Borsari, ChiaraSantarem, NunoCoertzen, DinaMazzolari , AsiaCorfu, Alexandra IoanaCoelho, CatarinaBarbosa, FranciscaTamborini, LuciaBirkholtz, Lyn-MarieRaffellini , LorenzoKeminer, OliverBasilico, NicolettaParapini, SilviaGul, SherazCordeiro-da-Silva, AnabelaConti, Paola2026-03-052026-03-052025-12Borsari, C., Santarem, N., Coertzen, D. et al. 2025, 'From pan-active to parasite-selective antiparasitic agents : a scaffold hopping approach', European Journal of Medicinal Chemistry, vol. 300, art. 118195, pp. 1-14. https://doi.org/10.1016/j.ejmech.2025.118095.0223-5234 (print)1768-3254 (online)10.1016/j.ejmech.2025.118095http://hdl.handle.net/2263/108768AVAILABILITY DATA STATEMENT : Data will be made available on request.Vector-borne parasitic diseases (VBPDs) represent a major global public health concern, with human African trypanosomiasis (HAT), Chagas disease, leishmaniasis, and malaria collectively threatening millions of people, particularly in developing regions. Climate change may further influence their transmission and geographic spread, increasing the global burden. As drug resistance continues to rise, there is an urgent need for novel therapeutic agents to expand treatment options and limit disease progression. Exploiting a cell-based phenotypic approach, we had previously developed 1,3,4-oxadiazole derivatives, as broad-spectrum low-toxicity agents active against protozoan parasites including Plasmodium falciparum, Leishmania spp. and Trypanosoma brucei. Herein, we applied a scaffold-hopping approach to develop novel chemotypes by replacing the central 1,3,4-oxadiazole core with 1,2,4-oxadiazole and oxazole rings. A systematic investigation allowed us to generate two novel libraries of compounds and carry out extensive Structure-Activity-Relationship studies and early drug discovery pharmacological liability characterization. Starting from pan-active 1,3,4-oxadiazole-based antiparasitic agents, we identified two anti-kinetoplastid molecules bearing the 1,2,4-oxadiazole core and one promising anti-T. brucei agent featuring an oxazole core. Our work paves the way for the development of novel chemotypes to successfully fight parasitic infections.en© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.Human African trypanosomiasis (HAT)LeishmaniasisMalariaScaffold hopping1,2,4-OxadiazoleOxazoleChagas diseaseArticle