Synthesis and Pharmacological Evaluation of New Chemical Entities from Ibuprofen as Novel Analgesic Candidates

A. Ahmadi; N. Naderi; M. Daniali; S. Kazemi; S. Aazami; N. Alizadeh; B. Nahri-Niknafs

doi:10.1055/s-0034-1376976

Drug Research, Table of Contents

Drug Res (Stuttg) 2015; 65(09): 457-462
DOI: 10.1055/s-0034-1376976

Original Article

Synthesis and Pharmacological Evaluation of New Chemical Entities from Ibuprofen as Novel Analgesic Candidates

A. Ahmadi

¹Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran

,

N. Naderi

²Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

,

M. Daniali

¹Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran

,

S. Kazemi

¹Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran

,

S. Aazami

¹Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran

,

N. Alizadeh

¹Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran

,

B. Nahri-Niknafs

¹Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran

› Author Affiliations

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are the first choice of drugs that are normally used for the treatment of pain and inflammation. Ibuprofen (I) and its analogues as the most widely used NSAIDs have been synthesized in recent years. In an effort to establish new candidates with improved analgesic properties, derivatives (II–VII) with substituted aromatic as well as aliphatic moieties were synthesized in this experiment and evaluated in formalin test with rats. The results were compared to ibuprofen and control groups. Findings indicated that derivatives with new alkylphenyl rings (VI and VII) had some similar or more analgesic activities relative to the control and ibuprofen groups, respectively; which could be justified as to more alkyl and phenyl groups instead of p-isobutylphenyl moiety in I.

Key words

NSAIDs - ibuprofen - analgesic - modified aromatic and aliphatic moieties

Full Text

References

References
1 Williams KM, Day RO, Breit SN. Biochemical actions and clinical pharmacology of anti-inflammatory drugs. Adv Drug Res 1993; 24: 121-198
2 Abdellatif KR, Chowdhury MA, Dong Y et al. Dinitroglyceryl and diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of aspirin, indomethacin and ibuprofen: synthesis, biological evaluation and nitric oxide release studies. Bioorg Med Chem Lett 2009; 1, 19: 3014-3018
3 Nagarapu L, Mateti J, Gaikwad HK et al. Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives. Bioorg Med Chem Lett 2011; 15, 21: 4138-4140
4 Hegazy GH, Ali HI. Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids. Bioorg Med Chem 2012; 20: 1259-1270
5 Sujith KV, Rao JN, Shetty P et al. Regioselective reaction: Synthesis and pharmacological study of Mannich bases containing ibuprofen moiety. Eur J Med Chem 2009; 44: 3697-3702
6 Sarkate AP, Lokwani DK, Patil AA et al. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenicity and nitric oxide-releasing studies of novel ibuprofen analogs as nonulcerogenic derivatives. Med Chem Res 2011; 20: 795-808
7 Manjunatha K, Poojary B, Lobo PL et al. Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives. Eur J Med Chem 2010; 45: 5225-5233
8 Ramachary DB, Prasad M. Sh. Direct amino acid-catalyzed cascade reductive alkylation of arylacetonitriles: high-yielding synthesis of ibuprofen analogs. Tetrahedron Lett 2010; 51: 5246-5251
9 Mehta N, Aggarwal S, Thareja S et al. Synthesis, pharmacological and toxicological evaluation of amide derivatives of ibuprofen. Inter J ChemTech Res 2010; 2: 233-238
10 Amir M, Kumar H, Javed SA. Condensed bridgehead nitrogen heterocyclic system: Synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid. Eur J Med Chem 2008; 43: 2056-2066
11 Olav G, Sirpa K, Günter H. Convenient routes to 2-aryl-2-fluoropropionic acids: synthesis of monofluorinated analogues of (±)-ibuprofen, (±)-naproxen and related compounds. Tetrahedron 1996; 52: 12761-12774
12 Kansara SG, Pandit RD, Bhawe VG. Synthesis of some new ibuprofen derivatives containing chief heterocyclic moiety like striazine and evaluated for their analgesic activity. Rasayan J Chem 2009; 2: 699-705
13 Amir M, Kumar S. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of ibuprofen derivatives. Acta Pharmaceut 2007; 57: 31-45
14 Arava VR, Siripalli UBR. Synthesis of novel 2-arylpropionic acids and their derivatives. Indian J Chem 2007; 46B: 1343-1346
15 De Wael F, Muccioli GG, Lambert DM et al. Chemistry around imidazopyrazine and ibuprofen: Discovery of novel fatty acid amide hydrolase (FAAH) inhibitors. Eur J Med Chem 2010; 45: 3564-3574
16 Neeraj M, Suresh Th, Saurabh A et al. Synthesis and invitro spleen cell proliferative activity of novel oxime derivative of ibuprofenamide. Der Pharma Chemica 2010; 2: 397-403
17 Tozkoparan B, Gökhan N, Aktay G et al. 6-Benzylidenethiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with ibuprofen: synthesis, characterization and evaluation of anti-inflammatory activity. Eur J Med Chem 2000; 35: 743-750
18 Guo CB, Cai ZF, Guo ZR et al. Design, Synthesis and in vitro Evaluation of Thiazole Derivatives of Ibuprofen as Cyclooxygenase-2 Inhibitors. Chinese Chem Lett 2006; 17: 325-328
19 Uludag MO, Caliskan Ergun B, Alkan DA et al. Stable ester and amide conjugates of some NSAIDs as analgesic and antiinflammatory compounds with improved biological activity. Turk J Chem 2011; 35: 427-439
20 Villa M, Smeyers NJ, Senent ML et al. An ab initio structural study of some derivatives of ibuprofen as possible anti-inflammatory agents. J Mol Struc-Theochem 2001; 537: 265-269
21 Aparicio L, Gayo N, Msupa Carretero J et al. 2-(4-Isobutyl phenyl)butyric acid, salts thereof, and pharmaceutical compositions containing the same. Assignee, Juste, S.A. Quimico-Farmaceutica, US, Patent Number: 4031243 1977;
22 Adams SS, Cliffe EE, Lessel B et al. Some biological properties of 2-(4-isobutylphenyl)-propionic acid. J Pharm Sci 1967; 56: 1686
23 Mills SB, Bloch M, Bruckner FE. Double-blind cross-over study of Ketoprofen and Ibuprofen in management of rheumatoid arthritis. Br Med J 1973; 4: 82-84
24 Chidambaram V. This is the appendix of his thesis dealing with ibuprufen. NCCR internal bulletin, ID Code: 1463, Deposited By: Prof Balasubramanian Viswanathan 2009; (Unpublished)
25 Schiene K, De Vry J, Tzschentke TM. Antinociceptive and Antihyperalgesic Effects of Tapentadol in Animal Models of Inflammatory Pain. J Pharmacol Exp Ther 2011; 339: 537-544
26 Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977; 4: 161-174
27 Shen TY. Burger’s Medicinal Chemistry. 4^th ed. vol. III. Wiley; New York: 1981: 1237-1241
28 Juby PF, Goodwin WR, Hudyma TW et al. Antiinflammatory activity of some indan-1-carboxylic acids and related compounds. J Med Chem 1972; 15: 1297-1306
29 Uzgören-Baran A, Tel BC, Sarıgöl D et al. Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance. Eur J Med Chem 2012; 57: 398-406
30 Goto K, Ochi H, Yasunaga Y et al. Analgesic effect of mofezolac, a non-steroidal anti-inflammatory drug, against phenylquinone-induced acute pain in mice. Prostaglandins Other Lipid Mediat 1998; 56: 245-254
31 Santana L, Teijeira M, Uriarte E et al. AM1 theoretical study, synthesis and biological evaluation of some benzofuran analogues of anti-inflammatory arylalkanoic acids. Eur J Pharm Sci 1999; 7: 161-166