Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis

Lotta Glans; Wanning Hu; Christian Jöst; Carmen de Kock; Peter J. Smith; Matti Haukka; Heike Bruhn; Ulrich Schatzschneider; Ebbe Nordlander

doi:10.1039/C2DT30077J

Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis†

Lotta Glans,^a Wanning Hu,^b Christian Jöst,^a Carmen de Kock,^c Peter J. Smith,^c Matti Haukka,^d Heike Bruhn,^e Ulrich Schatzschneider*^b and Ebbe Nordlander*^a

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* Corresponding authors

^a Inorganic Chemistry Research Group, Chemical Physics, Center for Chemistry and Chemical Engineering, Lund University, Box 124, SE-221 00 Lund, Sweden
E-mail: Ebbe.Nordlander@chemphys.lu.se
Fax: +46 46 222 4119
Tel: +46 46 222 8118

^b Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany
E-mail: ulrich.schatzschneider@uni-wuerzburg.de
Fax: +49 931 31 84605
Tel: +49 931 31 83636

^c Division of Pharmacology, Department of Medicine, University of Cape Town Medical School, Observatory 7925, South Africa

^d Department of Chemistry, University of Eastern Finland, Box 111, FIN-80101 Joensuu, Finland

^e Institut für Molekulare Infektionsbiologie, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2 D15, D-97080 Würzburg, Germany

Abstract

Organometallic analogues of chloroquine show promise as new antimalarial agents capable of overcoming resistance to the parent drug chloroquine. Here, the synthesis and characterization of three new cymantrene (CpMn(CO)₃) and cyrhetrene (CpRe(CO)₃) 4-aminoquinoline conjugates with either an amine or amide linker are reported. The antimalarial activity of the new organometallic conjugates N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide (3), N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide (4) and N-(7-chloroquinolin-4-yl)-N′-(cymantrenylmethyl)ethane-1,2-diamine (6) was evaluated against a chloroquine-sensitive (CQS) and a chloroquine-resistant strain (CQR) of the malaria parasite Plasmodium falciparum. The cymantrene complex with an amine linker (6) showed good activity against the CQS strain but was inactive against the CQR strain. In contrast, cymantrene and cyrhetrene compounds with an amide linker were active against both the CQS and the CQR strain. In addition, the antibacterial, anti-trypanosomal and anti-leishmanial activity of the compounds was evaluated. Compound 6 showed submicromolar activity against Trypanosoma brucei at a concentration where the toxicity to normal human cells is low. No significant effect was noticed on the exchange of manganese for rhenium in the CpM(CO)₃ moiety in any of the biological assays.

This article is part of the themed collection: Application of Inorganic Chemistry for non-Cancer Therapeutics

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Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis†

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Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis

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