Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition.

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold and their antitumor activity was evaluated. Compounds , , , , , and had the most potent antitumor activity (IC range: 5.13-17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives , , , and were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds and potently inhibited TNF-α (IC values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC=6.44 μM). Compounds and potently inhibited COX-2 (IC values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC=0.68 μM). Compounds , , and inhibited PDE4B (IC values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC=1.55 μM). The molecular docking of compounds and with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.