Design and Synthesis of Some Pyrazole Derivatives of Expected Anti-Inflammatory and Analgesic Activities
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MEDICINAL Med Chem Res (2012) 21:983–994 CHEMISTRY DOI 10.1007/s00044-011-9606-4 RESEARCH ORIGINAL RESEARCH Design and synthesis of some pyrazole derivatives of expected anti-inflammatory and analgesic activities Nagwa M. Abd-El Gawad • Ghaneya S. Hassan • Hanan Hanna Georgey Received: 12 November 2010 / Accepted: 9 February 2011 / Published online: 27 February 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Design and synthesis of some pyrazole deriv- Introduction atives 4–11 of expected anti-inflammatory and analgesic activities. In addition, docking of the tested compounds Inflammation is a normal and essential response to any into cyclooxygenase II using (MOE) was performed to noxious stimulus, which threatens the host and may rationalize the obtained biological results and their mech- vary from a localized response to a more generalized one anism of action. The structures of the new compounds were (Fylaktakidou et al., 2004). The inflammatory process is elucidated by spectral and elemental analyses. All the designed to provide a rapid mechanism by which the newly synthesized compounds were evaluated for their host can respond to the invasion of foreign materials and anti-inflammatory activity using the carrageenan-induced return to homeostatic equilibrium. Acute inflammation is rat paw edema method. Analgesic activity of the target mediated by the release of autacoids such as histamine, compounds was measured using the p-benzoquinone serotonin, bradykinin, prostaglandins, and leukotrienes writhing-induced method, and their ability to induce gastric (Lacerda et al., 2009). On the other hand, the chronic toxicity was also evaluated. Results showed that the newly inflammatory process involves the release of diverse synthesized compounds exhibited weak to good activities mediators, as interleukins, interferon, and tumor necrosis compared to ibuprofen and celecoxib as reference drugs. factor a (TNF-a), a cytokine that plays a major role in this Some compounds, such 4a and 11b exhibited significant kind of inflammatory process and whose production is anti-inflammatory activity with gastric ulcerogenic poten- associated with some inflammatory diseases such as rheu- tial less than that of ibuprofen. Results of the analgesic matoid arthritis, Crohn’s disease, and others (Lacerda activity showed that compounds possessing good anti- et al., 2009). inflammatory activity showed also good analgesic. Sub- Non-steroidal anti-inflammatory drugs (NSAIDs) are stitution of pyrazole ring with at least one aryl moiety was one of the most useful clinical therapies for the treatment found to be essential for anti-inflammatory and analgesic of pain, fever, and inflammation (Laufer and Luik, 2010). activities. Free NH (of pyrazole ring) and/or acidic group The major mechanism by which NSAIDs exert their (COOH) will improve the anti-inflammatory activity. anti-inflammatory activity is by the inhibition of cycloox- ygenase-derived prostaglandin synthesis, which is also Keywords Pyrazoles Á Anti-inflammatory Á responsible for the gastrointestinal (Sostres et al., 2010; Analgesic Á MOE Naesdal and Brown, 2006; Cryer, 2005; Lazzaroni and Bianchi Porro, 2004; James and Hawkey, 2003), renal (Schneider et al., 2006; Mounier et al., 2006; Zadrazil, 2006), and hepatic (Yanai et al., 2009) side effects that are observed mainly in chronic use of NSAIDs. Therefore, the challenge still exists for the pharmaceutical industry to & N. M. Abd-El Gawad Á G. S. Hassan Á H. H. Georgey ( ) develop effective anti-inflammatory agents with enhanced Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt safety profile. Literature survey revealed that many 2-pyr- e-mail: [email protected] azoline derivatives have been reported to exhibit various 123 984 Med Chem Res (2012) 21:983–994 pharmacological activities such as antimicrobial (Kart- O O Ar hikeyan et al., 2007; Ramiz et al., 2010), anti-inflammatory N O NH O (Barsoum et al., 2006; Shoman et al., 2009; Rathish et al., S N R R O 2009; Abbas et al., 2010), and antihypertensive (Turan- O NH Ar S Zitouni et al., 2000). Among the highly marketed COX-2 O + a inhibitors that comprise the pyrazole nucleus, celecoxib is N NH the one which is treated as a safe anti-inflammatory and R' analgesic agent. Some examples of pyrazole derivatives as 4 NSAIDs are mefobutazone, morazone, famprofazone, and 5 R' 6 ramifenazone (Reynold, 1993; Menozzi et al., 2003; Sakya O O et al., 2007; Patel et al., 2004). 6a R: CH3, R':CH3 Motivated by the aforementioned findings, it was Ar: 6b R: CH3, R': Cl 6c R: C6H5, R': CH3 designed to synthesize novel series of pyrazole derivatives 6d R:C6H5, R':Cl that would act as anti-inflammatory agents with reduced gastric toxicity. The synthesized compounds were tested in Scheme 2 Reagents and solvents: a toluene vivo for their anti-inflammatory and analgesic activities as well as their ulcerogenic liability. In order to rationalize the Ar O N S pharmacological results obtained and the mechanism of R C N Ar action, MOE (Molecular Operating Environment, 2005) O NH N R + docking studies of the synthesized compounds were per- N a N S formed using murine cyclooxygenase-2 co-crystallized H Cl with celecoxib (Protein Data Bank code PDB ID: 6COX) 4 as a template. 7 Cl 8 O Ar: Result and discussion 8a R: CH3 8b R: C6H5 O Chemistry Scheme 3 Reagents and solvents: a CH3CN, 0°C The synthesis routes for the preparation of the target compounds were illustrated in Schemes 1, 2, 3, and 4. Synthesis of the appropriate 1-(2,4-dimethoxyphenyl)alkyl/ Ar R Ar O aryl ketones 2a and 2b was carried out via the reaction of O R a 1,3-dimethoxybenzene with propionic acid or phenyl acetic O O O 9a R: CH3 9b R: C H 9 6 5 2 O O O O COOH b a R R N COOC2H5 R 2 O Ar N 1 N c Ar N 10a R: CH3, R': H b 10b R: CH3, R': Cl 11a R: CH3 10c R: C H , R': H 11b R: C H Cl 6 5 6 5 10d R: C6H5, R': Cl 11 O O O R' 10 R O O Ar: c O R N NH O Scheme 4 Reagents and solvents: a (COOC2H5)2/NaH/toluene, b 4 3 R’C6H4NHNH2ÁHCl/triethylamine/ethanol, and c KOH/methanol 2a, 3a, 4a R: CH3 2b, 3b, 4b R: C H 6 5 acid in polyphosphoric acid (Slotta and Heller, 1930). The structure of 2b was confirmed by appearance of a singlet Scheme 1 Reagents and solvents: a RCH2COOH/PAA, b HCHO/ piperdine/acetic acid, and c NH2NH2ÁH2O/ethanol at d 4.29 ppm corresponding to methylene protons. 123 Med Chem Res (2012) 21:983–994 985 Compounds 3a and 3b were synthesized from 2a and 2b, one strong absorption band at t 1738–1717 cm-1 corre- respectively, using Mannich reaction/elimination sequence. sponding to the carbonyl ester moiety. 1H-NMR also 1H-NMR spectrum of 3a had two doublets due to geminal confirmed the formation of the pyrazole ring from the coupling at d 2.93 (J: 7.4 Hz) and 3.04 ppm (J: 7.4 Hz) disappearance of the characteristic signal for the CH proton corresponding to the methylene protons and that of 3b that was observed in 9a and 9b (Scheme 4). Alkaline appeared at d 4.21 (J: 8.2 Hz) and 4.86 ppm (J: 8.2 Hz). hydrolysis of the ester containing compounds 10b and 10d Moreover, cyclocondensation of 3a and 3b with hydrazine gave the corresponding free carboxylic acid derivatives hydrate yielded the corresponding pyrazoline derivatives 11a,b. IR spectra showed a broad absorption band at t 4a and 4b. IR spectra of the prepared pyrazolines 4a and 4b 2950–2830 cm-1 for OH of the carboxylic group. 1H-NMR showed t (C=N) stretching at 1609–1604 cm-1 due to the confirmed the structures of the pyrazole derivatives 11a,b ring closure. In addition, a sharp band at 3422–3393 cm-1 from the appearance of an exchangeable proton at d due to the t (NH) stretching was also observed. 1H-NMR 11.00 ppm corresponding to COOH and disappearance of spectra recorded for the prepared compounds in CDCl3 the characteristic pattern of the ethyl protons (Scheme 4). clearly supported the proposed structures. Protons of pyr- Mass spectra of the newly synthesized compounds were azoline ring in compounds 4a and 4b showed a prominent concomitant with their molecular weight. ABX system, with protons Ha, Hb, and Hx seen as doublets of doublets at d 2.49–2.80, 3.39–3.81, and 5.00–5.10 ppm Pharmacological evaluation (JHa–Hb: 4.2–4.4, JHa–Hx: 7.4–8.2, JHb–Hx: 7.6 Hz), respec- tively. On the other hand, Hx of 4a appeared as multiplet as The experimental tests on animals have been performed in a result of CH3 substituent (Scheme 1). accordance with the Institutional Ethical Committee Coupling of 3,4-disubstituted pyrazolines 4a and 4b approval, Faculty of Pharmacy, Cairo University. with sulfonylated carbamic acid methyl esters 5a and 5b (Lange et al., 2004) afforded 6a–d. The structures of the LD50 prepared compounds were confirmed by the appearance of an additional strong absorption band of (C=O) stretching at LD50 of each compound was determined using Finney’s t 1683–1656 cm-1 in addition to absorption bands at t method (Finney, 1964). Intraperitoneal injection of the 1380–1327 and 1163–1155 cm-1 that were attributed to tested compounds in doses less than 75 mg/kg body weight 1 (SO2) stretching. Also, H-NMR spectra showed an failed to kill the mice within 24 h. LD50 celecoxib was increase in the integration of the aromatic protons com- 250 mg/kg body weight, and 2b, 3a, 4b, 9a, 9b, 10a, and pared to the parent pyrazolines 4a and 4b and an additional 10d were 277.5 mg/kg body weight.