Microwave-Enhanced Synthesis of 2-Styrylquinoline-4-Carboxamides With Promising Anti-Lymphoma Activity

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by significant clinical and molecular heterogeneity. Here, we report the design and synthesis of a novel series of 2-styrylquinoline-4-carboxamides via an efficient microwave-assisted organic synthesis (MAOS) approach. This strategy enabled the rapid and high-yielding isolation of derivatives 4a-z and 4aa-ah in three steps from commercially available isatin. Among the 34 compounds synthesized, 24 showed antiproliferative activity in vitro, with compound 4i displaying sub-micromolar IC₅₀ values across multiple lymphoma cell lines, including SU-DHL-8 and TOLEDO. Mechanism of action studies demonstrated that 4i was able to induce G₂/M cell-cycle arrest and DNA synthesis suppression, coupled with mitochondrial membrane depolarization and reactive oxygen species (ROS) accumulation, suggesting activation of the intrinsic apoptotic pathway. Importantly, active derivatives were nontoxic to healthy peripheral blood mononuclear cells (PBMCs), indicating a favorable therapeutic window. These results validate the quinoline scaffold as a promising chemotype, highlighting the utility of MAOS for the sustainable synthesis of bioactive heterocycles.