Discovery of New 4-Aminoquinoline–Thiazolidinone Hybrid Analogs as Antiproliferative Agents Inhibiting TLR4–LPS-Mediated Migration in Triple-Negative Breast Cancer Cells

Abstract

The Toll-like receptor 4 (TLR4) signaling pathway plays a leading role in triggering proinflammatory responses by targeting lipopolysaccharide (LPS) molecules from different bacteria. Meanwhile, it is also expressed at higher levels in breast cancer cells than in normal breast tissue. After LPS binding, it initiates downstream signaling pathways that promote inflammation and cell apoptosis. Thus, targeting TLR4–LPS presents a promising dual therapeutic strategy for breast cancer treatment by not only inhibiting tumor growth but also reducing inflammation within the tumor microenvironment. To achieve this, the discovery of a new antiinflammatory agent is needed to reduce LPS-mediated cancer cell proliferation and migration. In this study, a series of 4-aminoquinoline–thiazolidinone hybrid analogs (4a-m) have been synthesized to explore their antiinflammatory as well as anticancer activity to find a new lead. Among them, 4e revealed the most promising antiinflammatory (IC50 = 2.38 ± 0.77 μM) as well as anticancer activity (IC50 = 3.26 ± 1.06 μM) in RAW 267.7 cell line and triple-negative breast cancer (TNBC) cell line, respectively. Further structure–activity relationship study followed by MD simulation analysis was carried out to identify probable binding residues of TLR4 which may play a significant role in developing antiinflammatory activity for promoting cell apoptosis in cancer cells.