In the course of our search for new protein farnesyltransferase inhibitors with antiparasitic activity, we found that addition of a methionine residue at position 2 of 3-arylthiophenes greatly improved enzyme inhibition. To investigate the influence of this methionine residue on FTase and antiparasitic activities, 29 novel tetrasubstituted thiophenes bearing methionine or analogous moieties were synthesised. These new derivatives were evaluated on human and Trypanosoma brucei protein farnesyltransferases and on proliferation of 4 protozoan parasites: Plasmodium falciparum, Trypanosoma brucei brucei, Trypanosoma cruzi and Leishmania donovani. Some compounds showed promising low micromolar or submicromolar activities on T. b. brucei and L. donovani confirming the potential of this new class as antiparasitic agents.