Synthesis and evaluation of potential antileishmanial trypanothione mimetics

There is still a paucity of new drugs available for potential clinical treatment of the parasitic disease Leishmania. We herein report potential mimics of oxidised trypanothione TS2, with the intention of disrupting the Leishmania parasite metabolism. Bis-sidechain and single sidechain compounds as potential TS2 mimics, were successfully designed from the crystal structure data interactions of the TS2-TryR complex and synthesised from commercially available compounds. In preliminary screening, compounds 11, 12 and 4 were found to be cytotoxic against Leishmania major amastigotes at 100 μM. Whereas, compounds 19 and 20 showed a maximal inhibition of Leishmania major amastigotes of 60% at 100 μM and 50% at 100 μM respectively. The nitrite assays with compounds 4, 11, 12, 19 and 20 showed no nitrite production for the macrophage cells. Compound 20 was inactive and compound 12 displayed partial activity against Trypanosoma brucei trypanothione synthase (inhibition at >45 μM). ADMET analysis revealed high total polar surface area values for the compounds tested, which may contribute to the reduced activity levels against Leishmania major. These findings offer a better understanding of structural modifications to improve conformational constraints and TPSA values, guiding the future development of trypanothione mimics against Leishmania parasites.