The small molecule 4-hydroxy-3-methoxybenzaldehyde (5,6,7,8-tetrahydro[1]benzothieno[2,3-
d]pyrimidin-4-yl)hydrazone (Exo2) stimulates morphological changes at the mammalian Golgi and
trans-Golgi network that are virtually indistinguishable from those induced by brefeldin A. Both
brefeldin A and Exo2 protect cells from intoxication by Shiga(-like) toxins by acting on other
targets that operate at the early endosome, but do so at the cost of high toxicity to target cells. The
advantage of Exo2 is that it is much more amenable to chemical modification and here we report a
range of Exo2 analogues produced by modifying the tetrahydrobenzothienopyrimidine core, the
vanillin moiety and the hydrazone bond that links these two. These compounds were examined for
the morphological changes they stimulated at the Golgi stack, the trans Golgi network and the
transferrin receptor-positive early endosomes and this activity correlated with their inherent
toxicity towards the protein manufacturing ability of the cell and their protective effect against
toxin challenge. We have developed derivatives that can separate organelle morphology, target
specificity, innate toxicity and toxin protection. Our results provide unique compounds with low
toxicity and enhanced specificity to unpick the complexity of membrane trafficking networks
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