One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites

被引：31

作者：

Diedrich, Daniela ^{[1
]}

Stenzel, Katharina ^{[1
,2
]}

Hesping, Eva ^{[2
]}

Antonova-Koch, Yevgeniya ^{[3
]}

Gebru, Tamirat ^{[4
]}

Duffy, Sandra ^{[2
]}

Fisher, Gillian ^{[2
]}

Schoeler, Andrea ^{[5
]}

Meister, Stephan ^{[3
]}

Kurz, Thomas ^{[1
]}

Avery, Vicky M. ^{[2
]}

Winzeler, Elizabeth A. ^{[3
]}

Held, Jana ^{[4
]}

Andrews, Katherine T. ^{[2
]}

Hansen, Finn K. ^{[1
,5
]}

机构：

[1] Heinrich Heine Univ Dusseldorf, Inst Pharmazeut & Med Chem, Univ Str 1, D-40225 Dusseldorf, Germany

[2] Griffith Univ, Griffith Inst Drug Discovery, Don Young Rd,Nathan Campus, Nathan, Qld 4111, Australia

[3] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA

[4] Eberhard Karts Univ Tubingen, Inst Tropenmed, Wilhelmstr 27, D-72074 Tubingen, Germany

[5] Univ Leipzig, Med Fac, Inst Pharm, Pharmaceut Med Chem, Bruderstr 34, D-04103 Leipzig, Germany

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 158卷

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

Peptoid; HDAC inhibitor; Histone deacetylase; Malaria; Plasmodium falciparum; PLASMODIUM-FALCIPARUM; ANTIMALARIAL ACTIVITY; DISCOVERY; DESIGN; ACETYLATION; CANCER; GENES;

D O I：

10.1016/j.ejmech.2018.09.018

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC50: 4 nM; Pf Dd2 IC50: 1 nM) and P. berghei exoerythrocytic forms (Pb EEF IC50: 25 nM) with promising parasite-specific activity (SIPf 3D7/HepG2: 2496, SIPf 3D7/HepG2:9990, and SIPb EEF/HepG2: 400). (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：801 / 813

页数：13

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