Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

Nemorosone (Nem) and guttiferone A (GutA) are acyl phloroglucinol derivatives (APD) that are present in different natural products. For both compounds anti-cancer and anti-microbial properties have been reported. In particular, an anti-leishmanial activity of both compounds was demonstrated. The aim of this study was to explore the possible role of mitochondria in the anti-leishmanial activity of Nem and GutA in comparison with their action on mammalian mitochondria. Both APD inhibited the growth of promastigotes of Leishmania tarentolae (LtP) with half maximal inhibitory concentration (IC50) values of 0.67 +/- 0.17 and 6.2 +/- 2.6 mu M; while IC50 values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29.5 +/- 3.7 and 9.2 +/- 0.9 mu M, respectively. Nemorosone strongly inhibited LtP oxygen consumption, caused species-specific inhibition (P < 0.05) of succinate: ubiquinone oxidoreductase (complex II) from LtP-mitochondria and significantly increased (P < 0.05) the mitochondrial superoxide production. In contrast, GutA caused only a moderate reduction of respiration in LtP and triggered less superoxide radical production in LtP compared with Nem. In addition, GutA inhibited mitochondrial complex III in bovine heart submitochondrial particles, which is possibly involved in its mammalian toxicity. Both compounds demonstrated at low micromolar concentrations an effect on the mitochondrial membrane potential in LtP. The present study suggests that Nem caused its anti-leishmanial action due to specific inhibition of complexes II/III of mitochondrial respiratory chain of Leishmania parasites that could be responsible for increased production of reactive oxygen species that triggers parasite death.