| 1. |
- Ekengard, Erik, et al.
(författare)
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Antimalarial activity of ruthenium(ii) and osmium(ii) arene complexes with mono- and bidentate chloroquine analogue ligands.
- 2015
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 44:44, s. 19314-19329
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Tidskriftsartikel (refereegranskat)abstract
- Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands are salicylaldimine derivatives, where = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for , respectively. Ligand is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)()Cl] (Ru--Ru-, cym = p-cymene), [Os(η(6)-cym)()Cl] (Os--Os-, Os-, and Os-), [M(η(6)-cym)()Cl2] (M = Ru, Ru-; M = Os, Os-) and [M(η(6)-cym)()Cl]Cl (M = Ru, Ru-; M = Os, Os-). In complexes Ru--Ru- and Ru-, Os--Os-, Os- and Os- and Os-, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru- and Os-, monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes.
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| 2. |
- Glans, Lotta
(författare)
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Organometallic complexes with antimalarial properties
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malaria is a serious disease that causes around 800 000 deaths per year. Current malaria control efforts are hampered by the widespread resistance to common antimalarial drugs, such as the 4-aminoquinoline derivative called chloroquine. Previous research has shown that specific modifications of chloroquine, including inclusion of organometallic fragments into the organic framework, can result in compounds that are able to circumvent resistance. In the case of ferroquine, a ferrocene analogue of chloroquine, excellent results against both chloroquine sensitive and chloroquine resistant malaria parasites have been achieved and the drug has completed phase II clinical trials. This thesis describes the synthesis and evaluation of antimalarial activity of metal chloroquine analogues with an integrated “half sandwich” unit (an organometallic moiety with an aromatic π-system and three additional ligands). These complexes can be divided into two groups in which the side chain of the 4-aminoquinoline group is either covalently bound to the aromatic ring of the half sandwich unit or coordinated to the metal in the half sandwich unit. Organometallic complexes based on chromium, manganese, rhenium, ruthenium and osmium are presented. In the case of chromium, manganese and osmium, these are the first reported organometallic complexes with antimalarial activity. The chromium complex [η6-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine] tricarbonylchromium showed high antimalarial activity against both a chloroquine sensitive and a chloroquine resistant P. falciparum malaria strain and was more active than the corresponding organic ligand against resistant parasites. The manganese complexes N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide and N-(7-chloroquinolin-4-yl)-N’-(cymantrenylmethyl)ethane-1,2-diamine, and the rhenium complex N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenyl butanamide, all of which lack a terminal tertiary amine, were significantly less active. The ruthenium and osmium complexes [RuCl(η6-p-cymene)(L1)]Cl (L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [MCl(η6-p-cymene)(L2)]Cl (M = Ru, Os; L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) were less active than their corresponding ligands against both the chloroquine sensitive and the chloroquine resistant parasite strain. In contrast, the complexes [MCl(η6-p-cymene)(L3)] (M = Ru, Os; HL3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) were significantly more active than the ligand alone against both parasite strains. Overall, osmium complexes appear to exhibit higher activity than their ruthenium counterparts.
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| 3. |
- Glans, Lotta, et al.
(författare)
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Ruthenium(ii) arene complexes with chelating chloroquine analogue ligands: Synthesis, characterization and in vitro antimalarial activity.
- 2012
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 41:9, s. 2764-2773
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Tidskriftsartikel (refereegranskat)abstract
- Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η(6)-cym)(L(1))Cl]Cl (1, cym = p-cymene, L(1) = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η(6)-cym)(L(2))Cl]Cl (2, L(2) = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η(6)-cym)(L(3))Cl] (3, L(3) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1-3 and ligands L(1), L(2) and L(3), as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L(4)), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L(2) also shows good activity against both the chloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR(50)) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR(50) properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L(3) to ruthenium, to give a metal complex (3) with promising antimalarial activity.
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| 4. |
- Glans, Lotta, et al.
(författare)
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Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis.
- 2012
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 41:21, s. 6443-6450
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Tidskriftsartikel (refereegranskat)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 (), N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide () and N-(7-chloroquinolin-4-yl)-N'-(cymantrenylmethyl)ethane-1,2-diamine () 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 () 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 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.
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| 5. |
- Glans, Lotta, et al.
(författare)
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Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes.
- 2011
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 105:7, s. 985-990
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Tidskriftsartikel (refereegranskat)abstract
- Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η(6)-N-(7-chloroquinolin-4-yl)-N'-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η(6)-N-(7-chloroquinolin-4-yl)-N'-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η(6)-benzyldimethylamine)tricarbonylchromium 2, [η(6)-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η(6)-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC(50) values of 33.9nM versus 63.1nM).
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