Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

Abstract

A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8 b selectively inhibited the COX-2 enzyme (IC₅₀ = ∼0.20–0.69 μM), with SI values of (>72.5–250) compared with celecoxib (IC₅₀ = 0.16 μM, COX-2 SI: > 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC₅₀ > 50 μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10 μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition = ∼0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.

Keywords:

• NSAID thioesters
• in vitro
• antitumour
• COX-1/COX-2
• kinase inhibition assay
• molecular docking

Acknowledgements

The authors express their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-163. The authors thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support.

Disclosure statement

No potential conflict of interest was reported by the authors.