Improvement of both plasmepsin inhibitory activity and antimalarial activity by 2-aminoethylamino substitution.
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.
Miura
Takuya
T
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Hidaka
Koushi
K
Uemura
Tsuyoshi
T
Kashimoto
Keisuke
K
Hori
Yuto
Y
Kawasaki
Yuko
Y
Ruben
Adam J
AJ
Freire
Ernesto
E
Kimura
Tooru
T
Kiso
Yoshiaki
Y
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
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