Co-reporter:Kerri L. Shelton, Michael A. DeBord, Patrick O. Wagers, Marie R. Southerland, Alexandra Taraboletti, Nikki K. Robishaw, Daniel P. Jackson, Radisa Tosanovic, William G. Kofron, Claire A. Tessier, Sailaja Paruchuri, Leah P. Shriver, Matthew J. Panzner, Wiley J. Youngs
Tetrahedron 2016 Volume 72(Issue 38) pp:5729-5743
Publication Date(Web):22 September 2016
DOI:10.1016/j.tet.2016.07.068
The syntheses and characterization of C4 and C5 substituted N,N′-bis(arylmethyl)imidazolium salts with hydrophilic or lipophilic substituents on the imidazole ring are reported. A structure-activity relationship study revealed that the lipophilicity of groups at the C4 and C5 positions plays a crucial role in modulating the efficacy against select non-small cell lung cancer cell lines tested. Compounds 11–17 were determined to be the most active against the panel of cell lines studied. Compounds 11 and 12 were examined by the National Cancer Institute's Developmental Therapeutic Program where they were tested against the NCI-60 human cancer cell line panel in a one-dose and five-dose assay. Compound 11 had high activity against the nine lung cancer lines tested while 12 had cytotoxic effects against 59 of the 60 cell lines. Compound 11 was also studied in a murine model to determine its in vivo toxicity.
Co-reporter:Brian D. Wright;Michael C. Deblock;Patrick O. Wagers
Medicinal Chemistry Research 2015 Volume 24( Issue 7) pp:2838-2861
Publication Date(Web):2015 July
DOI:10.1007/s00044-015-1330-z
The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-small-cell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.
Co-reporter:Aditya Agrahari, Patrick Wagers, Steven M. Schildcrout, Wiley J. Youngs, John Masnovi
Journal of Molecular Structure 2014 1076() pp: 183-187
Publication Date(Web):5 November 2014
DOI:10.1016/j.molstruc.2014.07.052
•The stereochemistry of the title compound is established as meso.•The carbazole groups have no parallel planar close contacts (π-type interactions).•The nitrogens puckering due to packing forces as found in related structures.•Bond distances and angles agree with density functional calculations.•The molecular asymmetry for placement of the two carbazoles is intrinsic.The stereochemistry of the title compound is established as meso. The carbazole groups have no parallel planar close contacts (π-type interactions), which differs from the packing found previously for terminal 1,n-di(N-carbazolyl)alkanes. Bond distances, bond angles, and torsion angles are compared with those calculated for the isolated molecule using M06-2X density functional theory, which is designed to model intramolecular dispersion effects. The results indicate that dispersion effects have a significant influence on the molecular conformation, although packing effects likely determine the magnitude of the puckering about one of the nitrogens (N1) and give a crystal conformation closer to a theoretical local minimum than to the global minimum potential energy, which are calculated to differ by only 6.7 kJ/mol at 298 K.
Co-reporter:Brian D. Wright, Parth N. Shah, Lucas J. McDonald, Michael L. Shaeffer, Patrick O. Wagers, Matthew J. Panzner, Justin Smolen, Jasur Tagaev, Claire A. Tessier, Carolyn L. Cannon and Wiley J. Youngs
Dalton Transactions 2012 vol. 41(Issue 21) pp:6500-6506
Publication Date(Web):08 Mar 2012
DOI:10.1039/C2DT00055E
Silver N-heterocyclic carbene complexes have been shown to have great potential as antimicrobial agents, affecting a wide spectrum of both Gram-positive and Gram-negative bacteria. A new series of three silver carbene complexes (SCCs) based on 4,5,6,7-tetrachlorobenzimidazole has been synthesized, characterized, and tested against a panel of clinical strains of bacteria. The imidazolium salts and their precursors were characterized by elemental analysis, mass spectrometry, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction. The silver carbene complexes, SCC32, SCC33, and SCC34 were characterized by elemental analysis, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction. These complexes proved highly efficacious with minimum inhibitory concentrations (MICs) ranging from 0.25 to 6 μg mL−1. Overall, the complexes were effective against highly resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus (MRSA), weaponizable bacteria, such as Yersinia pestis, and pathogens found within the lungs of cystic fibrosis patients, such as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, and Burkholderia gladioli. SCC33 and SCC34 also showed clinically relevant activity against a silver-resistant strain of Escherichia coli based on MIC testing.
Co-reporter:Wiley J. Youngs, Amanda R. Knapp, Patrick O. Wagers and Claire A. Tessier
Dalton Transactions 2012 vol. 41(Issue 2) pp:327-336
Publication Date(Web):06 Oct 2011
DOI:10.1039/C1DT11100K
This perspective discusses the uses of silver for both antimicrobial and anticancer applications. It focuses on the synthesis of silver N-heterocyclic carbene complexes (SCCs) and their in vitro efficacy against a broad spectrum of bacteria, as well as their antitumor properties. Finally, different polymeric nanoparticles are discussed as delivery vehicles for the encapsulation of SCCs and other therapeutic agents for use in vivo.
Co-reporter:Yali Li, Khadijah Hindi, Kristin M. Watts, Jane B. Taylor, Ke Zhang, Zicheng Li, David A. Hunstad, Carolyn L. Cannon, Wiley J. Youngs and Karen L. Wooley
Chemical Communications 2010 vol. 46(Issue 1) pp:121-123
Publication Date(Web):09 Nov 2009
DOI:10.1039/B916559B
Amphiphilic polymer nanoparticles loaded with silver cations or/and N-heterocyclic carbene–silver complexes were assessed as antimicrobial agents against Gram-negative pathogens Escherichia coli and Pseudomonas aeruginosa.
Co-reporter:Amanda R. Knapp, Matthew J. Panzner, Doug A. Medvetz, Brian D. Wright, Claire A. Tessier, Wiley J. Youngs
Inorganica Chimica Acta 2010 Volume 364(Issue 1) pp:125-131
Publication Date(Web):15 December 2010
DOI:10.1016/j.ica.2010.08.008
Due to the properties of silver as an antimicrobial, our research group has synthesized many different silver carbene complexes. Two new silver N-heterocyclic carbene complexes derived from 4,5-dichloroimidazole and theobromine bearing methyl benzoate substituents were synthesized by in situ carbene formation using silver acetate as the base in the reaction. The new compounds were fully characterized by several methods including NMR spectroscopy and X-ray crystallography. Preliminary antimicrobial efficacy studies against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli were conducted. The results of this study demonstrated antimicrobial efficacy of the two complexes comparable to silver nitrate, showing their potential for use in the treatment of bacterial infections.Two new silver N-heterocyclic carbene complexes derived from 4,5-dichloroimidazole and theobromine bearing methyl benzoate substituents were synthesized, characterized by NMR and X-ray crystallography, and tested for their antimicrobial properties.
Co-reporter:Khadijah M. Hindi, Matthew J. Panzner, Claire A. Tessier, Carolyn L. Cannon and Wiley J. Youngs
Chemical Reviews 2009 Volume 109(Issue 8) pp:3859
Publication Date(Web):July 6, 2009
DOI:10.1021/cr800500u
Co-reporter:Matthew J. Panzner, Khadijah M. Hindi, Brian D. Wright, Jane B. Taylor, Daniel S. Han, Wiley J. Youngs and Carolyn L. Cannon
Dalton Transactions 2009 (Issue 35) pp:7308-7313
Publication Date(Web):2009/08/06
DOI:10.1039/B907726J
The increasing incidence of multidrug-resistant (MDR) pulmonary infections in the cystic fibrosis (CF) population has prompted the investigation of innovative silver based therapeutics. The functionalization of the naturally occurring xanthine theobromine at the N1 nitrogen atom with an ethanol substituent followed by the methylation of the N9 nitrogen atom gives the N-heterocyclic carbene precursor 1-(2-hydroxyethyl)-3,7,9-trimethylxanthinium iodide. The reaction of this xanthinium salt with silver acetate produces the highly hydrophilic silver carbene complex SCC8. The in vitro antimicrobial efficacy of this newly synthesized complex was evaluated with excellent results on a variety of virulent and MDR pathogens isolated from CF patients. A comparative in vivo study between the known caffeine derived silver carbene SCC1 and SCC8 demonstrated the ability of both complexes to improve the survival rates of mice in a pneumonia model utilizing the clinically isolated infectious strain of Pseudomonas aeruginosa PA M57-15.
Co-reporter:Lionel Delaude;Christopher W. Bielawski;D. Mark Estes;Carolyn L. Cannon;Jeff G. Leid;Cathleen M. Crudden;Luigi Cavallo
European Journal of Inorganic Chemistry 2009 Volume 2009( Issue 13) pp:
Publication Date(Web):
DOI:10.1002/ejic.200990030
Abstract
The cover picture is a composite design depicting the variety in NHC complex chemistry. Like pieces in a puzzle, all details contribute to our growing knowledge of these compounds. The first puzzle piece in the bottom left corner represents the carbene precursors, essential in all synthesis design (C. W. Bielawski et al.; p. 1729 ff). The background reflects the importance of these complexes, here in the homogeneous catalytic chemistry of gaseous molecules (C. M. Crudden et al.; p. 1746 ff), while the diverse structural types are highlighted by the zwitterionic “crabenes” mid right (L. Delaude; p. 1681 ff). Related aspects such as the physical chemistry or biological relevance are not forgotten: the sketch of the buried volume of an NHC ligand symbolizes the former (L. Cavallo et al.; p. 1759 ff), and the antimicrobial activity of silver–NHC complexes against biosafety level 3 bacteria typifies the latter (W. J. Youngs et al.; p. 1739 ff). Mr. François Nicks is acknowledged for drawing the “crabene”. The editorial office thanks all authors for their excellent contributions to this cover picture puzzle. Finally, there are many gaps. EurJIC hopes that this issue will stimulate you to discover another fragment that will complete the picture.
Co-reporter:Matthew J. Panzner;Arpaporn Deeraksa;Alyssa Smith;Brian D. Wright;Khadijah M. Hindi;Aysegul Kascatan-Nebioglu;Alfredo G. Torres;Barbara M. Judy;Christine E. Hovis;Julia K. Hilliard;Rebekah J. Mallett;Emily Cope;D. Mark Estes;Carolyn L. Cannon;Jeff G. Leid
European Journal of Inorganic Chemistry 2009 Volume 2009( Issue 13) pp:1739-1745
Publication Date(Web):
DOI:10.1002/ejic.200801159
Abstract
A series of N-heterocyclic carbene silver complexes have been synthesized and tested against the select group of biosafety level 3 bacteria Burkholderia pseudomallei, Burkholderia mallei, Bacillus anthracis, methicillin-resistant Staphylococcus aureus and Yersinia pestis. Minimal inhibitory concentrations, minimal bactericidal and killing assays demonstrated the exceptional efficacy of the complexes against these potentially weaponizable pathogens. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Co-reporter:Khadijah M. Hindi ; Tammy J. Siciliano ; Semih Durmus ; Matthew J. Panzner ; Doug A. Medvetz ; D. Venkat Reddy ; Lisa A. Hogue ; Christine E. Hovis ; Julia K. Hilliard ; Rebekah J. Mallet ; Claire A. Tessier ; Carolyn L. Cannon
Journal of Medicinal Chemistry 2008 Volume 51(Issue 6) pp:1577-1583
Publication Date(Web):February 21, 2008
DOI:10.1021/jm0708679
A series of methylated imidazolium salts with varying substituents on the 4 and 5 positions of the imidazole ring were synthesized. These salts were reacted with silver acetate to afford their corresponding silver N-heterocyclic carbene (NHC) complexes. These complexes were then evaluated for their stability in water as well as for their antimicrobial efficacy against a variety of bacterial strains associated with cystic fibrosis and chronic lung infections.
Co-reporter:Aysegul Kascatan-Nebioglu, Matthew J. Panzner, Claire A. Tessier, Carolyn L. Cannon, Wiley J. Youngs
Coordination Chemistry Reviews 2007 Volume 251(5–6) pp:884-895
Publication Date(Web):March 2007
DOI:10.1016/j.ccr.2006.08.019
N-Heterocyclic carbene (NHC)–silver complexes were synthesized from pyridine linked pincer ligands and methylated caffeine. Pincer NHC–silver complexes were found to have more potent antimicrobial activity than the conventionally used silver antimicrobials. Encapsulation of a gem-diol pincer NHC–silver complex in a polymer mat demonstrated a promising method for the sustained delivery of silver ions in wound care applications. An NHC precursor derived from caffeine was found to have a low toxicity and the resulting silver complex showed encouraging antimicrobial activity against numerous pathogens including resistant organisms isolated from the lungs of patients with cystic fibrosis (CF). Bacteria studied included members of the Burkholderia cepacia complex, which cause significant morbidity and mortality in infected CF patients. This review explores this newly growing area, focusing on the synthesis from pincer and xanthine ligands of new silver–NHC complexes and their antimicrobial activities.
Co-reporter:Jered C. Garrison, Matthew J. Panzner, Paul D. Custer, D. Venkat Reddy, Peter L. Rinaldi, Claire A. Tessier and Wiley J. Youngs
Chemical Communications 2006 (Issue 44) pp:4644-4646
Publication Date(Web):29 Sep 2006
DOI:10.1039/B608991G
The reaction of 4-ethynyl-pyridine with tert-butyl lithium followed by its addition to (Me3tacn)RhCl3 affords the facial octahedral complex (Me3tacn)Rh(CCPy)3, condensation of which with the square planar complex cis-(DCPE)Pt(NO3)2 results in a self-assembled trigonal bipyramidal cage with Rh(III) and Pt(II) atoms occupying the vertices.
Co-reporter:Jered C. Garrison, Claire A. Tessier, Wiley J. Youngs
Journal of Organometallic Chemistry 2005 Volume 690(24–25) pp:6008-6020
Publication Date(Web):1 December 2005
DOI:10.1016/j.jorganchem.2005.07.102
The potential for N-heterocyclic carbenes (NHCs) to be used as novel chelating ligands for bio-inorganic pharmaceuticals is discussed. In this paper, we design, synthesize and characterize two NHC precursors, 6 and 7, that we believe have potential for use as metal chelators for pharmaceuticals. The NHC precursors are composed of imidazolium and pyridine rings that would form mixed donor NHCs upon metallation with medicinally relevant metals. The exploration of the silver chemistry of 6 yielded the dimeric silver NHC complex 8[BPh4]2. The study of the silver chemistry of 7 gave 9[1/3(Ag4Br7)] and 10[NO3]3. Complex 9[1/3(Ag4Br7)] appears to be a silver biscarbene charge balanced by a silver bromide anionic cluster. Complex 10[NO3]3 is a trinuclear silver cluster that is stabilized by NHCs and pyridine rings. Silver NHCs have shown themselves to be excellent transmetallation agents for access to other metal NHC systems. It is envisioned that the silver NHCs 8[BPh4]2, 9[1/3(Ag4Br7)] and 10[NO3]3 will readily transfer to medicinally relevant metals, such 105Rh.Synthesis and structural characterization of two multi-donor NHC precursors and their silver complexes: Investigation of the potential use of NHCs in targeted pharmaceuticals.
Co-reporter:Carol A. Quezada, Jered C. Garrison, Claire A. Tessier, Wiley J. Youngs
Journal of Organometallic Chemistry 2003 Volume 671(1–2) pp:183-186
Publication Date(Web):1 April 2003
DOI:10.1016/S0022-328X(03)00100-1
The air stable syntheses of two new chelating N-heterocyclic carbene complexes of Pt(II), bis(1,1′-n-butylimidazolium)-3,3′-methylenePtI2 (2) and bis[bis(1,1′-n-butylimidazolium)-3,3′-methylene]PtI2 (3) are described.The first synthesis of two Pt(II) complexes of a chelating N-heterocyclic carbene in wet solvent is described. These complexes are novel because not many Pt(II) complexes have been synthesized. Previous syntheses of Pt N-heterocyclic carbene complexes have involved using the free carbene, a lengthy and difficult route. Here we describe the synthesis in aerobic conditions using conventional solvent.
Co-reporter:Aida Ibricevic, Steven L. Brody, Wiley J. Youngs, Carolyn L. Cannon
Toxicology and Applied Pharmacology (15 March 2010) Volume 243(Issue 3) pp:315-322
Publication Date(Web):15 March 2010
DOI:10.1016/j.taap.2009.11.023
Silver is a centuries-old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increased cell death in ATP7B shRNA-treated HepG2 cells. In addition, mTEC from ATP7B−/− mice showed enhanced loss of ciliated cells compared to wild type. These studies are the first to demonstrate a cell type-specific expression of the Ag+/Cu+ transporters ATP7A, ATP7B, and CTR1 in airway epithelial cells and a role for ATP7B in detoxification of these metals in the lung.
Co-reporter:Michael A. DeBord, Patrick O. Wagers, Steven R. Crabtree, Claire A. Tessier, Matthew J. Panzner, Wiley J. Youngs
Bioorganic & Medicinal Chemistry Letters (15 January 2017) Volume 27(Issue 2) pp:
Publication Date(Web):15 January 2017
DOI:10.1016/j.bmcl.2016.11.075
A series of C2-alkyl substituted N,N′-bis(arylmethyl)imidazolium salts were synthesized, characterized, and tested for their in vitro anti-cancer activity against multiple non-small cell lung cancer cell lines by our group and the National Cancer Institute’s-60 human tumor cell line screen to establish a structure-activity relationship. Compounds are related to previously published N,N′-bis(arylmethyl)imidazolium salts but utilize the historical quinoline motif and anion effects to increase the aqueous solubility. Multiple derivatives displayed high anti-cancer activity with IC50 values in the nanomolar to low micromolar range against a panel of non-small cell lung cancer cell lines. Several of these derivatives have high aqueous solubilities with potent anti-proliferative properties and are ideal candidates for future in vivo xenograft studies and have high potential to progress into clinic use.
Co-reporter:Michael A. DeBord, Marie R. Southerland, Patrick O. Wagers, Kristin M. Tiemann, Nikki K. Robishaw, Kyle T. Whiddon, Michael C. Konopka, Claire A. Tessier, Leah P. Shriver, Sailaja Paruchuri, David A. Hunstad, Matthew J. Panzner, Wiley J. Youngs
Bioorganic & Medicinal Chemistry Letters (15 February 2017) Volume 27(Issue 4) pp:
Publication Date(Web):15 February 2017
DOI:10.1016/j.bmcl.2017.01.035
•A series of N,N′-bisnaphthylmethyl-2-alkyl imidazolium salts was synthesized.•Compounds were characterized by 1H and 13C NMR and X-ray crystallography.•All compounds reported have high anti-cancer activity comparable to cisplatin.•NCI-60 cell line one-dose and five-dose assays.•Mechanism of action studies and in vivo toxicity study.Alkyl- and N,N′-bisnaphthyl-substituted imidazolium salts were tested in vitro for their anti-cancer activity against four non-small cell lung cancer cell lines (NCI–H460, NCI–H1975, HCC827, A549). All compounds had potent anticancer activity with 2 having IC50 values in the nanomolar range for three of the four cell lines, a 17-fold increase in activity against NCI-H1975 cells when compared to cisplatin. Compounds 1–4 also showed high anti-cancer activity against nine NSCLC cell lines in the NCI-60 human tumor cell line screen. In vitro studies performed using the Annexin V and JC-1 assays suggested that NCI-H460 cells treated with 2 undergo an apoptotic cell death pathway and that mitochondria could be the cellular target of 2 with the mechanism of action possibly related to a disruption of the mitochondrial membrane potential. The water solubilities of 1–4 was over 4.4 mg/mL using 2-hydroxypropyl-β-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.
Co-reporter:Kerri L. Shelton, Michael A. DeBord, Patrick O. Wagers, Marie R. Southerland, Travis M. Williams, Nikki K. Robishaw, Leah P. Shriver, Claire A. Tessier, Matthew J. Panzner, Wiley J. Youngs
Bioorganic & Medicinal Chemistry (1 January 2017) Volume 25(Issue 1) pp:
Publication Date(Web):1 January 2017
DOI:10.1016/j.bmc.2016.11.009
•Hydrophobic and hydrophilic benzimidazolium salts were synthesized/characterized.•Benzimidazolium salts were tested for their anti-cancer properties.•Lipophilic benzimidazolium salts have higher anti-cancer activity.•NCI’s DTP tested 21 compounds in the NCI-60 human tumor cell line screen.A series of N,N′-bis(arylmethyl)benzimidazolium salts have been synthesized and evaluated for their in vitro anti-cancer activity against select non-small cell lung cancer cell lines to create a structure activity relationship profile. The results indicate that hydrophobic substituents on the salts increase the overall anti-proliferative activity. Our data confirms that naphthylmethyl substituents at the nitrogen atoms (N1(N3)) and highly lipophilic substituents at the carbon atoms (C2 and C5(C6)) can generate benzimidazolium salts with anti-proliferative activity that is comparable to that of cisplatin. The National Cancer Institute’s Developmental Therapeutics Program tested 1, 3–5, 10, 11, 13–18, 20–25, and 28–30 in their 60 human tumor cell line screen. Results were supportive of data observed in our lab. Compounds with hydrophobic substituents have higher anti-cancer activity than compounds with hydrophilic substituents.
Co-reporter:Jered C. Garrison, Richard S. Simons, William G. Kofron, Claire A. Tessier and Wiley J. Youngs
Chemical Communications 2001(Issue 18) pp:NaN1781-1781
Publication Date(Web):2001/08/21
DOI:10.1039/B105751K
The synthesis of a dicationic imidazolium-linked cyclophane and a dimeric silver–N-heterocyclic carbene complex, that is the first silver complex with a N-heterocyclic carbene ligand involved in a π-bonding interaction, is reported.
Co-reporter:Yali Li, Khadijah Hindi, Kristin M. Watts, Jane B. Taylor, Ke Zhang, Zicheng Li, David A. Hunstad, Carolyn L. Cannon, Wiley J. Youngs and Karen L. Wooley
Chemical Communications 2010 - vol. 46(Issue 1) pp:NaN123-123
Publication Date(Web):2009/11/09
DOI:10.1039/B916559B
Amphiphilic polymer nanoparticles loaded with silver cations or/and N-heterocyclic carbene–silver complexes were assessed as antimicrobial agents against Gram-negative pathogens Escherichia coli and Pseudomonas aeruginosa.
Co-reporter:Wiley J. Youngs, Amanda R. Knapp, Patrick O. Wagers and Claire A. Tessier
Dalton Transactions 2012 - vol. 41(Issue 2) pp:NaN336-336
Publication Date(Web):2011/10/06
DOI:10.1039/C1DT11100K
This perspective discusses the uses of silver for both antimicrobial and anticancer applications. It focuses on the synthesis of silver N-heterocyclic carbene complexes (SCCs) and their in vitro efficacy against a broad spectrum of bacteria, as well as their antitumor properties. Finally, different polymeric nanoparticles are discussed as delivery vehicles for the encapsulation of SCCs and other therapeutic agents for use in vivo.
Co-reporter:Matthew J. Panzner, Khadijah M. Hindi, Brian D. Wright, Jane B. Taylor, Daniel S. Han, Wiley J. Youngs and Carolyn L. Cannon
Dalton Transactions 2009(Issue 35) pp:NaN7313-7313
Publication Date(Web):2009/08/06
DOI:10.1039/B907726J
The increasing incidence of multidrug-resistant (MDR) pulmonary infections in the cystic fibrosis (CF) population has prompted the investigation of innovative silver based therapeutics. The functionalization of the naturally occurring xanthine theobromine at the N1 nitrogen atom with an ethanol substituent followed by the methylation of the N9 nitrogen atom gives the N-heterocyclic carbene precursor 1-(2-hydroxyethyl)-3,7,9-trimethylxanthinium iodide. The reaction of this xanthinium salt with silver acetate produces the highly hydrophilic silver carbene complex SCC8. The in vitro antimicrobial efficacy of this newly synthesized complex was evaluated with excellent results on a variety of virulent and MDR pathogens isolated from CF patients. A comparative in vivo study between the known caffeine derived silver carbene SCC1 and SCC8 demonstrated the ability of both complexes to improve the survival rates of mice in a pneumonia model utilizing the clinically isolated infectious strain of Pseudomonas aeruginosa PA M57-15.
Co-reporter:Brian D. Wright, Parth N. Shah, Lucas J. McDonald, Michael L. Shaeffer, Patrick O. Wagers, Matthew J. Panzner, Justin Smolen, Jasur Tagaev, Claire A. Tessier, Carolyn L. Cannon and Wiley J. Youngs
Dalton Transactions 2012 - vol. 41(Issue 21) pp:NaN6506-6506
Publication Date(Web):2012/03/08
DOI:10.1039/C2DT00055E
Silver N-heterocyclic carbene complexes have been shown to have great potential as antimicrobial agents, affecting a wide spectrum of both Gram-positive and Gram-negative bacteria. A new series of three silver carbene complexes (SCCs) based on 4,5,6,7-tetrachlorobenzimidazole has been synthesized, characterized, and tested against a panel of clinical strains of bacteria. The imidazolium salts and their precursors were characterized by elemental analysis, mass spectrometry, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction. The silver carbene complexes, SCC32, SCC33, and SCC34 were characterized by elemental analysis, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction. These complexes proved highly efficacious with minimum inhibitory concentrations (MICs) ranging from 0.25 to 6 μg mL−1. Overall, the complexes were effective against highly resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus (MRSA), weaponizable bacteria, such as Yersinia pestis, and pathogens found within the lungs of cystic fibrosis patients, such as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, and Burkholderia gladioli. SCC33 and SCC34 also showed clinically relevant activity against a silver-resistant strain of Escherichia coli based on MIC testing.
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![Methyl 2-(1H-benzo[d]imidazol-2-yl)acetate](http://img.cochemist.com/ccimg/49700/49672-05-1_b.png)
