The planning, synthesis and antiparasitic evaluation of 1,2,4-oxadiazole-N-acylhydrazones have been the main research effort at the SintMed®. As the result, novel series of compounds exhibiting trypanocidal activity have been identified, targeting the molecular optimization and better understanding of their mechanisms of action. The association between the heterocycle 1,2,4-oxadiazole and the N-acylhydrazone scaffold guarantees the emergence of a large library of compounds potentially active against Trypanosoma cruzi. New 3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl-N-acylhydrazone derivatives have been found to disclose good outcomes, therefore, their molecular optimization has been investigated in order to discover new potent antiparasitic agents. The title compounds were synthesised under the catalysis of CeCl3 in short reaction times, high purity and stereoselectivity, leading exclusively to the E-isomers. Therefore, such compounds fulfil all necessary conditions required to the biological evaluation.