TY - JOUR
T1 - Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum
AU - Miura, Takuya
AU - Hidaka, Koushi
AU - Azai, Yukiko
AU - Kashimoto, Keisuke
AU - Kawasaki, Yuko
AU - Chen, Shen En
AU - De Freitas, Renato Ferreira
AU - Freire, Ernesto
AU - Kiso, Yoshiaki
N1 - Funding Information:
This research was supported in part by JSPS KAKENHI Grant Number 25460163 and Takada Science Foundation. E.F. would like to thank support from The National Institute of Health ( GM56550 and GM57144 ) and The National Science Foundation ( MCB-1157506 ). We gratefully acknowledge Mr. T. Hamada and Mr. H.-O. Kumada for mass spectrometry. We thank the Walter Reed Army Institute of Research for performing the antimalarial activity assays.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - The plasmepsins are specific aspartic proteases of the malaria parasite and a potential target for developing new antimalarial agents. Our previously reported peptidomimetic plasmepsin inhibitor with modified 2-aminoethylamino substituent, KNI-10740, was tested against chloroquine sensitive Plasmodium falciparum, D6, to be highly potent, however, the inhibitor exhibited about 5 times less activity against multi-drug resistant parasite (TM91C235). We hypothesized the potency reduction resulted from structural similarity between 2-aminoethylamino substituent of KNI-10740 and chloroquine. Then, we modified the moiety and finally identified compound 15d (KNI-10823), that could avoid drug-resistant mechanism of TM91C235 strain.
AB - The plasmepsins are specific aspartic proteases of the malaria parasite and a potential target for developing new antimalarial agents. Our previously reported peptidomimetic plasmepsin inhibitor with modified 2-aminoethylamino substituent, KNI-10740, was tested against chloroquine sensitive Plasmodium falciparum, D6, to be highly potent, however, the inhibitor exhibited about 5 times less activity against multi-drug resistant parasite (TM91C235). We hypothesized the potency reduction resulted from structural similarity between 2-aminoethylamino substituent of KNI-10740 and chloroquine. Then, we modified the moiety and finally identified compound 15d (KNI-10823), that could avoid drug-resistant mechanism of TM91C235 strain.
KW - Allophenylnorstatine
KW - Antimalarial drug
KW - Aspartic protease
KW - Drug-resistance
KW - Plasmepsin inhibitor
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U2 - 10.1016/j.bmcl.2014.02.051
DO - 10.1016/j.bmcl.2014.02.051
M3 - Article
C2 - 24631188
AN - SCOPUS:84897457641
SN - 0960-894X
VL - 24
SP - 1698
EP - 1701
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 7
ER -