Preclinical Optimization of antiplasmodial 3-Hydroxypropanamidines

Basic data for this project

Description

Malaria remains one of the most severe infectious diseases worldwide, causing high morbidity and mortality, particularly in sub‑Saharan Africa. Rising resistance to artemisinin derivatives and partner drugs threatens current therapies, creating an urgent need for antimalarials with novel mode of action and improved resistance profiles. We have developed 3‑hydroxypropanamidines (HPAs), a new chemotype combining features of aryl amino alcohol antimalarials with an amidine scaffold. The lead 7d (SAKK374), derived from TKK130, shows nanomolar potency against drug‑sensitive and resistant Plasmodium falciparum strains and clinical isolates. It inhibits heme detoxification, displays medium parasite‑killing kinetics, and cures infected mice after oral administration. HPAs also show a high barrier to resistance and favorable in vivo pharmacokinetics, while hERG K⁺ channel inhibition remains a key liability. Based on our filter system and MMV (Medicines for malaria venture) guidelines for preclinical drug development, the project will optimize HPAs by modifying the benzamidine moiety, replacing the phenanthrene core with alternative scaffolds, conducting comprehensive in vitro parasitology profiling (potency, selectivity, speed of action, resistance potential) and mode of action studies, evaluating pharmacokinetics, and assessing in vivo efficacy in mouse models, while carefully monitoring hERG K⁺ channel inhibition to enhance safety. This work aims to provide optimized HPA derivatives with improved efficacy and selectivity, advancing them toward late stage preclinical development.