Progress in the Optimization of 4(1H)-Quinolone Derivatives as Antimalarials Targeting the Erythrocytic, the Exoerythrocytic and the Transmitting Stages of the Malaria Parasite

Malaria is one of the leading infectious diseases occurring mainly in tropical and subtropical areas. Although available antimalarial tools have reduced the number of fatalities, there is still an urgent need for the development of new and more efficacious treatments to cure and eradicate malaria especially due to emerging resistance to all antimalarial drugs. Research was initiated to revisit antimalarial compounds which were deemed unsuitable as a result of poor understanding of physicochemical properties and the optimization thereof. The 4(1H)-quinolones are a class of compounds with demonstrated activity against malaria parasites. Recent optimization of the long-known core led to two highly promising compounds, i.e. P4Q-391 and ELQ-300, with great selective activity against all stages of the parasite's life cycle and good physicochemical properties. In this paper, we discuss the key steps on the way to these compounds, which fuel hope to find a suitable treatment for the prevention, cure and eradication of malaria

Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(