Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases.

Abstract

Leishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasites’ cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylates 13b and 13e, out of a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activity in vitro, while not showing cytotoxicity against host cells. In further investigations the mode of action was characterized in Leishmania major (L. major). It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CP C (CPC) and additionally mammalian CL. Although they induced cell death in Leishmania promastigotes and amastigotes in vitro, the induction of a pro-leishmanial T helper type 2 (Th2) response caused by host CL inhibition was observed in vivo. Therefore, we describe in the present study the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. They are based on 13b and 13e as lead structures. One of the most promising compounds of this series is s9, showing selective inhibition of the parasite CPs LmaCatB of L. major (a CB-like enzyme, also named: L. major CPC) and LmCPB2.8 ofLeishmania mexicana (L. mexicana) (a CL-like enzyme), while not affecting mammalian CLand CB. It displayed excellent leishmanicidal activity against L. major promastigotes (IC50 =37.4 μM) and amastigotes (IC50 = 2.3 μM).In summary, we demonstrated with s9 a new selective aziridine-2,3-dicarboxylatewhich might be a good candidate for future in vivo studies.