alpha-Substituted norstatines as the transition-state mimic in inhibitors of multiple digestive vacuole malaria aspartic proteases.
The impact of moving the P1 side-chain from the beta-position to the alpha-position in norstatine-containing plasmepsin inhibitors was investigated, generating two new classes of tertiary alcohol-comprising alpha-benzylnorstatines and alpha-phenylnorstatines. Twelve alpha-substituted norstatines were designed, synthesized and evaluated for their inhibitory potencies against plasmepsin II and the plasmepsin IV orthologues (PM4) present in the digestive vacuole of all four Plasmodium species causing malaria in man. New synthetic routes were developed for producing the desired alpha-substituted norstatines as pure stereoisomers. The best compounds provided K(i) values in the nanomolar range for all PM4, with a best value of 110nM in PM4 from Plasmodium ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to Plasmodium falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor-protein binding affinities using the linear interaction energy method (LIE).
Orrling
Kristina M
KM
Department of Medicinal Chemistry, Uppsala University, BMC, Sweden.
Marzahn
Melissa R
MR
Gutiérrez-de-Terán
Hugo
H
Aqvist
Johan
J
Dunn
Ben M
BM
Larhed
Mats
M
D000614:Aminocaproates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013816:Thermodynamics
D000614:Aminocaproates; D000962:Antimalarials; D011480:Protease Inhibitors; D015800:Protozoan Proteins; C034495:3-amino-2-hydroxy-5-methylhexanoic acid; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II