Hit‐To‐Lead Optimization of a Pyridylpiperazine Class Against Malaria: Pharmacokinetic Profile and In Vivo Efficacy of Optimized Compounds

Malaria remains a significant global health challenge caused by Plasmodium parasites. Current antimalarial treatment strategies face mounting challenges due to the rapid development of drug resistance. This work aimed at the hit‐to‐lead optimization of a pyridylpiperazine class by evaluating the in vitro pharmacokinetic profile and the in vivo efficacy and safety against malaria. The systematic in vitro assessment of ADME properties for 10 previously selected bioactive compounds enabled a detailed structure–ADME relationship analysis. This process highlighted compounds 7 and 9 as having the most promising profiles for improved bioavailability. These optimized compounds were then tested in an in vivo murine model of malaria, and reduced the likelihood of mice developing cerebral malaria. Compound 7 emerged as the most effective, reducing parasitemia by up to 91.7%. These results successfully validate that chemical modifications to the toluyl fragment of the initial hit optimized the pharmacodynamic and pharmacokinetic parameters, yielding two candidates with suitable ADME profiles and proven in vivo efficacy against malaria. This work supports the further development of the pyridylpiperazine class against malaria and highlights the need to explore modifications on other parts of the molecular scaffold and elucidate their mechanism of action.