This thesis describes several synthetic approaches to some novel indole alkaloids. The Introduction (Chapter One) outlines the need for continuous discovery of new antibiotics in todays environment. The family of Kinamycin antibiotics is described along with their biosynthesis and the evidence of the novel biosynthetic precursor known as Pre-Kinamycin. Chapter Two (2.1) deals with a retrosynthetic analysis leading to a study of Tandem Directed Ortho-Metallation reactions and a proposed synthesis of Pre-Kinamycin. Section 2.2 describes the study of stable analogues of indole-2,3-quinodimethane and the Dials–Alder reactions thereof. Also Dials-Alder reactions of pyrano[3,4-b]indol-3-ones with benzyne and the subsequent manipulation of the carbazole-based products are detailed. Section 2.3 outlines the study of the Friedel–Crafts acylation reaction with respect to the indole nucleus and the application of such a reaction to the synthesis of the Pre-Kinamycin skeleton. Investigations into acid mediated cyclisations to form quinones and the use of Weinreb amides as acylating agents are also described. Chapter Three (3.1) examines the problems of iron overload diseases (haemochromatosis) and the efforts to produce effective iron chelators. Section 3.2 describes the discovery of four novel indole alkaloids known as Uvarindoles and their possible consideration as iron chelators. Section 3.3 examines two retrosynthetic analyses towards Uvarindole B and the investigation into the synthesis thereof, involving similar methodology as that developed in section 2.3. Chapter Four describes the relevant experimental details for the intermediates described in sections 2.1 through 3.3 and the respective spectroscopic data obtained. Chapter Five gives the references for all the relevant work quoted in above sections.

Rate coefficients for the inactivation of several penicillin in acids and alkalis at 30°C have been determined by means of ultraviolet spectroscopy. The case of benzylpenicillin, though well investigated in the past, has been studied again and, in the light of new experiments, a scheme detailing the proportions of the various degradation products has been proposed. A number of substituted phenylpenicillins have been synthesised, and their reactions with acid have been investigated. Product analysis was carried out by means of TLG and NMR studies, the degradation products (penicilloic, penilloic, penillic and penicillenic acids) having been previously prepared and characterised. From the manner in which the phenyl substituent on the penicillin affects the rate coefficient, it is deduced that the mechanism of inactivation by acids involves a rate-determining intramolecular attack by the side-chain carbonyl group on the protonated β-lactam function. An intermediate oxazolone-thiazolidine structure is formed, which then reacts further by three different pathways. The proportions of the products obtained from the phenylpenicillins are different from those obtained from benazylpenicillin, principally because the phenylpenicillenic acids are easier to form and are less reactive towards acid than is benzylpenicillenic acid. The imidazole-catalysed isomerisation of benzylpenicillin into penicillenic acid has been studied. This reaction was investigated using a number of substituted imidazoles and, from the rate equations which were obtained, a unified reaction mechanism has been proposed. This involves a rate-determining proton-transfer to an intermediate penicilloylimidazole complex, which is followed by fast ring opening and expulsion of imidazole. Some studies on the novel mono-cyclic β-lactam antibiotic nocardicin A have been carried out; its reaction in dilute and moderately-concentrated acid has been studied. It is proposed that the mechanism of hydrolysis involves a fast β-lactam cleavage followed by slower hydrolysis of the oxime function. Unlike most oximes, that of nocardicin A was found to hydrolyse faster as the acidity was increased. It is suggested that this unusual behaviour arises from the proximity of an amide group to the oxime. Similar behaviour has been observed for benzoyl formamide oxime.

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Class of 2011 Abstract / OBJECTIVES: To determine the appropriateness of antimicrobial therapy in patients initiated on empiric meropenem therapy. METHODS: Adult patients prescribed empiric meropenem therapy between January 1, 2010 and March 31, 2010 at a tertiary care, academic medical center were included. Data collected included site of infection, culture and susceptibility data, risk factors for multi-drug resistant organisms, and changes in antimicrobial therapy during the first seven days after meropenem therapy was initiated. Demographic variables included age, sex, weight, and race. RESULTS: RESULTS: A total of 89 patients were included in the study analysis. Initial culture(s) was obtained before administration of antibiotics in only 58% of patients. During the first 24 hours of admission, four or more different antibiotics were prescribed in 26% of patients often with overlapping spectrums of activity. The majority of patients received meropenem for either less than 1 day or greater than 4 days. CONCLUSION: The primary issues identified with appropriate antibiotic prescribing involved the timing of cultures, and multiple changes in antibiotic therapy without culture-driven reasoning.

Class of 2011 Abstract / OBJECTIVES: To evaluate the quality of evidence in the literature substantiating major drug-drug interactions of the macrolide antibiotics azithromycin, clarithromycin, and erythromycin with digoxin, ergot alkaloids, and pimozide. METHODS: In this descriptive retrospective analysis, a list of articles reporting on each drug-drug interaction was compiled from the online databases Medline and International Pharmaceutical Abstracts, and the drug compendia Micromedex and Facts & Comparisons. The studies included in this analysis were primary literature reports, written in English, and consisted of human subjects. All studies included were evaluated using a 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions (van Roon scale). This scale rates the study type from lowest to highest quality, from zero to four. Case reports were additionally analyzed using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. RESULTS: Thirty-seven studies met the selection criteria. There were 28 studies involving digoxin, two studies involving pimozide and seven studies involving ergot alkaloids. The mean quality of evidence score on the van Roon scale was 2.3 + 0.75, where digoxin studies had a score of 2.3 + 0.74, ergot alkaloids had a score of 1.9 + 0.38 and pimozide only had two studies with evidence scores of 2 and 4. Sixty-two percent of the studies reviewed were case reports. CONCLUSION: The reports substantiating some drug-drug interactions may be of low quality and few in number.

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