Tetrasubstituted 3-arylthiophenes represent a new class of potential antiparasitic agents. To improve solubility and cell penetration, modifications on the 3-aryl moiety were realized such as the introduction of heteroatoms or homologation of the aryl bond. Syntheses of these new molecules are described along with their inhibition on human and Trypanosoma brucei protein farnesyltransferases and on Plasmodium falciparum and Trypanosoma brucei proliferation. Two of these analogues demonstrated promising submicromolar activities against T. brucei parasites. Whether their actual target is protein farnesyltransferase remains to be clarified by further investigations.