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

Abstract

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 falciparum 3D7 are presented. Remarkably, in vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071–1.8 μm), outperforming the clinical reference drug ganciclovir (EC50 2.6 μm). Against P. falciparum 3D7, 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).

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

“…Artemisinin, its semisynthetic derivative artesunate (ART) and related chemical compounds represent a promising antiherpesviral lead compound scaffold, which has intensively been investigated by our research group [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] and by other researchers [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. While the original drug artemisinin proved to be poor in anticytomegaloviral activity, its semisynthetic derivative ART possessed a relatively broad antiviral activity that extended over HCMV to other herpesviruses and even human pathogenic viruses of other families [ 17 , 23 , 24 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ].…”