Trypanosomatids are causative agents of Chagas’ disease, sleeping sickness and Leishmaniasis. Since effective vaccines are lacking, the control of these diseases is based on vector control and chemotherapy. However, the drugs currently available are characterized by high toxicity, limited efficacy and problems of drug resistance are emerging. Therefore, there is an urgent requirement for new, safe and effective drugs. The drug discovery process against these parasites is hampered by the intrinsic biology of these organisms that can include intracellular stages or central nervous system involvement. Herein, we discovered novel flavonol-like compounds bearing heteroaromatic rings and biphenyl rings as potent antiparasitic agents.