Integrated Phenotypic and Transcriptomic Analysis of the Effects of a Novel Arylaminoalcohol on Plasmodium falciparum

Malaria remains the leading parasitic infection worldwide, and the effectiveness of antimalarial drugs is increasingly threatened by the emergence of multidrug-resistant Plasmodium falciparum (P. falciparum) strains. In this context, our team previously developed a series of novel aminopyridinemethanol derivatives, among which GBPS336 showed potent nanomolar activity against P. falciparum strains with reduced susceptibility to reference antimalarials. Here, we investigated the effects of GBPS336 on the intraerythrocytic developmental cycle and transcriptional response of the parasite by combining microscopic phenotyping with whole-transcriptome RNA sequencing (Illumina) of synchronized P. falciparum 3D7 cultures exposed or not to the compound. In GBPS336-treated cultures, microscopic analysis revealed reduced parasitaemia, a marked delay and disruption of intraerythrocytic development and morphological alterations indicative of a parasite stress response. Transcriptomic profiling identified 356 differentially expressed genes at H24 post-exposition in ring-stage cultures with enrichment in functional categories associated with erythrocyte invasion and the parasite–host interface. Altogether, these findings demonstrate the antimalarial activity of GBPS336 and highlight invasion-related pathways as a potentially important component of its mechanism of action. Further studies will be required to determine whether these pathways are directly affected and to identify the molecular target(s) underlying the activity of the compound.