Design, Synthesis and Evaluation of some Novel Pyrazoline Derivatives as Potential Anti-inflammatory and Antitumor Agents

R. Y. Elbayaa; M. H. Badr; A. A. Khalil; M. Abdelhadi

doi:10.1055/s-0032-1333293

Drug Research, Table of Contents

Drug Res (Stuttg) 2013; 63(06): 271-281
DOI: 10.1055/s-0032-1333293

Original Article

Design, Synthesis and Evaluation of some Novel Pyrazoline Derivatives as Potential Anti-inflammatory and Antitumor Agents^[*]

R. Y. Elbayaa

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt

,

M. H. Badr

²Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt

,

A. A. Khalil

³Department of Protein Technology, Institute of Genetic Engineering and Biotechnology, City for Scientific Research, New Borg Elarab, Alexandria, Egypt

,

M. Abdelhadi

⁴Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

› Author Affiliations

Abstract

A new series of pyrazoline derivatives was designed and synthesized with the objective of developing agents with anti-inflammatory activity together with chemoprevention of hepatobiliary malignancies. The prepared compounds were evaluated for their anti-inflammatory activity using carrageenan-induced granuloma bioassay, using celecoxib as a reference drug. Ulcerogenic effect and acute toxicity profiles (ALD₅₀) for the most active compounds were also determined. Compound 5c was proved to display anti-inflammatory activity better than celecoxib. Compounds 4b, 5d, 5c and 8 were found to be safer than indomethacin with respect to ulcerogenic effect and were well tolerated by the experimental animals with high safety margin (ALD₅₀ >300 mg/Kg). Moreover, histopathological examination was carried out to detect the anti-inflammatory effect of the tested compounds on the livers of carrageenan-injected rats. On the other hand, compounds 4b, 4c, 4d, 5b, 5c, 5d, 6a, 6b, 6c, 6d, 8 and 9 were selected by the NCI to be evaluated for their anticancer activities but none has passed to the 5-dose assay. In addition, the ligand-receptor interactions of the most active compounds with COX-2 were investigated by performing docking studies using Molecular Operating Environment (MOE) version 2008.10.

Key words

pyrazoline - synthesis - design - anti-inflammatory activity - histopathology - malignancies - docking

Full Text

References

References
1 Hardman JG, Limbird LE, Molinoff PB. eds. Goodman and Gilsman’s the Pharmacological Basis of Therapeutics. 9^th ed. McGraw-Hill; New York: 1996: 617-658
2 Song Y, Connor DT, Doubleday R et al. Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazole series. J Med Chem 1999; 42: 1161-1169
3 Khanna IK, Weier RM, Yu Y et al. 1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents. J Med Chem 1997; 40: 1634-1647
4 Scheiman JM, Behler EM, Loeffler KM et al. Omeprazole ameliorates aspirin-induced gastroduodenal injury. Digestive Diseases and Sciences 1994; 39: 97-103
5 Botting RM.. Cyclooxygenase: Past, present and future, A tribute to John R. Vane (1927–2004) • Review article. J Therm Biol 2006; 31: 208-219
6 Naesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent them: A review of current treatment options. Drug Saf 2006; 29: 119-132
7 Cryer B. NSAID-Associated Deaths: The Rise and Fall of NSAID-Associated GI Mortality FREE. Am J Gastroenterol 2005; 100: 1694-1695
8 Palomer A, Cabré F, Pascual J et al. Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models. J Med Chem 2002; 45: 1402-1411
9 Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002; 94: 252-266
10 Taketo M. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998; 90: 1529-1536
11 Herendeen JM, Lindley C. Use of NSAIDs for the Chemoprevention of Colorectal Cancer. The Annals of Pharmacotherapy 2003; 37: 1664-1674
12 Penning TD, Talley JJ, Bertenshaw SR et al. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem 1997; 40: 1347-1365
13 Farghaly AM, Soliman FSG, El Semary MM et al. Polysubstituted Pyrazoles, Part 4: Synthesis, Antimicrobial and Anti-inflammatory Activity of Some Pyrazoles. Pharmazie 2001; 56: 28
14 Balsamo A, Coletta I, Guglielmotti A et al. Synthesis of heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)-(arylmethyloxy)amine COX-2 inhibitors: effects on the inhibitory activity of the replacement of the cyclopentene central core with pyrazole, thiophene or isoxazole ring. Eur J Med Chem 2003; 38: 157-168
15 Li MH, Yin LL, Cai MJ et al. Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives. Acta Pharmacol Sin 2005; 26: 865-872
16 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
17 Bansal E, Srivastava VK, Kumar A. Synthesis and anti-inflammatory activity of 1-acetyl-5-substitute daryl-3-(β-aminonaphthyl)-2-pyrazolines and β-(substitute daminoethyl) amidonaphthalenes. Eur J Med Chem 2001; 36: 81-92
18 Rani P, Srivastava VK, Kumar A. Synthesis and antiinflammatory activity of heterocyclic indole derivatives. Eur J Med Chem 2004; 39: 449-452
19 Abadi AH, Ibrahim TM, Abouzid KM 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
20 Auzias M, Therrien B, Süss-Fink G et al. Ferrocenoyl Pyridine Arene Ruthenium Complexes with Anticancer Properties: Synthesis, Structure, Electrochemistry, and Cytotoxicity. Inorg Chem 2008; 47: 578-583
21 Lam KH, Gambari R, Yuen MC et al. The preparation of 2,6-disubstituted pyridinyl phosphine oxides as novel anti-cancer agents. Bioorg Med Chem Lett 2009; 19: () 2266-2269
22 Leo AJ. Calculating log Poct from structures. Chem Rev 1993; 63: 1281-1306
23 Bonney RJ, Gery I, Lin TY et al. Mononuclear Phagocytes From Carrageenan-Induced Granulomas Isolation, Cultivation, and Characterization. J Exp Med 1978; 148: 261-275
24 Daidone G, Maggio B, Raffa D et al. Synthesis and Pharmacological Study Of Ethyl D-4-Oxo-3(4 h)-Quinazolinyl]-1 h-Pyrazole-4-Acetates. Eur J Med Chem 1994; 29: 707-711
25 Verma M, Tripathi M, Saxena AK et al. Antiinflammatory activity of novel indole derivatives. Eur J Med Chem 1994; 29: 941-946
26 Steele PR, Lowes JR. A histopathological study of the effects of intravenously administered lambda carrageenan in the mouse, with particular reference to the macrophage system. Br J Exp Pathol 1979; 60: 358-365
27 Fowler EF, Simpson JG, Thomson AW. Histological and ultrastructural changes following carrageenan injection in the mouse. The Journal of Pathology 1980; 132: 63-79
28 Monks A, Scudiero D, Skehan P et al. Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines. J Natl Cancer Inst 1991; 83: 757
29 Fahmy HT, Bekhit AA. Synthesis of Some New Bis-thiazoles as Possible Anticancer Agents. Pharmazie 2002; 57: 800
30 Molecular Operating Environment 2008.10 (MOE). Chemical Computing Group Inc.; Montreal, Quebec, Canada: http://www.chemcomp.com
31 Wang JL, Limburg D, Graneto MJ et al. The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life. Bioorg Med Chem Lett 2010; 20: 7159-7163
32 RCSB Protein Data Bank. http://www.pdb.org
33 Kalirajan R, Sivakumar SU, Jubie S et al. Synthesis and biological evaluation of some heterocyclic derivatives of Chalcones. Int J. Chem Tech Res 2009; 1: 27-34
34 Singh P, Negi JS, Pant GJ et al. 5-(3-Nitrophenyl)-3-phenyl-4,5-dihydro-1 H-pyrazole-1-carbaldehyde. www.mdpi.com/journal/molbank 2010; ISSN: 1422-8599 M650
35 El-Sabagh OI, Baraka MM, Ibrahim SM et al. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. Eur J Med Chem 2009; 44: 3746-3753
36 Gökhan-Kelekçi N, Yabanoğlu S, Küpeli E et al. A new therapeutic approach in Alzheimer disease: Some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics. Bioorg Med Chem 2007; 15: 5775-5786
37 Kubinyi H. Nonlinear dependence of biological activity on hydrophobic character: the bilinear model. Farmaco [Sci] 1979; 34: 248-276
38 Fini A, Laus M, Orienti I et al. Dissolution and partition thermodynamic functions of some nonsteroidal anti-inflammatory drugs. J Pharm Sci 1986; 75: 23-25

Design, Synthesis and Evaluation of some Novel Pyrazoline Derivatives as Potential Anti-inflammatory and Antitumor Agents[*]

Design, Synthesis and Evaluation of some Novel Pyrazoline Derivatives as Potential Anti-inflammatory and Antitumor Agents^[*]