title: Cyclopropyl carboxamides, a chemically novel class of antimalarial agents identified in a phenotypic screen.
abstract: Malaria is one of the deadliest infectious diseases in the world, with the eukaryotic parasite Plasmodium falciparum causing the most severe form of the disease. Discovery of new classes of antimalarial drugs has become an urgent task to counteract the increasing problem of drug resistance. Screening directly for compounds able to inhibit parasite growth in vitro is one of the main approaches the malaria research community is now pursuing for the identification of novel antimalarial drug leads. Very recently, thousands of compounds with potent activity against the parasite P. falciparum have been identified and information about their molecular descriptors, antiplasmodial potency, and cytotoxicity is publicly available. Now the challenges are how to identify the most promising chemotypes for further development and how best to progress these compounds through a lead optimization program to generate antimalarial drug candidates. We report here the first chemical series to be characterized from one of those screenings, a completely novel chemical class with the generic name cyclopropyl carboxamides that has never before been described as having antimalarial or other pharmacological activities. Cyclopropyl carboxamides are potent inhibitors of drug-sensitive and -resistant strains of P. falciparum in vitro and show in vivo oral efficacy in malaria mouse models. In the present work, we describe the biological characterization of this chemical family, showing that inhibition of their still unknown target has very favorable pharmacological consequences but the compounds themselves seem to select for resistance at a high frequency.
authors.affiliation: Tres Cantos Medicine Development Campus, Diseases of the Developing World, GlaxoSmithKline, C Severo Ochoa 2,28760 Tres Cantos, Madrid, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.forename: M Belen
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.forename: Benigno
authors.initials: B
authors.lastname: Crespo
authors.forename: Cristina
authors.initials: C
authors.lastname: De-Cozar
authors.forename: M Jesus
authors.initials: MJ
authors.lastname: Almela
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: Pablo
authors.initials: P
authors.lastname: Castañeda
authors.forename: Javier
authors.initials: J
authors.lastname: Ibañez
authors.forename: Esther Pilar
authors.initials: EP
authors.lastname: Fernández
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herreros
authors.forename: Sonia
authors.initials: S
authors.lastname: Lozano
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rueda
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: Jose F
authors.initials: JF
authors.lastname: García-Bustos
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
chemical_list: D000577:Amides; D000962:Antimalarials