Rational approaches to the correlation of chemical structure with biological activity

Brown, Ivor (1963) Rational approaches to the correlation of chemical structure with biological activity. PhD thesis, University of Glasgow.

Abstract

This thesis is divided into four distinct and self-contained parts whose unifying theme is contained in the general title "Rational Approaches to the Correlation of Chemical Structure with Biological Activity." Part I contains a physico-chemical approach to the problem, describing infrared spectroscopy studies made on several series of ortho-bromophenols with the object of determining the influence of steric compression, electronic and solvent effects, temperature, competitive intermolecular hydrogen-bonding and change of state on the intramolecular hydrogen bond normally found in these compounds. The postulate is made, based on suggestions in the literature, that the bactericidal activity of phenols could be dependent upon the ability of the phenolic hydroxyl group to bind with constituents of the living organism, and from the results obtained in the infrared studies, a prediction is made of the expected order of bactericidal potency of the compounds investigated. Part II describes a scheme for transforming the morphine ring system into the steroid ring system with a view to obtaining biologically-interesting 19-nor 9-substituted steroids bearing substituents capable of being utilised as centres for further reactions. The intermediates in the scheme would also be of considerable interest in view of the many attempts to produce analgesics devoid of addicting properties. The occurrence of an unexpected dimerisation in the first step of the projected conversions proved the original scheme to be unfeasible. Alternative procedures were not investigated owing to the lack of simplicity promised in the original. The dimerisation, which actually occurred in attempts to epimerise the hydrogen atom at c(14) in codeinone, is fully rationalised in terms of other work in the literature. Part III describes a traditional approach, that of chemically investigating a plant which has been reported to contain pharmacologically-active alkaloids and which has been used in native medical practice. The chemical examination of Bacopa monnieri (L) Pennel is reported in this instance, the alkaloidal content, however, being too small to permit of detailed investigation. The presence and characterisation of other organic components of the plant are reported. Part IV justifies the rationale of isosteric replacement in biologically-active molecules and deals with attempts to prepare 3-(2'-aminoethyl)-5-hydroxythionaphthen, the thionaphthen isostere of 5-hydroxytryptamine. Synthetic approaches to the thionaphthen isostere of 4-hydroxy-tryptamine are also descried. The first reported instance of a 16-memhered hydrogen-bonded dimer which was encountered during this work is recorded, and the formation of ortho diazo-oxides by the action of nitric acid on acetamido compounds is discussed.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: M Smith-Martin
• Keywords: Biochemistry
• Date of Award: 1963
• Depositing User: Enlighten Team
• Unique ID: glathesis:1963-73607
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jun 2019 08:56
• Last Modified: 14 Jun 2019 08:56
• URI: https://theses.gla.ac.uk/id/eprint/73607