Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC₅₀) ranging from 0.12 to 10 μM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC₅₀ range, 0.17 to 5 μM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC₅₀, 1.97 μM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.Tropical diseases due to parasitic protozoa cause great mortality and disability in the less developed world. Malaria and kinetoplastid diseases such as human African trypanosomiasis (HAT, or sleeping sickness), Chagas'' disease, and leishmaniases are among the main neglected parasitic diseases, affecting hundreds of millions of people worldwide (http://www.dndi.org/index.php/diseases.html?ids=2). However, the low income of the affected populations does not make it financially attractive for pharmaceutical companies to invest in the development of new drugs against these diseases. The number of antiprotozoal drugs available is limited, and they are old, toxic, and losing efficacy due to the emergence of resistant parasites. New drugs are thus urgently needed (37).The landscape of drug discovery and development for new antiparasitic drugs has changed in the past few years thanks to financial backing from not-for-profit organizations and the involvement of public-private partnerships. The collaboration of various pharmaceutical companies with the Special Programme for Research and Training in Tropical Diseases (TDR), giving access to their compound libraries to help scientists search for new antiparasitic drugs, is a good example of the pragmatic approach required for the development of new medicaments for those neglected diseases (15, 32, 40). The screening of compound libraries to discover new hit and lead compounds against protozoan parasites has been used very efficiently by our group for the past few years. Very potent antiprotozoal compounds, active in vitro and in vivo against Trypanosoma brucei rhodesiense and Plasmodium falciparum, were identified by our group (16, 17, 38). These lead compounds were discovered by screening against T. brucei and P. falciparum a small library (<100 molecules) of dicationic compounds structurally related to known antiparasitic drugs (e.g., pentamidine, diminazene) but primarily synthesized by us for different medicinal targets.Following this successful approach, we have now selected from our in-house compound collection another series of polyamine molecules that possess the 1-phenethyl-4-aminopiperidine skeleton (Fig. ​(Fig.1).1). These molecules were anticipated to display antiprotozoal activity because they are structurally related to the known antitrypanosomal alkylpolyamines MDL27695 (7, 22), CHE-3-7-3 (5), and BW-1 (43) and particularly to the 4-aminopiperidine-based antimalarial agents described recently by Ellman and coworkers (8, 9). To test this hypothesis, 44 1-phenethyl-4-aminopiperidine derivatives were tested in vitro against four protozoan parasites responsible for HAT (T. brucei rhodesiense), Chagas'' disease (Trypanosoma cruzi), visceral leishmaniasis (Leishmania donovani), and malaria (P. falciparum). Two compounds found to be active in vitro (50% inhibitory concentrations [IC₅₀], <0.2 μM) and displaying acceptable selectivity toward the parasites (selectivity index [SI], >100) were subjected to in vivo assays in mouse models of acute HAT (T. b. brucei) or malaria (Plasmodium berghei). SI is defined as (50% cytotoxic concentration [CC₅₀] for L-6 cells)/(IC₅₀ for the parasite).Open in a separate windowFIG. 1.General structures of 1-phenethyl-4-aminopiperidine derivatives screened in this study and of known alkylpolyamine analogues with antiprotozoal activity.