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

A new series of NSAID thioesters were synthesized and evaluated for their <i>in vitro</i> 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 <b>2b</b>, <b>3b</b>, <b>6a</b>, <b>7a</b>, <b>7b</b> and <b>8a</b> 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. <i>In vitro</i> COX-1/COX-2 enzyme inhibition assay results indicated that compounds <b>2b</b>, <b>3b</b>, <b>6a</b>, <b>7a</b>, <b>7b</b>, <b>8a</b> and <b>8 b</b> selectively inhibited the COX-2 enzyme (IC₅₀ = ∼0.20–0.69 μM), with SI values of (&gt;72.5–250) compared with celecoxib (IC₅₀ = 0.16 μM, COX-2 SI: &gt; 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC₅₀ &gt; 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 <b>2a</b>, <b>3b</b>, <b>6a</b>, <b>7a</b>, <b>7b</b> and <b>8a</b> 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.