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The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi , which cause human African trypanosomiasis (HAT) and Chagas disease, respectively, are responsible for considerable human suffering. Reduced case numbers and improved treatment options for HAT provide hope, but the outlook for Chagas disease is less promising, and safer, more efficacious chemotherapy is sorely needed. We previously reported the discovery and optimisation of a novel class of potent and selective trypanosomacidal 2-[(2-phenylthiazolyl)ethyl]ureas active against both T. brucei brucei and T. cruzi . In the current work, replacement of the core thiazole with alternative heterocycles has revealed that a contiguous arrangement of phenyl substituent, hydrogen-bond-accepting nitrogen, and alkyl linker are required to maintain activity. Compared to the parent thiazole, increased polarity of the core heterocycle in triazoles, tetrazoles and pyrimidines, leads to a drop in potency against T. b. brucei . A 2,6-disubsituted pyridine is tolerated but in general, 5-membered heterocycles are preferred. Analogues with oxazole, pyrazole and isomeric ('reverse') pyrazole cores displayed comparable T. b. brucei potency and selectivity to the parent thiazole, and in some cases improved lipophilic ligand efficiencies and metabolic stability. These compounds possessing more polar core heterocycles were generally 2-4 times less potent against T. cruzi (compared to T. b. brucei ). This study demonstrates robust structure-activity relationships across a variety of heterocyclic scaffolds, providing many options for further optimisation of this class of compounds., Competing Interests: The authors have no competing financial or other conflicts of interests., (This journal is © The Royal Society of Chemistry.)