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More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.

The properties and morphologies of blends of poly(butylene succinate) (PBS) and glycerol-plasticized thermoplastic starch (TPS) were investigated. Bis-pyrrolidone-type monomers (obtained from itaconic acid) with various sizes of alkylidene spacers were synthesized and polycondensed with various diamines. The resultant polycondensates were used as compatibilizers to improve interfacial adhesion in PBS/starch blends. The presence of long hydrophobic -CH2- sequences in the compatibilizers improved the elongation-at-break during tensile tests. The enhanced compatibilization induced by these copolymers is presumably because of the hydrophobic interaction with PBS and the hydrophilic hydrogen bonding with starch. The uncompatibilized TPS/PBS exhibited a dispersed morphology with blends of low- and high-starch content, whereas the compatibilized blends presented a co-continuous phase. Bis-pyrrolidone-type monomers (obtained from itaconic acid, which is a renewable chemical identified in the top 12 value-added chemicals from biomass) with alkylidene spacers of variable size were synthesized and polycondensed with various diamines. The resulting polycondensates were used as compatibilizers to improve interfacial adhesion in poly (butylene succinate) (PBS)/plasticized starch blends. The interfacial adhesion between PBS and plasticized starch was improved using these polycondensates.