Synthesis and Anti-inflammatory Activity of Some 3, 5-Diaryl-2-Pyrazoline Derivatives

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1 Est RIETAL JURAL CHEMISTRY An International pen ree Access, Peer Reviewed Research Journal ISS: X CDE: JCHEG 2011, Vol. 27, o. (4): Pg Synthesis and Anti-inflammatory Activity of Some 3, 5-Diaryl-2-Pyrazoline Derivatives MEYA M. KHALIL and HAA M. REAAT rganic Chemistry Department, aculty of Pharmacy, Cairo University, Cairo (Egypt). *Correspondign author: omneyafawzy@yahoo.com (Received: August 20, 2011; Accepted: ctober 27, 2011) ABSTRACT Eleven new 3-(4-bromophenyl)-5-(4-fluorophenyl)-2-pyrazoline derivatives 4-9 and were synthesized by using 1-(4-bromophenyl)-3-(4-fluorophenyl) prop-2-en-1-one (3). The newly synthesized compounds were evaluated for anti-inflammatory activity against carrageenan edema in albino rats at a dose of 10 mg/kg. All the compounds of this series showed promising anti-inflammatory activity. The most active compound of this series, 7 was found to be most potent, which has shown higher percentage of inhibition of edema than the standard drug indomethacin. Keywords: Synthesis; 3, 5-diaryl-2-pyrazolines; Anti-inflammatory activity. ITRDUCTI SAIDS nonsteroidal anti-inflammatory drugs are a type of pain reliever. These drugs also reduce inflammation. Inflammation is the body s response to irritation or injury and is characterized by redness, warmth, swelling, and pain. SAIDs are used to treat a variety of conditions that cause inflammation, including arthritis and tendinitis. SAIDs are also used to treat pain from injury or other causes of long-term pain. The development of an effective therapeutic agent for the treatment of inflammation continues to be a challenging problem in medicinal chemistry research. Pyrazolines are important nitrogencontaining five-membered heterocyclic compounds. Several pyrazoline derivatives possess wide-spread pharmacological activities and therefore they are useful materials in drug research. These derivatives are well known for their pronounced antiinflammatory activity 1, 2 (Chandra et al., 2010; Joshi et al., 2010) and are used as potent antimicrobial agents (Dawane et al., 2010; Abdel-Wahab et al., 2009). 3, 4 Pyrazolines are used as antiamoebic (Abid and Azam, 2006, Abid et al., 2009), 5, 6 antimalarial 7 (Acharya et al., 2010) and antidiabetic agents (Ahn et al., 2004). 8 Some of the pyrazoline derivatives are reported to possess antitubercular (Ali et al., 2007) 9 and antidepressant properties (Prasad et al., 2005; Gok et al., 2010). 10, 11 Pyrazoline derivatives are also useful as biodegradable agrochemicals (air et al., 2006). 12 Prompted by all these observations and in continuation of our earlier work on the synthesis of some chalcones and pyrazolines (Khalil, 2011), 13 we report herein the synthesis of some new

2 1582 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) pyrazoline derivatives, which have been found to possess an interesting profile of anti-inflammatory activity. EXPERIMETAL Melting points were obtained on a Griffin apparatus and are uncorrected. Microanalyses were carried out at the microanalytical center, aculty of Science, Cairo University. IR spectra were recorded on a Shimadzu 435 spectrometer, using K discs. 1 HMR and 13 CMR spectra were performed on a Varian Mercury VX-300 MHz MR Spectrometer.using TMS as the internal standard. 3-(4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazole (4) A solution of 1-(4-bromophenyl)-3-(4- fluorophenyl) prop-2-en-1-one (0.03 mol) 3 and hydrazine hydrate (0.06 mol) in ethanol (30 ml) was refluxed for 8 hours. The reaction mixture was cooled and kept at 0 C overnight. The resulting solid was crystallized from ethanol. mp: C; yield: 24 %; IR (cm -1 ): υ 3271 (H), 1589 (C=); 1 HMR (DMS-d 6 ): δ 3.16 (dd, 1H, pyrazoline H 4, J = 18.6, 3.6 Hz), 3.88 (dd, 1H, pyrazoline H 4, J = 18.3, 12 Hz), 5.13 (dd, 1H, pyrazoline H 5, J = 12, 3.9 Hz), 7.11 (d, 2H, Ar-H, J = 8.7 Hz), 7.31 (d, 2H, Ar-H, J = 8.7 Hz), 7.43 (s, 1H, H, D 2 exch.), 7.64 (d, 2H, Ar-H, J = 8.7 Hz), 7.86 (d, 2H, Ar-H, J = 8.7 Hz). 13 CMR (DMS-d 6 ): δ 39.50, 56.24, , , , , , , , , , , , , , , , , Anal. Calcd for C 15 H 12 2 (319.15): C, 56.44, H, 3.78,, ound: C, 56.60, H, 3.81,, General procedure for the synthesis of 1-substituted benzoyl-3-(4-bromophenyl)-5-(4- fluorophenyl)-4, 5-dihydro-1H-pyrazole 5, 6. To compound 4 (0.01mol) in pyridine (10ml), the appropriate benzoyl chloride (0.02mol) was added. The reaction mixture was heated on water bath for 3 h and poured over crushed ice mixed with dilute hydrochloric acid. The solid separated out was filtered, washed with water, dried and crystallized from ethanol. 1--(2-fluorobenzoyl)-3-(4-bromophenyl)-5-(4- fluorophenyl)-4, 5-dihydro-1H-pyrazole (5) mp; C; yield: 18 %; IR (cm -1 ): υ 1693 (C=), 1612 (C=) ; 1 HMR (DMS-d 6 ): δ 3.24 (dd, 1H, pyrazoline H 4, J = 18, 3.9 Hz), 3.88(dd, 1H, pyrazoline H 4, J = 17.7, 10.9 Hz)), 5.51 (dd, 1H, pyrazoline H 5, J = 11.1, 3.9 Hz), 7.11 (d, 2H, Ar-H, J = 8.7 Hz), 7.27 (d, 2H, Ar-H, J = 8.7 Hz), 7.30 (m, 1H, Ar-H), 7.40 (d, 2H, Ar-H, J = 8.1 Hz), 7.51 (m, 1H, Ar-H), 7.53 (m, 1H, Ar-H), 7.62 (d, 2H, Ar-H, J = 8.1 Hz), 7.87 (m, 1H, Ar-H). 13 CMR (DMS-d 6 ): δ 39.50, 51.52, 56.12, 99.84, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd for C 22 H (441.24): C, 59.88, H, 3.42,, ound: C, 60.01, H, 3.50,, (3-bromobenzoyl)- 3-(4-bromophenyl)-5-(4- fluorophenyl)-4, 5-dihydro-1H-pyrazole (6) mp: C; yield: 21 %; IR (cm -1 ): υ 1685 (C=), 1593 (C=); 1 HMR (DMS-d 6 ): δ 3.17(dd, 1H, pyrazoline H 4, J = 18.3, 4.5 Hz), 3.92 (dd, 1H, pyrazoline H 4, J = 18, 12 Hz), 5.35 (dd, 1H, pyrazoline H 5, J = 12.3, 4.5 Hz), 7.26 (d, 2H, Ar-H, J = 8.4 Hz), 7.44 (m, 2H, Ar-H), 7.74 (d, 2H, Ar-H, J = 8.4 Hz), 7.76 (d, 2H, Ar-H, J = 8.1 Hz), 7.84 (m, 1H, Ar-H), 7.92 (d, 2H, Ar-H, J = 8.1 Hz), 8.03 (s, 1H, Ar-H). 13 CMR (DMS-d 6 ): δ 39.50, 56.71, 99.82, , , , , , , , , , , , , , , , , , , Anal. Calcd for C 22 H (502.15): C, 52.62, H, 3.01,, ound: C, 52.58, H, 3.26,, (4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazole-1-carbaldehyde (7). A solution of the chalcone 3 (0.03 mol), hydrazine hydrate (0.06 mol) in 15 ml of formic acid was heated under reflux for 4 h, then poured onto crushed ice. The precipitate was separated by filtration, washed with water, and crystallized from ethanol. mp: C; yield: 69%; IR (cm -1 ): υ 1704 (C=), 1597 (C=); 1 HMR (DMS-d 6 ): δ 3.24 (dd, 1H, pyrazoline H 4, J = 18.9, 5.1 Hz), 3.87(dd, 1H, pyrazoline H 4, J = 18, 12 Hz)), 5.53 (dd, 1H,

3 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) 1583 pyrazoline H 5, J = 12, 5.1 Hz), 7.17 (d, 2H, Ar-H, J = 8.7 Hz), 7.29 (d, 2H, Ar-H, J = 8.4 Hz),, 7.62 (d, 2H, Ar-H, J = 8.1 Hz), 7.72 (d, 2H, Ar-H, J = 8.1 Hz), 8.88 (s, 1H, CH). 13 CMR (DMS-d 6 ): δ 39.50, 58.04, , , , , , , , , , , , , , , , , , , , , Anal. Calcd for C 16 H 12 2 (347.16): C, 55.35, H, 3.48,, ound: C, 55.42, H, 3.51,, General procedure for the synthesis of 3-[3-(4- bromophenyl)-5-(4-fluorophenyl)-4, 5-dihydro- 1H-pyrazol-1-yl]-1-aryl-2-propen-1-one 8, 9 A mixture of compound 7 (0.05 mol), 2- acetylthiophene, or 4-bromoacetophenone (0.05 mol) and 10% aqueous sodium hydroxide (10 ml) in ethanol (30 ml) was stirred at room temperature for about 3 hours. The resulting solid was filtered off, rinsed with water, dried and crystallized from ethanol. 3-[3-(4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazol-1-yl]-1-(2-thienyl)-2-propen- 1-one (8) mp: C; yield: 70 %; IR (cm -1 ): υ 1681(C=), 1585 (C=); 1 HMR (DMS-d 6 ): δ 3.41 (dd, 1H, pyrazoline H 4, J = 16.5, 5.7 Hz), 4.13 (dd, 1H, pyrazoline H 4, J = 16.5, 11.7 Hz), 4.71 (dd, 1H, pyrazoline H 5, J = 11.4, 5.7 Hz), 6.96 (dd, 1H, thiophene-h, J = 5.4, 3.3 Hz), 7.14 (dd, 1H, thiophene-h, J= 3, 1.5 Hz ), 7.18 (d, 2H, Ar-H, J = 8.1 Hz ), 7.30 (m, 1H, thiophene-h), 7.37 (d, 2H, Ar-H, J = 8.4 Hz), 7.40 (d, 1H, =CH, J= 14.4 Hz), 7.61 ( d, 1H, =CH, J= 14.4 Hz), 7.70 (d, 2H, Ar-H, J=8.7 Hz), 7.76 (d, 2H, Ar-H, J= 8.1 Hz). 13 CMR (DMS-d 6 ): δ 39.49, 59.27, 99.85, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd for C 22 H 16 2 S (455.33): C, 58.03, H, 3.54,, ound: C, 57.92, H, 3.30,, (4-omophenyl)-3-[3-(4-bromophenyl)-5-(4- fluorophenyl)-4, 5-dihydro-1H-pyrazol-1-yl]-2- propen-1-one (9) mp: C; yield: 72 %; IR (cm -1 ): υ 1685 (C=), 1585 (C=); 1 HMR (DMS-d 6 ): δ 3.11 (dd, 1H, pyrazoline H 4, J = 16.8, 5.7 Hz), 3.53 (dd, 1H, pyrazoline H 4, J = 16.2, 12.3 Hz), 4.80 (m, 1H, pyrazoline H 5 ), 7.01 (d, 2H, Ar-H, J = 8.7 Hz), 7.16 (d, 2H, Ar-H, J = 8.7 Hz), 7.32 (d, 2H, =CH, J = 15 Hz ), 7.70 (d, 2H, Ar-H, J = 8.4 Hz), 7.72 (d, 2H, =CH, J = 15 Hz), 7.75 (d, 2H, Ar-H, J = 8.7 Hz), 7.77 (d, 2H, Ar-H, J = 8.4 Hz), 7.84 (d, 2H, Ar-H, J = 8.7 Hz), 7.89 (d, 2H, Ar-H, J = 8.7 Hz), 7.93 (d, 2H, Ar-H, J = 8.7 Hz). 13 CMR (DMS-d 6 ): δ 39.51, 57.23, 99.84, , , , , , , , , , , , , , , , , , , , , , Anal. Calcd for C 24 H (528.19): C, 54.57, H, 3.24,, ound: C, 54.70, H, 3.35,, General procedure for the synthesis of 1-[3-(4- bromophenyl)-5-(4-fluorophenyl)-4, 5-dihydro- 1H-pyrazol-1-yl]-3-aryl-2-propen-1-one A mixture of compound 10 (0.05 mol), appropriate aromatic aldehyde (0.05 mol) and 10% aqueous sodium hydroxide (10 ml) in ethanol (30 ml) was stirred at room temperature for about 3 hours. The resulting solid was filtered off, rinsed with water, dried and crystallized from ethanol. 1-[3-(4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazol-1-yl]-3-(2-thienyl)-2-propen- 1-one (11). mp: C; yield: 56 %; IR (cm -1 ): υ 1662 (C=), 1593 (C=); 1 HMR (DMS-d 6 ): δ 3.12 (dd, 1H, pyrazoline H 4, J = 18.3, 4.5 Hz), 3.82 (dd, 1H, pyrazoline H 4, J = 18.3, 12 Hz), 5.54 (dd, 1H, pyrazoline H 5, J = 11.7, 4.5 Hz), 6.92 (dd, 1H, thiophene-h, J = 4.5, 2.7 Hz),7.11(d, 2H, Ar-H, J = 8.7 Hz), 7.14 (d, 2H, Ar-H, J = 8.7 Hz), 7.20 (m, 1H, thiophene-h), 7.23 (d, 2H, =CH, J = 14.1 Hz), 7.35 (m, 1H, thiophene-h), 7.64 (d, 1H, =CH, J=14.1 Hz), 7.71 (d, 2H, Ar-H, J = 8.4 Hz), 7.78 (d, 2H, Ar- H, J = 8.4 Hz). 13 CMR (DMS-d 6 ): δ 39.50, 58.96, 99.81, , , , , , , , , , , , , , , , Anal. Calcd for C 22 H 16 2 S (455.33): C, 58.03, H, 3.54,, ound: C, 58.20, H, 3.50,, [3-(4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazol-1-yl]-3-(4-fluorophenyl)-2- propen-1-one (12) mp: C; yield: 63%; IR (cm -1 ): υ

4 1584 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) 1658 (C=), 1589 (C=); 1 HMR (DMS-d 6 ): δ 3.13 (dd, 1H, pyrazoline H 4, J = 18, 4.2 Hz), 3.83 (dd, 1H, pyrazoline H 4, J = 18, 12.3 Hz),), 5.53 (dd, 1H, pyrazoline H 5, J = 12, 4.5 Hz), 7.10 (d, 2H, Ar-H, J=9 Hz), 7.14 (d, 2H, Ar-H, J = 9.3 Hz), 7.17 (d, 2H, Ar-H, J = 9.3 Hz), 7.21(d, 1H, =CH, J=15.6 Hz), 7.26 (d, 2H, Ar-H, J = 9.3 Hz), 7.62 (d, 2H, Ar-H, J = 8.4 Hz), 7.72 (d, 1H, =CH, J=15.3 Hz), 7.83(m, 2H, Ar-H). 13 CMR (DMS-d 6 ): δ 39.58, 58.95, 99.95, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd for C 24 H (467.28): C, 61.68, H, 3.66,, ound: C, 61.72, H, 3.69,, [3-(4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazol-1-yl]-3-(4-bromophenyl)-2- propen-1-one (13). mp: C; yield: 76 %; IR (cm -1 ): υ 1662 (C=), 1589 (C=); 1 HMR (DMS-d 6 ): δ 3.14 (dd, 1H, pyrazoline H 4, J = 18, 4.5 Hz), 3.84 (dd, 1H, pyrazoline H 4, J = 18, 12 Hz), 5.55 (dd, 1H, pyrazoline H 5, J = 12, 4.5 Hz ), 7.02 (d, 2H, Ar-H, J = 8.7 Hz), 7.11 (d, 2H, Ar-H, J = 9 Hz), 7.15 (d, 2H, Ar-H, J = 8.7 Hz), 7.23 (d, 2H, Ar-H, J = 9 Hz), 7.26 (d, 1H, =CH, J = 14.4 Hz), 7.66 (d, 2H, Ar-H, J = 8.4 Hz), 7.70 (d, 1H, =CH, J = 14.4 Hz), 7.73 (d, 2H, Ar-H, J = 8.4 Hz). 13 CMR (DMS-d 6 ): δ 39.5, 58.97, 59.79, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd for C 24 H (528.19): C, 54.57, H, 3.24,, ound: C, 54.62, H, 3.31,, (4-omophenyl)-5-(4-fluorophenyl)-1- propanoyl-4, 5-dihydro-1H-pyrazole (14). A solution of the chalcone 3 (0.03 mol), hydrazine hydrate (0.06 mol) in 15 ml of propionic acid was heated under reflux for 4 h, then poured onto crushed ice. The precipitate was separated by filtration, washed with water, and crystallized from ethanol. mp: C; yield: 82 %; IR (cm -1 ): υ 1662 (C=), 1589 (C=); 1 HMR (DMS-d 6 ): δ 1.05 (t, 3H, CH 3, J =7.2 Hz), 2.70 (q, 2H, CH, J =7.2 Hz), (dd, 1H, pyrazoline H 4, J = 18, 4.8 Hz), 3.81 (dd, 1H, pyrazoline H 4, J = 18, 12 Hz), 5.54 (dd, 1H, pyrazoline H 5, J = 12, 4.8 Hz), 7.11 (d, 1H, Ar-H, J = 8.4 Hz), 7.23 (d, 2H, Ar-H, J = 8.1 Hz), 7.64 (d, 2H, Ar-H, J = 8.4 Hz), 7.70 (d, 2H, Ar-H, J = 8.1 Hz). 13 CMR (DMS-d 6 ): δ 8.88, 26.86, 39.51, 59.06, , , , , , , , , , , , , , , Anal. Calcd for C 18 H 16 2 (375.22): C, 57.61, H, 4.29,, ound: C, 57.42, H, 4.43,, (4-omophenyl)-5-(4-fluorophenyl)-4, 5- dihydro-1h-pyrazole-1-thiocarboxamide (15). Sodium hydroxide (0.025 mol) in 5 ml of water was added to a solution of the chalcone 3 (0.01 mol) and thiosemicarbazide (0.012 mol) in 25 ml of ethanol and refluxed for 8 h. The products were poured into crushed ice and the solid mass which separated out was filtered, dried and crystallized from chloroform. mp: C; yield: 78 %; IR (cm -1 ): υ 3475, 3352 (H 2 ), 1604 (C=), 1361(C=S); 1 HMR (DMS-d 6 ): δ 3.14 (dd, 1H, pyrazoline H 4, J = 18.0, 3.6 Hz), 3.88 (dd, 1H, pyrazoline H 4, J = 18.0, 11.7 Hz), 5.92 (dd, 1H, pyrazoline H 5, J = 11.7, 3.6 Hz), 7.09 (d, 2H, Ar-H, J= 8.7 Hz), 7.17(d, 2H, Ar-H, J = 9.0 Hz), 7.64 (d, 2H, Ar-H, J = 8.4 Hz), 7.80 (d, 2H, Ar-H, J= 8.4 Hz), 7.95 (s, 1H, H 2, D 2 exch.), 8.07 (s, 1H, H 2, D 2 exch.). 13 CMR (DMS-d 6 ): δ 39.50, 40.05, 62.38, , , , , , , , , , , , , , , Anal. Calcd for C 16 H 13 3 S (378.24): C, 50.80, H, 3.46,, ound: C, 51.10, H, 3.54,, Anti-inflammatory activity screening Adult male albino rats ( g) were used. All animals were kept under uniform and controlled conditions of temperature and light/dark (12/12 h) cycles, fed with standard rodent diet and water ad libitum. Animals were allowed to adapt to the laboratory environment for one week prior to experiments. The experimental tests on animals have been performed in accordance with the Institutional Ethical Committee approval. The antiinflammatory effect of the newly synthesized compounds was evaluated in correspondence to the carrageenan-induced paw edema method

5 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) 1585 (Winter et al., 1962). 14 ourteen groups of animals each consisting of five rats weighing g were selected. The first group was injected with 0.05 ml of 1% carrageenan in the subplantar tissue of the right hind paw and served as untreated control. The positive control group was given 10 mg/kg i.p. indomethacin one hour before carrageenan injection. The test compounds were suspended in 0.5% carboxymethylcellulose (CMC) and given to the rats at a dose of 10 mg/kg i.p. one hour prior to carrageenan injection. The paw volume of each rat was measured before 1 h and after 3 h of carrageenan treatment with the help of a Plethysmometer. Quantitative variables from normal distribution were expressed as means ± SE standard error. The significant difference between groups was tested by using one-way AVA and the chosen level of significance was p < The anti-inflammatory activity was expressed as percentage inhibition of edema volume in treated animals in comparison with the control group (Table 1, igs. 1-3): %Inhibition of edema = Vc - Vt / Vc 100 where, Vc and Vt are the volumes of edema for the control and drug- treated animal groups, respectively. Potency of the tested compounds was calculated relative to indomethacin reference standard treated group according to the following equation: Potency = (% edema inhibition of tested compound treated group) (% edema inhibition of indomethacin treated group). RESULTS AD DISCUSSI The synthesis of the target compounds was accomplished according to the reaction sequence illustrated in Schemes 1 and 2. 1-(4-bromophenyl)-3-(4-fluorophenyl) prop-2-en-1-one (3) was prepared by reacting 4- Table 1: Anti-inflammatory activity of the test compounds assessed in comparison to indomethacin as reference. Compound Mean swelling %Inhibition Potency c volume (ml) of edema Control 0.55 ± Indomethacin 0.23 ± ± ± ± a ± ± b ± ± ± ± b ± ± ± a Statistically significant from the control at p < 0.05 b Statistically significant from the indomethacin at p < 0.05 c Potency was expressed as % edema inhibition of the tested compounds relative to % edema inhibition of indomethacin reference standard

6 1586 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) bromoacetophenone with 4-fluorobenzaldehyde in the presence of potassium hydroxide by conventional Claisen-Schmidt condensation (Dutkiewicz et al., 2010). 15 Reaction between chalcone 3 and hydrazine hydrate in ethanol led to synthesis of 3-(4-bromophenyl)-5-(4-fluorophenyl)- 4, 5-dihydro-1H-pyrazole (4), which on treatment with substituted benzoyl chlorides afforded respective 1--substituted benzoyl-3,5-diaryl-2- pyrazolines 5 and 6 in modest yields (18-21%) ah H 2 H 2 C 2 H 5 H 4 H R Cl R 3 5, 6 5:R= 2-6:R= 3- H 2 H 2 HCH 7 ArCCH 3 / ah Ar 8, 9 8:Ar= 2-thienyl 9:Ar= 4--C 6 H 4 Scheme 1: Synthesis of compounds 4-9

7 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) 1587 Cyclization of the chalcone 3 with hydrazine hydrate in formic or propionic acid separately gave 1-formyl and propionyl derivatives 7and 14 respectively in good yields. n the other hand, the reaction of 1-(4-bromophenyl)-3-(4-fluorophenyl) prop-2-en-1-one 3 with thiosemicarbazide in refluxing ethanol, in the presence of excess sodium hydroxide, afforded 3-(4-bromophenyl)-5-(4- fluorophenyl)-1-thiocarbamoyl-2-pyrazoline (15). In order to obtain the pyrazolic chalcones, the corresponding 1-formyl pyrazolic precursor 7 was reacted with the acetophenones to afford 8 and 9. urthermore, condensation of 1-acetyl-2-pyrazoline derivative with the appropriate aldehydes resulted in the formation of the corresponding pyrazolic chalcones IR, 1 HMR and 13 CMR of all the synthesized compounds were recorded H 2 H 2 CH 3 CH 10 ArCH/ ah 11: Ar= 2-thienyl 12: Ar= 4--C 6 H 4 13: Ar= 4--C 6 H Ar 3 H 2 H 2 CH 3 CH 2 CH 14 H 2 CSHH 2 H 2 15 S Scheme 2: Synthesis of compounds 10-15

8 1588 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) Mean swelling volume Control Indomethacin Test Compounds ig. 1: Mean edema volume (ml) of the test compounds. Control Indomethacin % Inhibition of edema Test Compounds ig. 2: % Inhibition of edema for the test compounds. % Inhibition of edema Control Indomethacin Test Compounds ig. 3: Anti-inflammatory activity potency of the test compounds relative to indomethacin which was used as a reference standard

9 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) 1589 and found in full agreement with the proposed structures. All the newly synthesized pyrazoline derivatives were screened for their anti-inflammatory activities. All the compounds have shown antiinflammatory activity ranging from 3.61 to 62.45% at the dose of 10 mg/kg given in Table 1, whereas standard drug indomethacin showed 58.84% inhibition. Compound 4 did not have any substitution on position-1. It showed similar or improved activity than its benzoyl derivatives 5, 6. Compound 7 with 1--formyl group (62.45% edema inhibition) exhibited more potent anti-inflammatory activity than that of indomethacin (58.84%). Meanwhile, 1-thiocarbamoyl derivative, 15 showed inhibitory activity of about 85.89% of indomethacin. Attachment of a propyl group oriented at 1-position in compound 14 exhibited significant activity (37.91% edema inhibition). n the other hand, introduction of an acetyl group at -1, compound 10, resulted in a decrease in anti-inflammatory activity. urthermore, replacement of the acetyl group of compound 10 (8.30% inhibition) by an enone function of chalcone moiety enhanced the biological activity of compounds ( %). It is also obvious that, adopting a thienyl function 3-position of pyrazolyl chalcone derivative, seems preferable for obtaining an effective pharmacological agent as exhibited in compound 11 (potency, 71.78). n the other hand, compounds 8 and 9 having a 4, 5-dihydro-1H-pyrazol-1-yl group at position-3 of chalcone moiety showed a sharp decrease in anti-inflammatory activity (13.00 and 3.61%) respectively. CCLUSI Structure activity relationships based on the observed results indicated that, the type of substitution attached to the 1- position of pyrazoline nucleus plays a controlling role for developing the exhibited pharmacological properties. Among the twelve compounds synthesized four compounds; 7, 15, 11 and 14 were found to be most active compounds with potency, , 85.89, and respectively. Hence, it may be concluded that the presence of -1 formyl, thiocarbamoyl, propyl or 3-(thiophen-2-yl)-2-propen- 1-yl-1-one as a substituent elicit a remarkable increase in anti-inflammatory activity. Therefore, they deserve further attention in order to develop new leads. ACKWLEDGMETS The author is thankful to Associate professor Dr. Hala ahmi, Department of Toxicology and Pharmacology, aculty of Pharmacy, Cairo University for her valuable support and laboratory facilities for pharmacological studies. REERECES 1. Chandra, T., Garg,., Lata, S., Saxena, K.K., Kumar, A., Eur. J. Med. Chem., 45: 1772 (2010). 2. Joshi, R.S., Mandhane, P.G., Diwakar, S.D., Dabhade, S.K., Gill, C.H., Bioorg. Med. Chem. Lett., 20: 3721 (2010). 3. Abdel-Wahab, B.., Abdel-Aziz, H.A., Ahmed, E.M., Eur. J. Med. Chem., 44: 2632 (2009). 4. Dawane, B.S., Konda, S.G., Mandawad, G.G., Shaikh, G.G.., Eur. J. Med. Chem., 45: 387 (2010). 5. Abid, M., Azam, A., Bioorg. Med. Chem. Lett., 16: 2812 (2006). 6. Abid, M., Bhat, A.R., Athar,., Azam, A., Eur. J. Med. Chem., 44: 417 (2009). 7. Acharya, B.., Saraswat, B.., Tiwari, M., Shrivastava, A.K., Ghorpade, R., Bapna, S., Kaushik, M.P., Eur. J. Med. Chem., 45: 430 (2010).

10 1590 KHALIL & REAAT, rient. J. Chem., Vol. 27(4), (2011) 8. Ahn, J.H., Kim, H.M., Jung, S.H., Kang, S.K., Kim, K.R., Rhee, S.D., Yang, S.D., Cheon, H.G., Kim, S.S., Bioorg. Med. Chem. Lett., 14: 4461 (2004). 9. Ali, M.A., Shaharyar, M., Siddiqui, A.A., Eur. J. Med. Chem., 42: 268 (2007). 10. Prasad, Y.R., Rao, A.L., Prasoona, L., Murali, K., Kumar, P.R., Bioorg. Med. Chem. Lett, 15: 5030 (2005). 11. Gok, S., Demet, M.M., zdemir, A., Turan- Zitouni, G., Med. Chem. Res., 19: 94 (2010). 12. air, V., Biju, A.T., Mohanan, K., Suresh, E. rg. Lett., 8: 2213, (2006). 13. Khalil,.M., Arch. Pharm., 344: 242 (2011). 14. Winter, C.A., isley, E.A., uss, G.W., Proc. Soc. Exp. Biol. Med., 111, 544 (1962). 15. Dutkiewicz, G., Veena, K., arayana, B., Yathirajan, H.S., Kubick, M., Acta Crystall, E66, o1243 (2010). 16. Lv P.-C, Sun J., Luo Y., Yang Y., Zhu H.-L., Bioorg. Med. Chem. Lett., 20: 4657 (2010).