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

Abstract

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 μM), 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-α. Compounds 4a and 13 potently inhibited TNF-α (IC₅₀ values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC₅₀=6.44 μM). Compounds 4b and 13 potently inhibited COX-2 (IC₅₀ values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC₅₀=0.68 μM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC₅₀ values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC₅₀=1.55 μM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.

Highlights

• Antitumor 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.

Graphical Abstract

Keywords:

• Synthesis
• 2-cyclopentyloxyanisole scaffold
• antitumor activity
• enzyme inhibition assay; docking study

Acknowledgements

The authors thank the Deanship of Scientific Research and RSSU at the King Saud University for their technical support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

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.