A Methyl-Substituted Spiro-Hydroquinone Exerts Antiplatelet Activity by Blocking Mitochondrial Function In Vitro

The primary goal of antiplatelet therapy is to inhibit platelet aggregation without increasing the risk of bleeding. Treatment resistance and recurrence of thrombotic events are common, underscoring the need to identify new molecules with antiplatelet activity. In this research, we synthesized and characterized spiro-hydroquinone derivatives substituted with various aliphatic chain lengths (1-9 carbons) and evaluated the effect of these modifications on platelet activation. The structure-activity relationship study revealed that increasing the aliphatic chain length did not enhance antiplatelet activity; instead, it increased cytotoxicity and negatively affected solubility. Notably, the shortest molecule, SD3A, inhibits mitochondrial function and acts selectively on collagen-mediated activation, resulting in reduced thrombus formation without affecting coagulation, thereby representing a low risk of bleeding in vitro. These results identify ortho-carbonylhydroquinone spiro derivatives, specifically SD3A, as a promising antiplatelet molecule, demonstrating an optimal combination of low cytotoxicity and pathway-selective activity against collagen.