Photoredox and PIFA-mediated synthesis of N-aryl azacoumestanes: Antileukemic activity and venetoclax synergism in acute myeloid leukemia.

N-Aryl azacoumestanes, nitrogen-bridged analogs of natural coumestanes, represent a structurally appealing yet underexplored scaffold in medicinal chemistry. Here, we describe a concise three-step synthesis of these derivatives from 4-hydroxycoumarin and anilines, combining a visible-light [Ru(bpy)₃]Cl₂-mediated photoredox CC arylation with a PIFA-promoted intramolecular oxidative CN cyclization in 2,2,2-trifluoroethanol (TFE). This transformation furnishes the rigid fused azacoumestane core in up to 93% yield under mild, metal-free, room-temperature conditions. Screening of hypervalent iodine (III) reagents identified PIFA as uniquely effective, consistent with its higher oxidizing power and hydrogen-bond-assisted activation in TFE. Matched-pair comparison of rigid azacoumestanes (8a-g) and flexible precursors (7) did not support a uniform correlation between rigidity and activity; nevertheless, conformational restriction was beneficial for specific derivatives, with a pronounced effect observed for the ester-substituted derivative, LSO227. This lead compound inhibited MOLM-13 acute myeloid leukemia cells (IC₅₀ = 1.98 μM ± 0.37) with a selectivity index of 10 relative to PBMCs and induced mitochondria-mediated, cell-cycle-independent apoptosis. Combination studies revealed significant pharmacological synergism with venetoclax at sub-effective concentrations, consistently validated across four models using SynergyFinder+ (Bliss = 8.4, p = 0.032; Loewe = 14.23, p = 0.021; ZIP = 8.4, p = 0.032; HSA = 14.87, p = 0.019). In silico ADMET profiling supports an early-stage drug-like profile. Overall, this work introduces N-aryl azacoumestanes as a new bioactive scaffold, integrating an efficient synthetic route, rigidity-driven SAR insights, venetoclax-sensitizing activity, and a preliminary in silico early-stage drug-like profile.