One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites.
One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites.
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DOI：
10.1016/j.ejmech.2018.09.018
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发表时间：
2018-10-05
影响因子：
6.7
通讯作者：
Hansen FK
中科院分区：
文献类型：
--
作者：
Diedrich D;Stenzel K;Hesping E;Antonova-Koch Y;Gebru T;Duffy S;Fisher G;Schöler A;Meister S;Kurz T;Avery VM;Winzeler EA;Held J;Andrews KT;Hansen FK
疟疾药物发现已经从关注靶向无性血液阶段寄生虫转变为开发也可以靶向红细胞外形式和/或配子体的药物，以预防疟疾和/或寄生虫传播。在这项工作中，我们的目的是开发寄生虫选择性组蛋白脱乙酰酶抑制剂（HDACi），其具有针对疟原虫疟疾寄生虫的致病无性血液阶段的活性以及具有因果预防和/或传播阻断性质。使用通过顺序Ugi四组分反应和羟基胺解的优化的一锅法、多组分方案来制备一组基于类肽的HDACi。几种化合物显示出针对药物敏感性和耐药性恶性疟原虫无性血液阶段的有效活性、高寄生虫选择性和针对伯氏疟原虫的红细胞外形式的亚微摩尔活性。我们的优化研究发现了命中化合物1u，其结合了对无性血液阶段寄生虫的高活性（Pf 3D 7 IC 50：4 nM; Pf Dd 2 IC 50：1 nM）和伯氏疟原虫红细胞外型（Pb EEF IC 50：25 nM），具有有希望的寄生虫特异性活性（SIPf 3D 7/HepG 2：2496，SIPf Dd 2/HepG 2：9990和SIPb EEF/HepG 2：400）。
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 exo-erythrocytic forms (Pb EEF IC50: 25 nM) with promising parasite-specific activity (SIPf 3D7/HepG2: 2496, SIPf Dd2/HepG2: 9990, and SIPb EEF/HepG2: 400).
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DOI：
10.1016/j.ijpddr.2015.05.004
发表时间：
2015-12
期刊：
International journal for parasitology. Drugs and drug resistance
影响因子：
--
作者：
Engel JA;Jones AJ;Avery VM;Sumanadasa SD;Ng SS;Fairlie DP;Skinner-Adams T;Andrews KT
通讯作者：
Andrews KT
影响因子：
6.7
作者：
Hansen FK;Sumanadasa SD;Stenzel K;Duffy S;Meister S;Marek L;Schmetter R;Kuna K;Hamacher A;Mordmüller B;Kassack MU;Winzeler EA;Avery VM;Andrews KT;Kurz T
通讯作者：
Kurz T
影响因子：
7.3
作者：
Hailu, Gebremedhin S.;Robaa, Dina;Mai, Antonello
通讯作者：
Mai, Antonello
影响因子：
4.9
作者：
Gebru, Tamirat;Mordmueller, Benjamin;Held, Jana
通讯作者：
Held, Jana
影响因子：
11.5
作者：
Garnock-Jones, Karly P.
通讯作者：
Garnock-Jones, Karly P.