Synthesis, Anti-Inflammatory and Anti- Nociceptive Activities and Cytotoxic Effect of Novel Thiazolidin-4-ones Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors

Document Type: Original Article

Authors

1 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 2 Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 3 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

4 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

5 Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

6 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 5 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

 




Objective(s): Nowadays, COX-
2 inhibitors such as valdecoxib are removed from the market because of their cardiovascular toxicity and their potential to increase the risk of strokes. In response to this, medicinal chemists have attempted to synthesize new classes of COX-2 Inhibitors.
 
Materials and Methods:
In this study, three novel analogues of thiazolidin-4-ones derivatives 2a-c
were synthesized. The ability of these compounds to inhibit ovine COX-1 and COX-2 (0.2- 0.8 μM) was determined using a colorimetric method. The cytotoxic effect of the synthesized compounds (25-100 M) was also investigated by measuring their cytotoxicity against Caco-2 and MCF-7 cell lines using MTT assay. Cell apoptosis was determined by flow cytometry. Writhing test (7.5-75 mg/kg) was used to examine the antinociceptive effects in mice. The effect of the analogues against acute inflammation (7.5-75 mg/kg) was also studied using xylene-induced ear edema test in mice.
 
Results:
The synthesized compounds showed a weak capacity to inhibit the proliferation of Caco-2 and MCF-7 cell lines. The COX-2 inhibition potency and selectivity index for test compounds 2a–b were as follows; celecoxib > 2b > 2a
. On the other hand, all three analogues exhibited strong antinociceptive activity against acetic acid-induced writhing. The anti-inflammatory and antinociceptive effects of the analogues were markedly more than positive control, celecoxib.
Conclusion: This study demonstrates that the antinociceptive and anti-inflammatory activity profiles exhibited by the novel synthesized compounds are independent from their COX-2 inhibitory potencies. The found antinociceptive and anti-inflammatory effects can be caused by interaction with other target; independent from COX-2. Accordingly, the compounds 2a-c could serve as lead compounds to develop novel anti-inflammation and antinociceptive drugs.
 
 
 

Keywords


1. Fletcher BS, Kujubu DA, Perrin DM, Herschman HR.

Structure of the mitogen-inducible TIS10 gene and

demonstration that the TIS10-encoded protein is a

functional prostaglandin G/H synthase. J Biol Chem

1992; 267: 4338-4443.

2. Crofford LJ. COX-1 and COX-2 tissue expression:

implications and predictions. J Rheumatol 1997;

24:49-52.

3. Coffey RJ, Hawkey CJ, Damstrup L, Graves DR, Daniel

VC, Dempsey PJ,

et al.

Epidermal growth factor receptor

activation induces nuclear targeting of cyclooxygenase-

 

2, basolateral release of prostaglandins, and mitogenesis

 

in polarizing colon cancer cells. Proc Natl Acad Sci USA

 

1997; 94:657-662.

 

4. Mitchell JA, Evans TW. Cyclooxygenase-2 as a

 

therapeutic target. Inflamm Res 1998; 47:88-92.

 

5. Bijlsma JW, Van de Putte LB. Non-steroidal antiinflammatory

 

agents (NSAID's) with lesser side

 

effects by selective inhibition of cyclo-oxygenase-2.

 

Ned Tijdschr Geneeskd 1998; 142:1762-1765.

 

6. Dammann HG. Preferential COX-2 inhibition: its

 

clinical relevance for gastrointestinal non-steroidal

 

anti-inflammatory rheumatic drug toxicity. Z

 

Gastroenterol 1999; 37:45-53.

 

7. Chen LC, Ashcroft DM

 

 

.

. Risk of myocardial

infarction associated with selective COX-2 inhibitors:

 

meta-analysis of randomized controlled trials.

 

Pharmacoepidemiol Drug Saf 2007; 16:762

 

 

772.

8. Bing RJ, Lomnicka M. Why do cyclo-oxygenase-2

 

inhibitors cause cardiovascular events? J Am Coll

 

Cardiol 2002; 39:521-522.

 

9. Chen CS, Tan CM, Huang CH, Chang LC, Wang JP,

 

Cheng FC. Discovery of 3-(4-bromophenyl)-6

 

nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide as a

 

novel dual cyclooxygenase/5-lipoxygenase inhibitor

 

that also inhibits tumor necrosis factor-[alpha]

 

production. Bioorg Med Chem 2010; 8:597-604.

 

10. Hadizadeh F, Mehrparvfar A. Synthesis of Some New

 

1-[2-(alkylthio-1-benzyl-5-imidazolyl)carbonyl]-4-[3-

 

(isopropyl amino) -2-pydridyl] piperazines as Anti-HIV.

 

J Sci Islam Repub Iran 2004; 15:131-134.

 

11. Entezari Heravi R, Hadizadeh F, Sankian M,

 

Tavakol Afshari J, Taghdisi SM, Jafarian H,

 

 

et al.

Novel

selective Cox-2 inhibitors induce apoptosis in Caco-2

 

colorectal carcinoma cell line. Eur J Pharm Sci 2011;

 

44:479-486.

 

12. Hosseinzadeh H, Ramezani M, Salmani G.

 

Antinociceptive, anti-inflammatory and acute toxicity

 

effects of Zataria multiflora Boiss extracts in mice and

 

rats. J Ethnopharmacol 2000; 73:379-385.

 

13. Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz

 

JL, Kozak KR, Kalgutkar AS. A novel mechanism of

 

cyclooxygenase-2 inhibition involving interactions

 

with Ser-530 and Tyr-385. J Biol Chem 2003;

 

278:45763-45769.

 

14. Smigel K. Arthritis drug approved for polyp

 

prevention blazes trail for other prevention trials J

 

Natl Cancer Inst 2000; 92:297-299.

 

15. Becerra CR, Frenkel EP, Ashfaq R, Gaynor RB.

 

Increased toxicity and lack of efficacy of Rofecoxib in

 

combination with chemotherapy for treatment of

 

metastatic colorectal cancer: A phase II study. Int J

 

Cancer 2003; 20: 868-872.

 

16. Badieyan, ZS, Moalem SA, Mehri, S, Shahsavand S,

 

Hadizadeh, F. Virtual Screening for finding novel

 

COX-2 inhibitors as cytotoxic agents. Open Med Chem

 

J 2012; 6:15-19.

 

17. James MJ, Cook-Johnson RJ, Cleland LG. Selective

 

COX-2 inhibitors, eicosanoid synthesis and clinical

 

outcomes: a case study of system failure. Lipids 2007;

 

42:779-785.

 

18. Dajani EZ, Islam K. Cardiovascular and

 

gastrointestinal toxicity of selective cyclo-oxygenase-

 

2 inhibitors in man. J Physiol Pharmacol 2008;

 

59:117-133.