title: A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides.
abstract: Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.
authors.affiliation: †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Keurulainen
authors.affiliation: †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Vahermo
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Puente-Felipe
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sandoval-Izquierdo
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Benigno
authors.initials: B
authors.lastname: Crespo-Fernández
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guijarro-López
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Huertas-Valentín
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: de las Heras-Dueña
authors.affiliation: †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
authors.forename: Teppo O
authors.initials: TO
authors.lastname: Leino
authors.affiliation: †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Siiskonen
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell-Pages
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Castañeda-Casado
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: M Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Martínez-Martínez
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Viera
authors.affiliation: †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Kiuru
authors.affiliation: ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Calderón
authors.affiliation: †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000577:Amides; D000962:Antimalarials; D001549:Benzamides; D001562:Benzimidazoles; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels