Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment

被引：10

作者：

Johansson, Niklas G. ^{[4
]}

Turku, Ainoleena ^{[4
]}

Vidilaseris, Keni ^{[1
]}

Dreano, Loic ^{[4
]}

Khattab, Ayman ^{[5
]}

Perez, Daniel Ayuso ^{[4
]}

Wilkinson, Aaron ^{[6
]}

Zhang, Yuezhou ^{[4
]}

Tamminen, Matti ^{[4
]}

Grazhdankin, Evgeni ^{[4
]}

Kiriazis, Alexandros ^{[4
]}

Fishwick, Colin W. G. ^{[6
]}

Meri, Seppo ^{[5
]}

Yli-Kauhaluoma, Jari ^{[4
]}

Goldman, Adrian ^{[1
,2
,3
]}

af Gennas, Gustav Boije ^{[4
]}

Xhaard, Henri ^{[4
]}

机构：

[1] Univ Helsinki, Div Biochem, Dept Biosci, FI-00014 Helsinki, Finland

[2] Univ Leeds, Sch Biomed Sci, Leeds LS2 9JT, W Yorkshire, England

[3] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England

[4] Univ Helsinki, Drug Res Program, Div Pharmaceut Chem & Technol, Fac Pharm, FI-00014 Helsinki, Finland

[5] Univ Helsinki, Malaria Res Lab, Translat Immunol Res Program, Dept Bacteriol & Immunol,Haartman Inst, FI-00014 Helsinki, Finland

[6] Univ Leeds, Sch Chem, Leeds LS2 9JT, W Yorkshire, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 04期

基金：

英国生物技术与生命科学研究理事会; 芬兰科学院;

关键词：

Membrane-bound pyrophosphatase; protozoan diseases; drug design; isoxazoles; TRYPANOSOMA-BRUCEI; PUMPING PYROPHOSPHATASES; ACIDOCALCISOMES; BISPHOSPHONATES; TARGET;

D O I：

10.1021/acsmedchemlett.9b00537

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of small mPPase inhibitors with 6-10 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.

引用

页码：605 / 610

页数：6

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