title: Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis.
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.
authors.affiliation: Chemical Physics, Center for Chemistry and Chemical Engineering, Lund University, Lund, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Glans
authors.forename: Wanning
authors.initials: W
authors.lastname: Hu
authors.forename: Christian
authors.initials: C
authors.lastname: Jöst
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Matti
authors.initials: M
authors.lastname: Haukka
authors.forename: Heike
authors.initials: H
authors.lastname: Bruhn
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schatzschneider
authors.forename: Ebbe
authors.initials: E
authors.lastname: Nordlander
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D009942:Organometallic Compounds / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014345:Trypanosoma / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D009942:Organometallic Compounds; D014344:Trypanocidal Agents; C044679:manganese cyclopentadienyl tricarbonyl