| 1. |
- Ekengard, Erik, et al.
(författare)
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A pyrazine amide – 4-aminoquinoline hybrid and its rhodium and iridium pentamethylcyclopentadienyl complexes; evaluation of anti-mycobacterial and anti-plasmodial activities
- 2017
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Ingår i: Journal of the Mexican Chemical Society. - 1870-249X. ; 61:2, s. 158-166
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and characterization of N-(2-((7-chloroquino-lin-4-yl)amino)ethyl)pyrazine-2-carboxamide (L), an aminoquinoline – pyrazinamide hybrid, and the complexes (N-(2-((7-chloroquino-lin-4-yl)amino)ethyl)pyrazine-2-carboxamide)(cyclopentadienyl) chlorido-rhodium or iridium hexafluorophosphate ([M(L)(Cp*)Cl] PF6; M = Rh, Ir) and the corresponding chlorido salts ([M(L)(Cp*) Cl]Cl; M = Rh, Ir) are described. The ligand and the hexafluorophosphate salts of the metal complexes have been evaluated for anti-plasmodial and anti-mycobacterial activity. The rhodium and the iridium complexes were significantly more active against M. tuberculosis than the free ligand. The crystallographically determined molecular structures of complexes (N-(2-((7-chloroquinolin-4-yl)amino)ethyl) pyrazine-2-carboxamide)(cyclopentadienyl) chlororhodium hexafluoro-phosphate and (N-(2-((7-chloroquinolin-4-yl)amino)ethyl)pyr-azine-2-carboxamide)(cyclopentadienyl)chloro-iridium chloride are presented.
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| 2. |
- 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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| 3. |
- Ekengard, Erik
(författare)
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Half-sandwich complexes with amino-quinoline ligands - synthesis, antiplasmodial and antimycobacterial activities
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malaria and tuberculosis are two of the most deadly infectious diseases that exist. Both diseases predominantly affect the most vunerable parts of society. Additionally the treatment of both diseases are complicated by growing and spreading resistance against the drugs used to treat them. Chloroquine was once described as a wonder drug for its combination of efficacy, low price and tolerable side effects. Most P. falciparum malaria today is resistant against chloroquine and in many areas of the world its usage has been discontinued. Ferroquine is a chloroquine derivative that overcomes chloroquine resistance by incorporation of a ferrocene moiety into the chloroquine side chain. This thesis deals with attempts to overcome chloroquine resistance by incorporation of half-sandwich moieties. In Paper I, eight of new 4-aminoquinoline-based ligands and a large number of ruthenium and osmium half sandwichcomplexes with these ligands are prepared and tested for antimalarial activity. The ligands are highly active against a chloroquine sensitive strain of P. falciparum, but exhibit cross-resistance with chloroquine. The ruthenium and osmium complexes are less active than the free ligands and do not overcome chloroquine resistance. The antimalarial activity of the ligands correlates with electronic properties of substituents on a phenol ring. In Paper II, the same ligand family as in Paper I are used to prepare 20 new rhodium and iridium pentamethylcyclopentadienyl complexes. The rhodium comlexes are more active than iridium complexes, and both are more active than ruthenium or osmium complexes. Only occasionally though are a metal complex more active than the free ligands, but complexes share the cross-resistance of the free ligands. The correlation between ligand substituents and antimalarial activity extends to the rhodium and iridium complexes. Paper III introduces a 4-aminoquinoline-pyrazinamide hybrid which has limited antimalarial and antimycobacterial acitivity. Metal complexes are more active against M. tuberculosis. Paper IV examines the effect of halide ligands in complexes from earlier papers. No clear conclusion can be drawn, although halide exchange can affect antimalarial activity. Paper V introduces 2 pyrazole-based 4-aminoquinoline ligands. Ligands and half sandwich complexes are reasonably active against CQS parasites, Pd and Pt complexes are much less active.
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| 4. |
- Ekengard, Erik, et al.
(författare)
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Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.
- 2016
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 45:9, s. 3905-3917
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(iii) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(iii) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(iii) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(iii) chloride, the crystal structure of which is also reported.
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| 5. |
- Elantabli, Fatma M., et al.
(författare)
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Thiophene based imino-pyridyl palladium(II) complexes : Synthesis, molecular structures and Heck coupling reactions
- 2017
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Ingår i: Journal of Organometallic Chemistry. - : Elsevier BV. - 0022-328X. ; 843, s. 40-47
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Tidskriftsartikel (refereegranskat)abstract
- The new compounds (5-methyl-2-thiophene-2-pyridyl(R))imine [R = methyl (L1); R = ethyl (L2)] and (5-bromo-2-thiophene-2-pyridyl(R)imine [R = methyl (L3); R = ethyl (L4)] were successfully synthesized via Schiff base condensation reaction and obtained in good yields. These potential ligands were reacted with [PdCl2(COD)] and [PdClMe(COD)] to give the corresponding complexes [PdCl2(L)] (L = L1-L4; 1–4) and [PdClMe(L)] (L = L1-L4; 5–8). All compounds were characterized by IR, 1H and 13C NMR spectroscopy, elemental analysis and mass spectrometry. The molecular structures of 1, 2, 6 and 8 were confirmed by X-ray crystallography. The complexes were evaluated as catalyst precursors for standard Heck coupling reactions and showed significant catalytic activities that could be correlated with steric and electronic influences.
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| 6. |
- Gama, Ntombenhle, et al.
(författare)
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Gold(I) complex of 1,1'-bis(diphenylphosphino) ferrocene-quinoline conjugate: a virostatic agent against HIV-1.
- 2016
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Ingår i: BioMetals. - : Springer Science and Business Media LLC. - 1572-8773 .- 0966-0844. ; 29:3, s. 389-397
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Tidskriftsartikel (refereegranskat)abstract
- HIV infection is known for replicating in proliferating CD(+) T-cells. Treatment of these cells with cytostatic (anti-proliferation) compounds such as hydroxyurea interferes with the cells's ability support HIV replication. Combinations of such cytostatic compounds with proven anti-retroviral drugs (like ddI) are known as virostatic, and have been shown to aid in the control of the infection. The use of two different drugs in virostatic combinations however, carries the risk of adverse effects including drug-drug interactions, which could lead to augmented toxicities and reduced efficacy. Here, a novel digold(I) complex of ferrocene-quinoline (3) was investigated for cytostatic behaviour as well as anti-viral activity which if demonstrated would eliminate concerns of drug-drug interactions. The complex was synthesized and characterized by NMR, FT-IR and mass spectroscopy and the molecular structure was confirmed by X-ray crystallography. Bio-screening involved viability dyes, real time electronic sensing and whole virus assays. The complex showed significant (p = 0.0092) inhibition of virus infectivity (83 %) at 10 ug/mL. This same concentration caused cytostatic behaviour in TZM-bl cells with significant (p < 0.01) S and G2/M phase cell cycle arrest. These data supports 3 as a virostatic agent, possessing both anti-viral and cytostatic characteristics. In the absence of 3, TZM-bl cells were infected by a pseudovirus and this was demonstrated through luminescence in a luciferase assay. Pre-incubation of the virus with 3 decreased luminescence, indicating the anti-viral activity of 3. Complex 3 also showed cytostatic behavior with increased S-phase and G2/M phase cell cycle arrest.
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| 7. |
- Martínez, Alberto, et al.
(författare)
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Novel multi-target compounds in the quest for new chemotherapies against Alzheimer's disease : An experimental and theoretical study
- 2018
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Ingår i: Bioorganic and Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 26:17, s. 4823-4840
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Tidskriftsartikel (refereegranskat)abstract
- The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer's disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (1–4), inspired by previously described ionophoric polyphenols, have been synthesized and studied. These compounds have been designed to target important aspects of AD, including BACE 1 enzymatic activity, Aβ aggregation, toxic concentrations of Cu2+ metal ions and/or ROS production. Two other compounds (5 and 6), previously reported by some of us as antimalarial agents, have also been studied because of their potential as multi-target species against AD. Interestingly, compounds 3 and 5 showed moderate to good ability to inhibit BACE 1 enzymatic activity in a FRET assay, with IC50′s in the low micromolar range (4.4 ± 0.3 and 1.7 ± 0.3 μM, respectively), comparable to other multi-target species, and showing that the observed activity was in part due to a competitive binding of the compounds at the active site of the enzyme. Theoretical docking calculations overall agreed with FRET assay results, displaying the strongest binding affinities for 3 and 5 at the active site of the enzyme. In addition, all compounds selectively interacted with Cu2+ metal ions forming 2:1 complexes, inhibited the production of Aβ-Cu2+ catalyzed hydroxyl radicals up to a ∼100% extent, and scavenged AAPH-induced peroxyl radical species comparably to resveratrol, a compound used as reference in this work. Our results also show good anti-amyloidogenic ability: compounds 1–6 inhibited both the Cu2+-induced and self-induced Aβ(1–40) fibril aggregation to an extent that ranged from 31% to 77%, while they disaggregated pre-formed Aβ(1–40) mature fibrils up to a 37% and a 69% extent in absence and presence of Cu2+, respectively. Cytotoxicity was additionally studied in Tetrahymena thermophila and HEK293 cells, and compared to that of resveratrol, showing that compounds 1–6 display lower toxicity than that of resveratrol, a well-known non-toxic polyphenol.
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