.||Heidari MR, Foroumadi A, Noroozi H, Samzadeh Kermani A, Azimzadeh BS. Study of the anti-inflammatory and analgesic effects of novel rigid benzofuran-3, 4-dihydroxy chalcone by formalin, hot-plate and carrageenan tests in mice. Pak J Pharm Sci. 2009;22:395–401 |
|46.||Araico A, Terencio MC, Alcaraz MJ, Domínguez JN, León C, Ferrándiz ML. Evaluation of the anti-inflammatory and analgesic activity of Me-UCH9, a dual cyclooxygenase-2/5-lipoxygenase inhibitor. Life Sci. 2007;80:2108–2117 |
|47.||Tabarelli Z, Rubin MA, Berlese DB, Sauzem PD, Missio TP, Teixeira MV, et al. Antinociceptive effect of novel pyrazolines in mice. Braz J Med Biol Res. 2004;37:1531–1540 |
|48.||Kaplancikli ZA, Turan Zitouni G, Ozdemir A, Can O, Chevallet P. Synthesis and antinociceptive activities of some pyrazoline derivatives. Eur J Med Chem. 2009;44:2606–2610 |
|49.||Machado P, Rosa FA, Rossatto M, da S, Sant’Anna G, Sauzem PD, Siqueira da Silva RM, et al. Synthesis and structure of novel 4,5-dihydro-1H-pyrazoles: salicylic acid based analgesic agents. ARKIVOC. 2008;2007:281–297 |
|50.||Mohy El Din MM, Senbel AM, Bistawroos AA, El Mallah A, Nour El Din NA, Bekhit AA, et al. A novel COX-2 inhibitor pyrazole derivative proven effective as an anti-inflammatory and analgesic drug. Basic Clin Pharmacol Toxicol. 2011;108:263–273 |
|51.||Sahu SK, Banerjee M, Sahu D, Behera CC, Pradhan GC, Azam MA. Synthesis, analgesic and antimicrobial activities of some novel isoxazole derivatives. Dhaka Univ J Pharm Sci. 2008;7:113–118 |
|52.||Di Nunno L, Vitale P, Scilimati A, Tacconelli S, Patrignani P. Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: reversal cyclooxygenase-2 selectivity by sulfonamide group removal. J Med Chem. 2004;47:4881–4890 |
[Table 1], [Table 2], [Table 3], [Table 4]