Laurequinone-based synthetic quinones as agents against Leishmania amazonensis

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.