Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: a study on C/Si/Ge bioisosterism

Tacke, Reinhold; Kornek, T.; Heinrich, T.; Burschka, Christian; Penka, Martin; Pülm, Melanie; Keim, Christine; Mutschler, E.; Lambrecht, Günter

doi:10.1016/s0022-328x(01)01179-2

Cited by 63 publications

(15 citation statements)

References 12 publications

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“…To combat this resistance, new strategies in drug design are required. In this regard, several transition metal complexes of chloroquine have been synthesized and evaluated for antiplasmodial activity with varying degrees of success. − In some instances transition metals seem to provide additional stability to the drug and a better means of delivery to their desired targets. − The most notable example of an organometallic antimalarial drug is ferroquine (Figure ), which has a ferrocene moiety incorporated into the lateral side chain of chloroquine. Ferroquine and its derivatives display high antimalarial activity against chloroquine-resistant strains − and is currently in phase IIb clinical trials .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and Pharmacological Evaluation of Silicon-Containing Aminoquinoline Organometallic Complexes As Antiplasmodial, Antitumor, and Antimycobacterial Agents

Kock

Smith

et al. 2012

Organometallics

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Two silicon-containing analogues (1, 2) of chloroquine, modified in the lateral side chain with organosilicon moieties, were synthesized. Compounds 1 and 2 were further reacted with dinuclear half-sandwich transition metal precursors [Ru(Ar)(μ-Cl)Cl]2 (Ar = η6-p-iPrC6H4Me; η6-C6H6; η6-C6H5OCH2CH2OH), [Rh(COD)(μ-Cl)]2, and [RhCp*(μ-Cl)Cl]2, to yield a series of neutral mononuclear Ru(II), Rh(I), and Rh(III) silicon-aminoquinoline complexes (3–12). Compounds 1 and 2 act as monodentate donors that coordinate to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. All the compounds were characterized using various analytical and spectroscopic techniques, and the molecular structures of compounds 2 and 11 were elucidated by single-crystal X-ray diffraction analysis. Furthermore, the in vitro pharmacological activities of compounds 1–12 were established against chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malarial parasite Plasmodium falciparum and against the pathogenic bacterium Mycobacterium tuberculosis H37Rv, as well as an esophageal (WHCO1) cancer cell line.

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Section: Introductionmentioning

confidence: 99%

“…The hydrophobic ferrocene core is thought to enhance lipophilicity and, in turn, enhances transmembrane interactions . Several research groups have also introduced various organometallic fragments in the basic amine side chain in an attempt to enhance the antimalarial activity. ,− , …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and Pharmacological Evaluation of Silicon-Containing Aminoquinoline Organometallic Complexes As Antiplasmodial, Antitumor, and Antimycobacterial Agents

Kock

Smith

et al. 2012

Organometallics

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“…2-Cyclopentyl-2-phenylacetonitrile (P 12 ). 28 The crude product was purified by column chromatography (silica as the stationary phase and a mixture of hexanes and ethylacetate (9.0:1.0) as the eluent) to give pure product P 12 as a colorless oil (0.778 g, 84%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.40−7.27 (m, 5H), 3.72 (d, J = 7 Hz, 1H), 2.38− 2.24 (m, 1H), 1.91−1.80 (m, 1H), 1.78−1.48 (m, 6H), 1.40−1.29 (m, 1H).…”

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confidence: 99%

Efficient α-Alkylation of Arylacetonitriles with Secondary Alcohols Catalyzed by a Phosphine-Free Air-Stable Iridium(III) Complex

et al. 2020

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A well-defined and readily available air-stable dimeric iridium(III) complex catalyzed α-alkylation of arylacetonitriles using secondary alcohols with the liberation of water as the only byproduct is reported. The α-alkylations were efficiently performed at 120 °C under solvent-free conditions with very low (0.1–0.01 mol %) catalyst loading. Various secondary alcohols including cyclic and acyclic alcohols and a wide variety of arylacetonitriles bearing different functional groups were converted into the corresponding α-alkylated products in good yields. Mechanistic study revealed that the reaction proceeds via alcohol activation by metal–ligand cooperation with the formation of reactive iridium-hydride species.

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“…Homologous compounds with a similar chiral center, but lacking the Si-O bond, often exhibit a large difference in the antimuscarinic effects of the enantiomers (Tacke et al, 1995(Tacke et al, , 2001). Thus, it is possible that the different effects of pFHHSiD (i.e., competitive antagonism and nonmuscarinic receptor mediated inhibition) observed in this study are mediated by different enantiomers.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Antimuscarinic Action of p-Fluorohexahydrosiladifenidol in Ileal and Tracheal Smooth Muscle

Ehlert

Hsu²,

Leung³

et al. 2004

J Pharmacol Exp Ther

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We investigated the ability of the muscarinic antagonist pfluorohexahydrosiladifenidol to inhibit muscarinic agonist-induced contractions and phosphoinositide hydrolysis in the guinea pig ileum and trachea. This antagonist displayed higher potency at blocking oxotremorine-M-induced contractions of the ileum compared with those of the trachea. When estimated using a simple model for competitive antagonism, the observed dissociation constant of p-fluorohexahydrosiladifenidol exhibited approximately 12-fold higher potency in the ileum compared with the trachea. We also investigated the ability of p-fluorohexahydrosiladifenidol to affect the inhibition of contraction caused by the known competitive muscarinic antagonist atropine. Using resultant analysis to analyze this interaction, we found that the true dissociation constant of p-fluorohexahydrosiladifenidol for competitively antagonizing oxotremorine-M-induced contractions in the ileum exhibited significantly lower potency than when calculated assuming a simple competitive model. In contrast, resultant analysis showed little difference between the true and observed potencies of p-fluorohexahydrosiladifenidol for antagonizing oxotremorine-M-induced contractions in the trachea. Using a simple competitive model, we found little difference in the observed dissociation constant of p-fluorohexahydrosiladifenidol for antagonizing oxotremorine-M-induced phosphoinositide hydrolysis in guinea pig ileum and bovine trachea. We also noted that p-fluorohexahydrosiladifenidol (0.3-1.0 M) moderately inhibited histamine-induced contractions of ileum but not of trachea. Our results suggest that p-fluorohexahydrosiladifenidol does not discriminate markedly between M 3 muscarinic receptors in the ileum and trachea and that it may posses a more potent, nonmuscarinic inhibitory effect on contraction in the ileum.

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Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: a study on C/Si/Ge bioisosterism

Cited by 63 publications

References 12 publications

Synthesis, Characterization, and Pharmacological Evaluation of Silicon-Containing Aminoquinoline Organometallic Complexes As Antiplasmodial, Antitumor, and Antimycobacterial Agents

Synthesis, Characterization, and Pharmacological Evaluation of Silicon-Containing Aminoquinoline Organometallic Complexes As Antiplasmodial, Antitumor, and Antimycobacterial Agents

Efficient α-Alkylation of Arylacetonitriles with Secondary Alcohols Catalyzed by a Phosphine-Free Air-Stable Iridium(III) Complex

Comparison of the Antimuscarinic Action of p-Fluorohexahydrosiladifenidol in Ileal and Tracheal Smooth Muscle

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