title: Discovery of carbohybrid-based 2-aminopyrimidine analogues as a new class of rapid-acting antimalarial agents using image-based cytological profiling assay.
abstract: New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 μM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites.
authors.affiliation: Early Discovery Program, Institut Pasteur Korea , Seongnam-si, Gyeonggi-do 463-400, Korea.
authors.forename: Sukjun
authors.initials: S
authors.lastname: Lee
authors.forename: Donghyun
authors.initials: D
authors.lastname: Lim
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: Nakyung
authors.initials: N
authors.lastname: Lee
authors.forename: Hong-Gun
authors.initials: HG
authors.lastname: Lee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cechetto
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Sangmi
authors.initials: S
authors.lastname: Oh
authors.forename: Lawrence
authors.initials: L
authors.lastname: Ayong
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects*; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D015394:Molecular Structure; D016788:Plasmodium chabaudi / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011743:Pyrimidines; C012180:2-aminopyrimidine