title: Improvement of both plasmepsin inhibitory activity and antimalarial activity by 2-aminoethylamino substitution.
abstract: We attached 2-aminoethylamino groups to allophenylnorstatine-containing plasmepsin (Plm) inhibitors and investigated SAR of the methyl or ethyl substitutions on the amino groups. Unexpectedly, compounds 22 (KNI-10743) and 25 (KNI-10742) exhibited extremely potent Plm II inhibitory activities (K(i)<0.1 nM). Moreover, among our peptidomimetic Plm inhibitors, we identified the compounds with the highest antimalarial activity using a SYBR Green I-based fluorescence assay.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Miura
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Uemura
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kashimoto
authors.forename: Yuto
authors.initials: Y
authors.lastname: Hori
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ruben
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010654:Phenylbutyrates / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D005029:Ethylenediamines; C553339:KNI 10742; C553338:KNI 10743; D010654:Phenylbutyrates; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D013844:Thiazoles; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II