Synthesis of Thymoquinone-Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents

Journal article

Publication Details

Author(s): Fröhlich T, Reiter C, Saeed MEM, Hutterer C, Hahn F, Leidenberger M, Friedrich O, Kappes B, Marschall M, Efferth T, Tsogoeva S
Journal: Acs Medicinal Chemistry Letters
Publication year: 2018
Volume: 9
Journal issue: 6
Pages range: 534-539
ISSN: 1948-5875


A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10 alpha-acetate 14 starting from a 1:1 mixture of C-10 alpha- to C-10 beta-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone artemisinin hybrids 6a/b stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy human foreskin fibroblasts and thus being selective. They exhibited EC50 values of 0.2 mu M against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Moreover, they showed to be five times more active than the standard drug ganciclovir and nearly eight times more active than artesunic acid against HCMV. In addition, hybrids 6a/b possessed excellent antimalarial activity (EC50 = 5.9/3.7 nM), which was better than that of artesunic acid (EC50 = 8.2 nM) and chloroquine (EC50 = 9.8 nM). Overall, most of the presented thymoquinone artemisinin-based hybrids exhibit an excellent and broad variety of biological activities (anticancer, antimalarial, and antiviral) combined with a low toxicity/high selectivity profile.

FAU Authors / FAU Editors

Friedrich, Oliver Prof. Dr. Dr.
Lehrstuhl für Medizinische Biotechnologie
Fröhlich, Tony
Professur für Organische Chemie
Hahn, Friedrich
Professur für Virologie
Kappes, Bärbel Prof. Dr.
Lehrstuhl für Medizinische Biotechnologie
Leidenberger, Maria
Lehrstuhl für Medizinische Biotechnologie
Reiter, Christoph
Professur für Organische Chemie
Tsogoeva, Svetlana Prof. Dr.
Professur für Organische Chemie

External institutions with authors

Johannes Gutenberg-Universität Mainz

How to cite

Fröhlich, T., Reiter, C., Saeed, M.E.M., Hutterer, C., Hahn, F., Leidenberger, M.,... Tsogoeva, S. (2018). Synthesis of Thymoquinone-Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents. Acs Medicinal Chemistry Letters, 9(6), 534-539.

Fröhlich, Tony, et al. "Synthesis of Thymoquinone-Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents." Acs Medicinal Chemistry Letters 9.6 (2018): 534-539.


Last updated on 2019-21-07 at 07:24