Structural alterations based on naproxen scaffold: Synthesis, evaluation of antitumor activity and COX-2 inhibition, and molecular docking

Abstract

A new series of non-carboxylic naproxen analogues, bearing a variety of ring systems, such as oxadiazoles 3a–c and 6a–c, cycloalkanes 4a–d, cyclic imides 5a–c, and triazoles 7–9 and 10a–c, was synthesized. In addition, in vitro antitumor activity and cyclooxygenase isozymes (COX-1/COX-2) inhibition assay of the target compounds 3–10 was studied. The results of the antitumor activity assays indicated that compounds 4b, 6c, 10b, and 10c exhibited the greatest antitumor activities against the tested cell lines MCF-7, MDA-231, HeLa, and HCT-116, with an IC50 range of 4.83–14.49 μM. By comparison, the reference drugs doxorubicin, afatinib, and celecoxib yielded IC50 values of 3.18–26.79, 6.20–11.40, and 22.79–42.74 μM, respectively. Furthermore, in vitro COX-1/COX-2 inhibition testing showed that the compounds 4b, 6c, 10b, and 10c exhibited effective COX-2 inhibition, with IC50 values of 0.40–1.20 μM, and selectivity index (SI) values of >62.50–20.83, using celecoxib as a reference drug (IC50 = 0.11 μM; COX-2 SI: >227.20). Compounds 6c and 10c, which were potent COX-2 inhibitors, were docked into the COX-2 binding site, where these compounds exhibited strong interactions.