Expanding the scope of N,N´-disubstituted diamines as antiparasitic agents

RECIO-BALSELLS, ALEJANDRO; FERREIRA, BIANCA; COSER, ELIZABETH; REIGADA, CHANTAL; PEREIRA, CA; COELHO, ADRIANO; LABADIE, GUILLERMO

Evento virtual

Conferencia; Network NTD Early Career Researcher Researcher Conference; 2021

University of Durham

Our group has synthesized a library of N,N'-disubstituted aliphatic diamines (N,N'-di) that displayed potent activity against several pathogenic parasites, including trypanosomatids (Trypanosoma cruzi, Leishmania donovani, Trypanosoma brucei) and apicomplexa (Plasmodium falciparum is and Toxoplasmosis gondii).In order to expand the scope as antiparasitic drug candidates, we selected nine derivatives to be tested in new World Leishmania species (L. amazoniensis-L.a., L. braziliensis-L.b. and L. infantum-L.i). Additionally, to elucidate the mechanism of action of these compounds, we selected eight diamines with potent activity against T. cruzi epimastigote and/or amastigote to determine if they are inhibitors of the Leishmania, showed activities below 1 µM against amastigotes for L.a. and L.i., and seven of them, for L.b. whereas the cytotoxicity values in bone-marrow-derived macrophage (BMDM) were in the range of 0.56-3.20 µM. Being more cytotoxic than for Vero cells. However, seven of the nine compounds presented Selectivity index (SI) >10 for L.a., five for L.i and four for L.b (SI= IC50-amast./EC50-BMDM). In addition, polyamines transport. All the selected compounds concerning compounds L2, L5 and L6, displayed SI>10 for the three species tested (N1,N8-bis(4-(benzyloxy)benzyl)octane-1,8-diamine, SI 15.1-21.5; N1,N12-dibenzyldodecane-1,12-diamine SI 14-22; N1,N12-bis(4-fluorobenzyl)dodecane-1,12-diamine 19-57).Preliminary results on the polyamine transport inhibition shown that some derivatives decrease the internalization of putrescine in T. cruzi epimastigotes. However, this inhibition was variable between analogs. In particular, Tc8 (N1,N10-dibenzyldecane-1,10-diamine) was the most potent polyamine transport inhibitor (IC50=10.5 µM), and also have as antichagasic (T. cruzi epimastigotes IC50=0.60 µM).In conclusion, diamines are promising antiparasitic compounds with potent activity against a wide range of Leishmania spp. In addition, part of the mechanism of action could be related to the inhibition of polyamine transport.