Bioactivity of Farnesyltransferase Inhibitors Against Entamoeba histolytica and Schistosoma mansoni

In this study, we phenotypically screened E. histolytica and S. mansoni in vitro with the established FT inhibitors, lonafarnib and tipifarnib, and with 125 tipifarnib analogues previously screened against both the whole organism and/or the FT of Trypanosoma brucei and Trypanosoma cruzi. For E. histolytica, we also explored whether synergy arises by combining lonafarnib and metronidazole or lonafarnib with statins that modulate protein prenylation. We demonstrate the antiamebic and antischistosomal activities of lonafarnib and tipifarnib, and identify 17 tipifarnib analogues with more than 75% growth inhibition at 50 µM against E. histolytica. Apart from five analogues of tipifarnib exhibiting activity against both E. histolytica and S. mansoni, 10 additional analogues demonstrated antischistosomal activity (severe degenerative changes at 10 µM after 24 h). Analysis of the structure-activity relationship available for the T. brucei FT suggests that FT may not be the relevant target in E. histolytica and S. mansoni. For E. histolytica, combination of metronidazole and lonafarnib resulted in synergism for growth inhibition. Also, of a number of statins tested, simvastatin exhibited moderate antiamebic activity which, when combined with lonafarnib, resulted in slight synergism. Even in the absence of a definitive molecular target, identification of potent antiparasitic tipifarnib analogues encourages further exploration while the synergistic combination of metronidazole and lo...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research