Abstract
BackgroundCanine leishmaniasis is a zoonotic disease caused by Leishmania infantum, being the dogs one of the major reservoirs of human visceral leishmaniasis. DNA topology is a consolidated target for drug discovery. In this regard, topoisomerase IB – one of the enzymes controlling DNA topology – has been poisoned by hundreds of compounds that increase DNA fragility and cell death. Aromathecins are novel molecules with a multiheterocyclic ring scaffold that have higher stability than camptothecins.ResultsAromathecins showed strong activity against both forms of L. infantum parasites, free-living promastigotes and intra-macrophagic amastigotes harbored in ex vivo splenic explant cultures obtained from infected BALB/c mice. However, they prevented the relaxation activity of leishmanial topoisomerase IB weakly, which suggests that the inhibition of topoisomerase IB partially explains the antileishmanial effect of these compounds. The effect of aromathecins was also studied against a strain resistant to camptothecin, and results suggested that the trafficking of these compounds is not through the ABCG6 transporter.ConclusionsAromathecins are promising novel compounds against canine leishmaniasis that can circumvent potential resistances based on drug efflux pumps.
Highlights
Canine leishmaniasis is a zoonotic disease caused by Leishmania infantum, being the dogs one of the major reservoirs of human visceral leishmaniasis
We describe the antileishmanial activity of two series of aromathecins, which have been kindly provided by Dr Mark Cushman (Dpt. of Medicinal Chemistry, Purdue University, Indiana, USA), against both stages of L. infantum; free-living promastigotes and intra-macrophagic amastigotes present in splenic explants obtained from infected BALB/c mice
Two series of aromathecins (Table 1) have been tested against both stages of L. infantum, free-living promastigotes and intracellular amastigotes harbored in mouse splenic cells
Summary
Canine leishmaniasis is a zoonotic disease caused by Leishmania infantum, being the dogs one of the major reservoirs of human visceral leishmaniasis. DNA topology is a consolidated target for drug discovery. Canine leishmaniasis (CanL) is a serious zoonotic disease caused by L. infantum in the Old World and L. infantum chagasi in the New World. Dogs affected by this disease become reservoirs of human visceral leishmaniasis, being extremely relevant the presence of L. infantum as its subspecies in Latin America, mainly in Brazil. DNA topoisomerases are consolidated targets for drug development in cancer and infectious diseases. DNA topoisomerase IB (TopIB) is involved in relaxing supercoiled DNA by a DNA breaking and rejoining process. In this process TopIB cleaves one DNA strand by nucleophilic attack from the catalytic tyrosine placed in the active site, which becomes linked to 3′ phosphate end of Reguera et al BMC Veterinary Research (2019) 15:405
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