Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K_iσ₁R = 38 ± 3.7; K_iσ₂R = 2917 ± 769 and HDACs IC₅₀ = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC₅₀ of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ₁R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.