Deeper Insight into the Six-Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

被引：6

作者：

Bock, Christina M. ^{[1
,2
]}

Parameshwarappa, Gangajji ^{[1
,2
]}

Boenisch, Simon ^{[3
,4
]}

Bauer, Walter ^{[1
,2
]}

Hutterer, Corina ^{[5
]}

Leidenberger, Maria ^{[6
]}

Friedrich, Oliver ^{[6
]}

Marschall, Manfred ^{[5
]}

Kappes, Barbara ^{[6
]}

Goerling, Andreas ^{[3
,4
]}

Tsogoeva, Svetlana B. ^{[1
,2
]}

机构：

[1] Friedrich Alexander Univ Erlangen Nurnberg, Inst Organ Chem 1, Henkestr 42, D-91054 Erlangen, Germany

[2] Friedrich Alexander Univ Erlangen Nurnberg, Interdisciplinary Ctr Mol Mat, Henkestr 42, D-91054 Erlangen, Germany

[3] Friedrich Alexander Univ Erlangen Nurnberg, Chair Theoret Chem, Egerlandstr 3, D-91058 Erlangen, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Interdisciplinary Ctr Mol Mat, Egerlandstr 3, D-91058 Erlangen, Germany

[5] Friedrich Alexander Univ Erlangen Nurnberg, Inst Clin & Mol Virol, Schlossgarten 4, D-91054 Erlangen, Germany

[6] Friedrich Alexander Univ Erlangen Nurnberg, Inst Med Biotechnol, Paul Gordan Str 3, D-91052 Erlangen, Germany

来源：

CHEMISTRYOPEN | 2017年 / 6卷 / 03期

关键词：

antimalarial agents; antiviral agents; density functional calculations; domino reactions; organocatalysis; ARTEMISININ-DERIVED DIMERS; DIELS-ALDER REACTIONS; HUMAN LEUKEMIA-CELLS; ASYMMETRIC ORGANOCATALYSIS; CONTIGUOUS STEREOCENTERS; PLASMODIUM-FALCIPARUM; ENANTIOSELECTIVE CONSTRUCTION; HUMAN CYTOMEGALOVIRUS; QUATERNARY CENTERS; HYBRID MOLECULES;

D O I：

10.1002/open.201700005

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The straightforward and efficient synthesis of complex aza- and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal-free six-step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen-containing molecules. Presented here is a deeper investigation of this atom-economical domino process by extending the scope of aldehydes, performing post-modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi-empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin-containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparum3D7 are presented. Remarkably, invitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071-1.8 mu M), outperforming the clinical reference drug ganciclovir (EC50 2.6 mu m). Against P.falciparum3D7, three of the investigated artemisinin-derived domino products (EC50 0.72-1.8 nM) were more potent than the clinical drug chloroquine (EC50 9.1 nM).

引用

页码：364 / 374

页数：11