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

Abstract

L eishmaniasis is one of the 17 neglected tropical diseases (NTDs) assigned by the World Health Organization (WHO). NTDs affect 1 billion people worldwide (1). The primary occurrences are in low-income countries in sub-Saharan Africa, Asia, and Latin America, but the Mediterranean countries of Europe are also concerned (2). Among the NTDs is the group of "most neglected diseases," affecting the poorest, mainly rural areas, including leishmaniases, sleeping sickness (African trypanosomiasis), and Chagas' disease (3). These three NTDs have the highest rates of death. However, the NTD drug discovery pipeline is almost empty, thus leading to a lack of efficient and safe drugs (2, 4). Because of climate warming and tourism, the occurrence of leishmaniasis is also reported in states around the Mediterranean Sea (1).Leishmaniasis is caused by more than 20 species of protozoan parasites belonging to the genus Leishmania. The parasite life cycle is characterized by two morphological stages: extracellular flagellated promastigotes, occurring in the insect vector, and intracellular aflagellated amastigotes, occurring in the mammalian host. The promastigotes are transmitted by an insect bite into the skin of the host, where they are internalized by macrophages, dendritic cells, neutrophils, and fibroblasts and differentiate into amastigotes residing and replicating in parasitophorous vacuoles of these phagocytes. The parasites disseminate through the lymphatic and vascular systems. During the blood meal of an (uninfected) sand fly, amastigotes are transmitted back from the infected mammalian host to the insect vector and differentiate again into promastigotes (5, 6).The clinical outcome of leishmaniasis depends on the complex interactions between the virulence characteristics of the infecting species and the type of immune response of the host. There are three clinical forms: cutaneous, mucocutaneous, and visceral leishmaniases (6).Concerning the treatment of leishmaniasis, it is obvious that new drugs must circumvent the limitations of currently established chemotherapies, i.e., toxicity, long courses of treatment, the frequent need for parenteral administration, high costs in countries where the disease is endemic, and the emergence of resistance. Therefore, it is important not only to test and apply combinations of existing drugs to avoid resistance but also to develop new potential leishmanicidal compounds with alternative mechanisms, as well as vaccination strategies (7,8).Cysteine proteases (CPs) of parasites such as Plasmodium, Trypanosoma, and worms are druggable targets for developing a new promising strategy for chemotherapy based on protease inhi-

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (3): Kinetoplastids

“…To discriminate between host and parasite CPs, more selective inhibitors were synthesized based on both compounds. Compound s9 showed selective inhibitory potency against L. major CPC and L. mexicana CPB2.8, but not against mammalian CATHs B and L. It showed excellent IC50 against L. major promastigotes and amastigotes in vitro [103] .…”

Recent developments in the utility of saturated azaheterocycles in peptidomimetics

“…Schad et al reported a new class of antileishmanial aziridine-2,3-dicarboxylate-based synthetic peptides as inhibitors of cysteine proteases (CPs) in Leishmania major ( L. major ) parasite. 61 L. major causes leishmaniasis and is wide spread in low-income countries in sub-Saharan Africa, Asia, and Latin America. According to the World Health Organization (WHO), leishmaniasis is among the 17 neglected tropical diseases (NTDs).…”

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

“…These include peptide‐based inhibitors bearing an electrophilic warhead that covalently traps the catalytic thiolate such as dipeptidyl vinyl sulfone 1 , dipeptidyl α‐ketoheterocycles 2 and aziridinyl peptides (e.g. 3 ), semicarbazone 4 , thiosemicarbazones 5 , triazine nitrile 6 , natural compounds (e.g. morelloflavones 7 ), and a decorated fused benzo[ b ]thiophene inhibitor 8 acting through a time‐dependent bimodal mechanism of action (Figure ) …”