Browsing by Author "Karpin, George W."

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    Bis[bis-(penta-methyl-cyclo-penta-dien-yl)cobalt(III)] tetra-chlorido-cobaltate(II) di-chloro-methane disolvate.
    Merola, Joseph S.; Ngo, Mai; Karpin, George W. (International Union of Crystallography, 2013)
    The title compound, [Co(C10H15)2]2[CoCl4]·2CH2Cl2, was isolated as a dichloromethane solvate and was formed in the reaction between lithium pentamethylcyclopentadienide and anyhydrous cobalt(II) chloride in tetrahydrofuran. There are two decamethylcobaltocenium cations, one tetrachloridocobaltate(II) anion and two dichloromethane solvent molecules in the formula unit. There is a slight disorder of the dichloromethane solvent which was treated with a two-site model [occupancy rates = 0.765 (4) and 0.235 (4)]. The dichloromethane molecules display significant C-HCl interactions with the tetrachloridocobaltate(II) dianion. The cobalt atom of the decamethylcobaltocenium cation sits on a twofold rotation axis, with only one pentamethylcyclopentadiene ligand being unique and the second generated by symmetry. The cobalt atom of the [CoCl4]-2 ion sits on a special site with -4 symmetry, with one unique chloride ligand and the others generated by the fourfold inversion axis.
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    Identification of the Target for a Transition Metal-alpha-Amino Acid Complex Antibiotic Against Mycobacterium smegmatis
    Karpin, George W.; Merola, Joseph S.; Falkinham, Joseph O. III (2021-06-25)
    Spontaneous mutants of Mycobacterium smegmatis strain mc(2)155 resistant to 1-PG (iridium-L-phenylglycine complex), an antimycobacterial antibiotic, were isolated. Based on the discovery that some 1-PG-resistant mutants (1-PG(R)) were also resistant to high concentrations of clarithromycin (>= 250 mu g/ml), but no other anti-mycobacterial antibiotics, the 23S rRNA region spanning the peptidyl transferase domain was sequenced and mutations shown to be localized in the peptidyl transferase domain of the 23S rRNA gene. Measurements showed that 1-PG bound to ribosomes isolated from the 1-PG-sensitive parental strain, but the ribosome binding values for the 1-PG(R) mutant reduced.
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    Synthesis and Antimicrobial Activity of Half-Sandwich Ir(III), Rh(III), and Co(III)  Complexes
    Karpin, George W. (Virginia Tech, 2017-09-25)
    This dissertation describes the synthesis and antimicrobial use of a series of half-sandwich Ir(III), Rh(III), Co(III) amino acid and ethylenediamine complexes. This investigation focuses on the formulation (ηn-arene)M(L)X, (L = ethylenediamine or α-amino carboxylate), (M= Ir, Rh, Ru, Co). Arene, Ligand and metal center variations were designed to tailor antimicrobial activity specific for each organism studied (Staphylococcus aureus or Mycobacteria). Each of the D/L-amino acids formed a diasteromeric complex with chiral centers on both the metal center and amino acid ligand. The unique chirality of each center elicits different antimicrobial activity against the Mycobacteria studied. The metal center (M), arene ligand (ηn-arene), and amino acid (aa), were changed independently and studied for the antimicrobial activity. In a similar fashion, each of the complexes modified with ethylenediamine and diamine derivatives were studied for their antimicrobial activity against S.aureus. All complexes were synthesized,characterized by nuclear magnetic resonance (NMR), high-resolution mass spectroscopy (HRMS), single-crystal X-ray diffraction, and elemental analysis. During the course of this work it was found that the amino acid complexes with all metal centers were specific for antimicrobial activity against all types of Mycobacteria, while the diamine derivatives were active against different strains of S.aureus. Acitvity was measured to be as low as 2 ug/mL respectively depending on the complex used. A structure activity relationship was developed to determine what combinations of ligand, metal and arene were necessary to achieve the highest antimicrobial activity. The optimal arene R-chain length for CpR was determined to be R=hexyl for all complexes studied. The most active amino acidcomplex was determined to be that of L-phenylglycine for Mycobacteria, the cis-1,2-diaminocyclohexane complex is the most active ligand against S.aureus. Each metal center had similar activity levels. Toxicological studies were performed to test their viablity to be used in mammalian systems. The complexes with the highest activity were studied against several mammailan cell lines and revealed that mammailan cells were undergoing normal cellular processes at up to 40 times the minimal inhibitory concentration (MIC). A study of the MOA or mechanism of action revealed the ability of the amino acid complexes to affect the peptidyl transferase region on the 23s ribosomal subunit of M.smegmatis. This was accomplished by isolating resistant strains of M.smegmatis towards the most effective complex (Cp*hexyl)Ir(L-phenylglycine)-Cl. Cross drug resistance of these mutants was shown with clarithromycin. The DNA of the 23s ribosomal subunit was sequenced revealing a deletion/insertion mutation within domain V (bases 2057-2058).
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    Transition metal diamine complexes with antimicrobial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA)
    Karpin, George W.; Morris, David M.; Ngo, Mai T.; Merola, Joseph S.; Falkinham, Joseph O. III (Royal Society of Chemistry, 2015-06)
    Pentaalkylcyclopentadienyl (Cp*R) iridium (Ir) and cobalt (Co) 1,2-diamine complexes were synthesized. Susceptibility of Staphylococcus aureus and recent patient methicillin-resistant S. aureus (MRSA) isolates to the transition metal–diamine complexes were measured by broth microdilution and reported as the MIC and MBC. Hemolytic activities of the transition metal-complexes as well as toxicity toward Vero cells were also measured. The transition metal complex of Cp*RIr with cis-1,2-diaminocyclohexane, had strong antibi- otic activity against S. aureus and MRSA (MIC = 4 μg mL−1, MBC = 8 μg mL−1) strains and killed 99% of S. aureus cells in 6 hours. Stronger antibiotic activity was associated with the presence of octyl linked to the cyclopentadienyl group and cyclohexane as the diamine backbone. Activity was greatly diminished by tri- or tetramethylation of the nitrogen of the diamine. A cyclopentadienylcobalt complex of cis-1,2-diamino- cyclohexane also showed significant anti-microbial activity against both S. aureus and MRSA strains. The absence of hemolytic activity, Vero cell cytotoxicity and the significant anti-microbial activity of several members of the family of compounds reported suggest this is an area worth further development.