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

摘要

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13-17.95 mu M), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-alpha. Compounds 4a and 13 potently inhibited TNF-alpha (IC50 values: 2.01 and 6.72 mu M, respectively) compared with celecoxib (IC50=6.44 mu M). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 mu M, respectively) comparable to that of celecoxib (IC50=0.68 mu M). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 mu M, respectively) compared with the reference drug roflumilast (IC50=1.55 mu M). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.