Design, synthesis and anti-bladder cancer activity of novel dihydroartemisinin-ibuprofen hybrids.

Bladder cancer imposes a heavy burden on global socio-economic systems. Despite some clinical benefits, it continues to exhibit elevated mortality due to its high recurrence rate. To address or mitigate the existing therapeutic limitations, novel dihydroartemisinin-ibuprofen hybrids (2a, 3a, 3b) were designed and synthesized. Our study demonstrated that among these hybrids, 2a showed the most potent anti-bladder cancer activity, with IC₅₀ values of 0.44 ± 0.08 μM in T24 cells and 0.49 ± 0.07 μM in 5637 cells, significantly surpassing the efficacy of the parent compound dihydroartemisinin. Furthermore, 2a displayed favorable selectivity indices of 10.25 and 9.20 against T24 and 5637 cells, respectively. Mechanistically, 2a induced G0/G1 phase cell cycle arrest by suppressing CDK4 and CyclinD1 expression, with molecular docking confirming its stable and selective binding to CDK4. Pharmacokinetic profiling in rats revealed a promising oral bioavailability of 16.4%, which surpassed in silico projections, along with rapid absorption evidenced by a Tmax of 1.0 h. Collectively, these findings identify compound 2a as a compelling therapeutic candidate, highlighting its dihydroartemisinin-inspired rational drug design strategy and its potential for advancing CDK4-targeted therapies in bladder cancer.