2. Academic Validation
  3. A Methyl-Substituted Spiro-Hydroquinone Exerts Antiplatelet Activity by Blocking Mitochondrial Function In Vitro

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

  • ACS Pharmacol Transl Sci. 2025 Oct 30;8(11):4122-4137. doi: 10.1021/acsptsci.5c00541.
Lisandra Morales-Malvarez 1,  Diego Méndez 2,  Bessy Deras 3,  Héctor Leonardo Montecino-Garrido 4,  Felipe Lagos 4,  Diego Arauna 5,  Victoria Villalobos 5,  Ramiro Araya-Maturana 6,  Eduardo Fuentes 5
Affiliations

Affiliations

  • 1 Doctorado en Ciencias mención Investigación y Desarrollo de Productos Bioactivos, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca 3460000, Chile.
  • 2 Doctorado en Ciencias Biomédicas, Faculty of Health Sciences, Universidad de Talca, Talca 3460000, Chile.
  • 3 Universidad Nacional Autónoma de Honduras, Tegucigalpa 11101, Honduras.
  • 4 Centro de Estudios en Alimentos Procesados (CEAP), Fortalecimiento Científico Centros Regionales ANID R20F0001, Talca 3460000, Chile.
  • 5 Thrombosis and Healthy Aging Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca 3460000, Chile.
  • 6 Instituto de Química de Recursos Naturales, Universidad de Talca, Talca 3460000, Chile.
PMID: 41262561 DOI: 10.1021/acsptsci.5c00541
Abstract

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.

Keywords

antiplatelet; collagen; hydroquinones; mitochondria; spiro-derivatives; thrombosis.

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