Facile synthesis and biological evaluation of glomuferrin and rhizoferrin as ferroptosis inhibitors in rice blast disease

Iron homeostasis has recently emerged as a key determinant in the early stages of plant-pathogen interactions, particularly in phytopathogens that exploit iron-dependent cell death (known as ferroptosis) to initiate host invasion. In Pyricularia oryzae, the causal agent of rice blast disease, appressorium formation is tightly linked to ferroptotic events in germinating conidia. Accumulation of intracellular Fe3⁺ and reactive oxygen species (ROS) promotes lipid peroxidation, ultimately triggering conidial cell death and, consequently, appressorium maturation. Therefore, inhibition of ferroptosis by targeting fungal iron homeostasis represents a promising strategy to suppress appressorium development and block subsequent host infection. Rhizoferrin, an α-hydroxy carboxylate siderophore secreted by Rhizopus microspora, was identified as a suitable precursor of its ring-closed derivative glomuferrin. The obtainment of an unexpected succinimide intermediate within the synthetic pathway enabled the access to both rhizoferrin and, to our knowledge for the first time, glomuferrin. Chelation evaluation revealed that rhizoferrin exhibits significantly higher affinity for iron than glomuferrin. The effects of these siderophores on conidial germination and appressorium formation were evaluated in wild-type and strobilurin-resistant P. oryzae strains, at concentrations ranging from 5 mM to 200 μM. The promising activity observed, especially for rhizoferrin, highlights the potential of α-hydroxy carboxylate siderophores as ferroptosis inhibitors and offers new perspectives for their development in crop protection.