Doctor of Philosophy / Department of Chemistry / Duy H. Hua / Four research projects were carried out and they are described in this dissertation. Glycogen synthase kinase-3 beta (GSK3β) plays a pivotal and central role in the pathogenesis of Alzheimer's disease (AD) and protein kinase C (PKC) controls the function of other proteins via phosphorylation and involves in tumor promotion. In pursuit of identifying novel GSK3β and/or PKC inhibitors, substituted quinoline molecules were designed and synthesized based on the structure-activity-relationship studies. Synthesized molecules were evaluated for their neural protective activities and selected molecules were further tested for inhibitory activities on GSK3β and PKC enzymes. Among these compounds, compound 2 was found to have better GSK3β enzyme inhibitory and MC65 cell protection activities at low nanomolar concentrations and poor PKC inhibitory activity whereas compound 3 shows better PKC inhibitory activity. This demonstrates the potential for uses of quinoline scaffold in designing novel compounds for AD and cancer. Pharmacokinetics and distribution profiles of two anti-Alzheimer molecules, CP2 and TP70, discovered in our laboratory were assessed using HPLC/MS. Plasma samples of mice and rats fed with TP70 via different routes over various times were analyzed to quantify the amounts of TP70 in plasma of both species. Distribution profiles of TP70 in various tissues of mice were studied and results show that TP70 penetrated the blood brain barrier and accumulated in the brain tissue in significant amounts. Similarly, the amount of CP2 in plasma of mice was analyzed. The HPLC analysis revealed that both compounds have good PK profiles and bioavailability, which would make them suitable candidates for further in vivo efficacy studies. Nanodelivery of specific dsRNA for suppressing the western corn rootworm (WCR, Diabrotica virgifera virgifera) genes was studied using modified chitosan or modified polyvinylpyrrolidinone (PVP) as nanocarriers. Computational simulation studies of dsRNA with these polymers revealed that nanoparticles can be formed between dsRNA and modified chitosan and PVP polymers. Nanocarriers of hydroxylated PVP (HO-PVP) and chitosan conjugated with polyethylene glycol (PEG) were synthesized, and analyzed using IR spectroscopy. Particle sizes and morphology were evaluated using AFM and encapsulation was studied using UV spectroscopy. However, the formation of stable nanoparticles with dsRNA could not be achieved with either of the polymers, and further efforts are ongoing to discover a better nanocarrier for nanodelivery of siRNA by using chitosan-galactose nanocarrier. In our efforts to discover a novel class of tripeptidyl anti-norovirus compounds that can strongly inhibit NV3CLpro, a set of tripeptidyl molecules were synthesized by modifying the P1 - P3 of the substrate peptide including a warhead. It was found that the replacement of P1 glutamine surrogate with triazole functionality does not improve the inhibitory activities of the compounds. In addition, the synthesis of a known dipeptidyl compound (GC376) was carried out for evaluating its efficacy on feline infectious peritonitis (FIP) in cats.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / Three research projects were carried out and they are described below. The synthesis of substituted phenolic compounds including halogenated di- and trihydroxybenzenes, aminophenols, and substituted di-tert-butylphenols are described. Redox potentials of the synthesized molecules along with various known laccase substrates were measured, and an inverse relationship between the oxidation potential and the efficiency of oxidation by laccase of halogenated hydroxybenzenes and aminophenols is demonstrated. The synthesized substituted phenols were found to be substrates but not inhibitors of laccase. We discovered a new class of di-tert-butylphenols compounds that inhibits the growth of mosquito larvae at low concentrations. Compound 17, 2,4-di-tert-butyl-6-(3-methyl-2-butenyl) phenol caused greater than 98% mortality of third-instar larvae of Anopheles gambiae in the concentration of 0.18 µM. These compounds do not inhibit laccases. It appears that they affect a new target of the mosquito that is different from those of currently existing pesticides. Two anti-Alzheimer molecules, CP2 and TP70, discovered in our laboratory were studied for their pharmacokinetics and distribution. The distribution of CP2 and TP70 in mouse brain region and various tissues of mice were examined. HPLC analysis revealed that CP2 treatment in primary neurons accumulates in mitochondria fraction. Similarly, the amount of CP2 in the brain tissue from wild type and APP/PS1 mice treated with 25 mg/kg/daily for 2 months also have the highest concentration in the mitochondria fractions in the hippocampus. The results show that CP2 and TP70 can penetrate the blood brain barrier and accumulate in the tissue in significant amounts. Pharmacokinetics and bioavailability of compound TP70 were determined. Area under the curve and bioavailability value F were calculated, and data show that TP70 has a good PK profile and bioavailability. For the preparation of a novel tripeptidyl norovirus 3C-like protease (3CL[superscript]pro) inhibitor, the P3 unnatural amino acid, (S)-3-hydroxyphenylalanine was synthesized. The P3 is designed to increase the polarity with the addition of the alcohol group. After combining the P3 unnatural amino acid with the P1 and P2 to form the novel tripeptidyl compound, a study comparing the relations between the structure and its activity (SAR) will confirm whether prediction is correct in our pursuit for an antiviral therapeutic drug in the form of a protease inhibitor.