2. Academic Validation
  3. Laurequinone-based synthetic quinones as agents against Leishmania amazonensis

Laurequinone-based synthetic quinones as agents against Leishmania amazonensis

  • Bioorg Chem. 2025 Sep:164:108897. doi: 10.1016/j.bioorg.2025.108897.
Sara García-Davis 1,  Atteneri López-Arencibia 2,  Carlos J Bethencourt-Estrella 2,  Ana R Díaz-Marrero 3,  Jacob Lorenzo-Morales 2,  José E Piñero 2,  José J Fernández 4
Affiliations

Affiliations

  • 1 Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain; Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
  • 2 Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez s/n, 38206 La Laguna, Tenerife, Spain; Consorcio Centro de Investigación Biomédica en Red M.P. de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28006 Madrid, Spain; Departamento de Obstetricia y Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Avenida Astrofísico Francisco Sánchez s/n, 38206 La Laguna, Tenerife, Spain.
  • 3 Instituto de Productos Naturales y Agrobiología (IPNA), Consejo Superior de Investigaciones Científicas (CSIC), Avenida Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain; Biotecnología Marina, Unidad Asociada al IPNA-CSIC por el IUBO-ULL, 38206 La Laguna, Tenerife, Spain. Electronic address: adiazmar@ipna.csic.es.
  • 4 Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain; Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain; Biotecnología Marina, Unidad Asociada al IPNA-CSIC por el IUBO-ULL, 38206 La Laguna, Tenerife, Spain. Electronic address: jjfercas@ull.edu.es.
PMID: 40865236 DOI: 10.1016/j.bioorg.2025.108897
Abstract

Leishmaniasis affect millions of people worldwide and current treatment options against these protozoa Parasite are limited and induce multiple undesired effects. To develop alternative treatments against Leishmania amazonensis, this work explores new synthetic compounds based on the marine natural sesquiterpene laurequinone (1). Using a molecular simplification strategy focused on the elimination of stereogenic centers, the fragment 2-(1S,2R,5R)-1,2-dimethylbicyclo [3.1.0]hexan-2-yl in laurequinone was modified to a cyclopentyl moiety in 2 position to afford an active lead compound prototype 2. Optimization by homologation of the cyclopentyl ring to a cyclohexyl leads to the most active compound of the series, 2-cyclohexyl-5-methylcyclohexa-2,5-diene-1,4-dione (6), with an IC50 of 0.29 ± 0.05 μM and a selectivity index of 43.0 against promastigotes of L. amazonensis. Compound 6, which pharmacophore moiety resembles that of ubiquinone, causes a decrease in the mitochondrial membrane potential and a reduction in ATP production levels, leading to an excess of ROS. These effects in the Parasite mitochondrion could be rationalized by a blockage in the electron transport chain, where ubiquinone intervenes.

Keywords

Laurequinone; Leishmania amazonensis; Leishmaniasis; Synthetic quinone.

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