Design, synthesis and bioactive evaluation of novel quinoline-linked sulfonamide-pyridine derivatives as PI3K/HDAC dual-target inhibitors

In the treatment of malignant tumors, dual-target inhibitors can effectively avoid the compensatory activation of other signaling pathways caused by single-target administration, as well as the pharmacokinetic changes and poor patient compliance associated with co-administration. For this study, we selected phosphatidylinositol 3-kinase (PI3K) and histone deacetylase (HDAC), two critical targets in tumor cell development, and designed dual inhibitors displaying various types and lengths of linkage chains. A quinoline-linked sulfonamide-pyridine fragment as the pharmacophore for PI3K inhibition, and an o-aminobenzamide fragment as the pharmacophore for the Zn²⁺-binding group (ZBG) of HDAC have been chosen in order to maximize the pharmacokinetic properties of both targets. Using these linkage chains, we designed 41 novel quinoline-linked sulfonamide-pyridine PI3K/HDAC dual-target inhibitors with unique structures. Most of these compounds exhibited strong antiproliferative effects on Jurkat, K562, MCF-7, and PC9R cells. Specifically, SJY26 not only demonstrated potent antiproliferative activity against tumor cells but also exhibited outstanding inhibitory activity against PI3Kα and HDAC1. Moreover, SJY26 significantly inhibited the migration of PC9R cells at 1.25 μM, reduced AKT phosphorylation, and decreased histone H3 deacetylation. In summary, this research highlights the promising therapeutic potential of novel quinoline-linked sulfonamide-pyridine derivatives as PI3K/HDAC dual-target inhibitors, warranting further investigation.