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As there is a continuous need for novel anti-infectives, the present study aimed to fuse two modes of action into a novel 3-nitroimidazo[1,2- b ]pyridazine scaffold to improve antiparasitic efficacy. For this purpose, we combined known structural elements of phosphodiesterase inhibitors, a target recently proposed for Trypanosoma brucei and Giardia lamblia , with a nitroimidazole scaffold to generate nitrosative stress. The compounds were evaluated in vitro against a panel of protozoal parasites, namely Giardia lamblia , Trypanosoma brucei , T. cruzi , Leishmania infantum and Plasmodium falciparum and for cytotoxicity on MRC-5 cells. Interestingly, selective sub-nanomolar activity was obtained against G. lamblia , and by testing several analogues with and without the nitro group, it was shown that the presence of a nitro group, but not PDE inhibition, is responsible for the low IC 50 values of these novel compounds. Adding the favourable drug-like properties (low molecular weight, cLogP (1.2–4.1) and low polar surface area), the key compounds from the 3-nitroimidazo[1,2- b ]pyridazine series can be considered as valuable hits for further anti-giardiasis drug exploration and development. [Display omitted] • Analogues fusing a nitroimidazole moiety and a PDE inhibitor scaffold were prepared. • These compounds were tested in vitro against a panel of protozoal parasites. • Against Giardia lamblia , sub-nanomolar IC 50 values were determined. • PDE inhibition provided no significant contribution to the anti- Giardia potency. • High potency with drug-like properties warrants further study of this hit series. [ABSTRACT FROM AUTHOR]