This dissertation describes kinetic and mechanistic studies of high performance polyimide formation, synthesis and characterization of fully cyclized, molecular weight and end group controlled polyimides, and investigations of high performance polymer blends based upon polyimides and polybenzimidazole. Imidization kinetics were successfully followed by the quantitative non-aqueous titration of the amic acid functional groups as a function of reaction conditions. The homogeneous solution imidization processes were described by auto-acid catalyzed second order kinetics. The effects of heteroatom bridging groups in the diamines and dianhydrides on reaction rates have been investigated and a possible reaction mechanism for the solution imidization processes has been proposed. Detailed mechanistic investigations of the thermal solution imidization of polyamic acids were performed. A small amount of hydrolysis and possibly some unimolecular decomposition of amide bonds in the polyamic acid during thermal solution imidization processes were observed via combination of NMR and intrinsic viscosity measurements. However, complete "recombination" of the degraded polymer chains and their further cycloimidization could be achieved under proper imidization conditions. Potential side reactions involving intermolecular imide formation reaction were also investigated using a well characterized polyimide and also a model imide. For polyimide systems containing benzophenone tetracarboxylic acid dianhydride (BTDA), direct evidence for network formation involving imine crosslinking, was observed by high field lH-NMR spectroscopy. The gel formation was a strong function of reaction conditions, occurring under extremely dry reaction conditions and being favored at moderate reaction temperatures. Various polyimide homo- and copolymers with controlled molecular weight and end groups were synthesized by the classic two step method and their thermal properties and solution viscosities were evaluated. Further, miscibility behavior of high performance polymer blends based upon polyimide (PI) and polybenzimidazole (PBI) was investigated. Several miscible PI/PBI blend material systems were identified, some of which showed a lower critical solution temperature (LCST), which was consistent with earlier observations. It was found that miscibility was a strong function of polarity and possible specific interactions with the polyimide components. Thus, miscibility was possible over a wide composition range with polyimides containing polar groups such as ketones, sulfones and ethers. However, immiscible blends were obtained when these polar polyimide components were replaced by non-polar groups such as the hexafluoroisopropylidene linkages. / Ph. D.

This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Medicinal Chemistry / PhD / Dissertation

This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Medicinal Chemistry / PhD; / Dissertation;

Anthelmintic treatment of livestock is an important aspect of the control of gastrointestinal parasites. Resistance to anthelmintics is common, and an understanding of resistance requires knowledge of an anthelmintic's mode(s) of action and mechanism(s) of resistance. The parasitic nematode, Haemonchus contortus, has developed resistance to benzimidazoles and avermectins/milbemycins. Proposed mechanisms of resistance are here supported by genetic changes observed in genes whose protein products are believed to interact with these anthelmintics. Statistically significant differences in allele frequencies were observed between untreated and ivermectin- and moxidectin-treated strains in a gene encoding a putative glutamate-gated chloride channel alpha subunit, a proposed target of avermectins/milbemycins. One allele appeared to be associated with resistance. Similar changes in allele frequencies in the same strains occurred in a gene encoding a subunit of a gamma-aminobutyric acid receptor. Significant differences in allele frequencies of a gene encoding a P-glycoprotein were found in strains of H. contortus treated with ivermectin and moxidectin compared to derived, untreated strains. In all treated strains, one allele appeared to be associated with resistance. Similarly, allele frequencies of this gene were significantly different between a cambendazole-treated strain and its derived, untreated strain. These results implicate glutamate-gated chloride channels and gamma-aminobutyric acid receptors in mechanisms of resistance to avermectins/milbemycins and implicate P-glycoprotein in a mechanism of resistance to avermectins/milbemycins and benzimidazoles in H. contortus.

Association between albendazole anthelmintic resistance and a panel of life history traits in Heligmosomoides polygyrus was investigated both prior to and during drug-selection. Associations prior to anthelmintic application were studied in ten independent lines isolated without drug treatment from a susceptible stock population by random genetic drift. Variation among lines was detected in several life history traits (i.e., establishment, development and survival), and, despite lack of previous exposure to albendazole, lines also varied in their tolerance to the drug. No significant correlations were detected between drug-tolerance and any of the life history traits after 11 generations of isolation. The apparent lack of fitness differential between lesser and more drug-tolerant individuals of the susceptible population is not in accordance with the assumption that the low frequency of drug tolerant individuals in the susceptible population is explained by their lower fitness, but is consistent with the neutral theory. Associations between life history traits and drug resistance were also studied using two lines selected for albendazole resistance from the stock population, and two control lines exposed to the same monthly passage procedure but not to the drug. After 10 generations of selection, drug resistance increased from an LC50 of 0.48 $ mu$M to 2.03 $ mu$M. In a primary infection, the higher establishment and higher worm numbers one-month post-infection in the resistant parasites compared to the stock parasites occurred only in the drug-selected lines. Changes in these traits were attributed to the drug selection regime. In contrast, both drug-selected lines and passaged lines showed a faster rate of development and higher early egg production compared with the stock parasites; these changes were attributed to the passage procedure that presumably acted as a selective force on early life history traits. In immunized hosts, changes in several traits that o

The aim of this research was to determine the influence of route of administration, drug formulation and modified-liver metabolism on the pharmacokinetic and metabolic patterns of benzimidazole anthelmintics in ruminants. Both route of administration and formulation dramatically affected the bioconversion of netobimin (NTB) pro-drug, N-methoxycarbonyl-N$ sp prime$-(2-nitro-5-propylphenylthio)-${ rm N} sp{ prime prime}$-(2-ethyl sulphonic acid) guanidine, and the bioavailability and disposition kinetics of its active albendazole (ABZ) metabolites in both sheep and cattle. The efficacy of NTB conversion by the gastrointestinal (GI) microflora, was markedly lower after subcutaneous (SC) administration of NTB pro-drug compared with enteral administrations in both species. Although trisamine and zwitterion formulations of NTB were bioequivalent after SC treatment, the zwitterion suspension was two-fold more bioavailable in terms of ABZ metabolites, after oral administration to cattle. ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO$ sb2$), the main metabolites found in plasma, were reversibly exchanged between plasma and GI compartments and concentrated in the abomasum. ABZ, ABZSO and ABZSO$ sb2$ were detected in the GI tract for 72 h post-NTB administration to cattle. In vitro, ABZ was oxidized into ABZSO and ABZSO$ sb2$ by liver microsomes and ruminal and ileal fluids. However, only ABZSO was reduced (back to ABZ) by these GI fluids. The rate of ABZ sulphoxidation by liver microsomes was significantly lower in cattle compared to sheep. However, while the oxidizing activity was greater in GI fluids of cattle, the reducing activity was prevalent in those of sheep. This was consistent with the higher ABZSO$ sb2$/ABZSO ratio and the markedly faster disposition of both metabolites in cattle compared to sheep. The co-administration of NTB with different oxidation-impairing compounds, largely methimazole (MTZ), in both species, resulted in an increased bioavailability and/o

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2005. / Härtill 5 uppsatser.

Thesis (M.S.)--Duquesne University, 2009. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 106-112) and index.

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