Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

被引：14

作者：

Cox, Brian ^{[2
]}

Duffy, James ^{[1
]}

Zdorichenko, Victor ^{[2
]}

Bellanger, Corentin ^{[2
]}

Hurcum, Jessica ^{[3
]}

Laleu, Benoit ^{[1
]}

Booker-Milburn, Kevin, I ^{[4
,5
]}

Elliott, Luke D. ^{[4
]}

Robertson-Ralph, Michael ^{[5
]}

Swain, Christopher J. ^{[6
]}

Bishop, Stephen J. ^{[2
]}

Hallyburton, Irene ^{[7
]}

Anderson, Mark ^{[7
]}

机构：

[1] Med Malaria Venture, CH-1215 Geneva 15, Switzerland

[2] Univ Sussex, Photodivers Ltd, Sch Life Sci, Brighton BN1 9QJ, E Sussex, England

[3] Univ Sussex, Sch Life Sci, Brighton BN1 9QJ, E Sussex, England

[4] Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England

[5] Univ Bristol, Sch Chem, Photodivers Ltd, Bristol BS8 1TS, Avon, England

[6] Cambridge MedChem Consulting, Cambridge CB22 4RN, England

[7] Univ Dundee, Wellcome Ctr Antiinfect Res, Drug Discovery Unit, Dundee DD1 5EH, Scotland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 12期

基金：

英国工程与自然科学研究理事会;

关键词：

Drug discovery; antimalarial; photochemistry; sp(3)-rich substituted bridged pyrrolidines; 3D character; 2,4-METHANOPROLINE;

D O I：

10.1021/acsmedchemlett.0c00486

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We utilized synthetic photochemistry to generate novel sp 3 -rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-azabicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 mu M range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.

引用

页码：2497 / 2503

页数：7

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