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

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: Anti-Inflammatory; Anticancer; Antinociceptive; COX-2 inhibitor; Celecoxib; Thiazolidin-4-ones.

Figure    1

Schematic representation of chemical synthesis of Thiazolidin-4-ones derivatives 2a–c

Figure    2

Effects of compounds 2a–b and celecoxib on apoptosis induction were quantified as percent sub-diploid cells. A) MCF-7 cells. Untreated MCF-7 cell was used as control; B) Caco-2 cells. Untreated Caco-2 cell was used as control. The results of flow cytometry was not determined for compound 2c

Figure 3

Impacts of compounds 2a–b and celecoxib on apoptosis induction

Figure 4

Docked SC-558 (blue) and co-crystalized one (red) are almost at the same position revealing the accuracy of docking protocol

Figure 5

Docked compounds in active site cavity of enzyme, crystalized SC-558 is shown in red stick lines

Figure 6

Interactions between 2a (A), celecoxib(B), SC-558 (C) and mouse COX-2 enzyme