Malaria is one of the most dangerous infectious diseases. Because the causative Plasmod-ium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutene-dione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase Pf GSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.
Bibliographical noteFunding Information:
Funding: The project was funded by the German Federal Ministry of Education and Research (BMBF BioDisc 7; 13GW0024) awarded to R.D. and C.K., A.A. is supported by a Jürgen Manchot-Stiftung fellowship. We acknowledge support by the German Research Foundation and the Open Access Publication Funds of Technische Universität Braunschweig.
The project was funded by the German Federal Ministry of Education and Research (BMBF BioDisc 7; 13GW0024) awarded to R.D. and C.K., A.A. is supported by a J?rgen Manchot-Stiftung fellowship. We acknowledge support by the German Research Foundation and the Open Access Publication Funds of Technische Universit?t Braunschweig.Acknowledgments: We are grateful to Sophia Reindl, Christian L?w and Samuel Pazicky for advice on the purification of recombinant Pf GSK-3.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Drug design
- Drug screening
- Friedel-Crafts reaction
- Glycogen synthase kinase-3
- Molecular docking
- drug design
- drug screening
- glycogen synthase kinase-3
- molecular docking