The synthesis and evaluation of some anti-infective agents

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Allcock, R.W., 2000. The synthesis and evaluation of some anti-infective agents. PhD, Nottingham Trent University.

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Abstract

Previous research at The Nottingham Trent University, directed towards the synthesis and evaluation of novel specific calmodulin antagonists, identified a series of compounds with the general structure Ar-0-(CH2)nNR2 as possessing significant antifungal activity. In the present study the most potent, PCAB 300, has been subjected to a variety of structural modifications to improve its potency in a broad- spectrum human pathogenic fungal screen operated by Zeneca Pharmaceuticals.

A significant increase in potency was achieved by the substitution of the pyrrolidine moiety of PCAB 300 with methylamine. The investigation also established that the structural features required for optimal in vitro antifungal activity are a naphthalene ring substituted in the 6-position by bromine and in the 2-position by an alkoxy side chain, of eight to ten carbons long, possessing a terminal N-methyl substituent.

The results of this investigation are the subject of a patent application, UK-9922446.1 (1999), by BTG, and it is intended that selected potent inhibitors will undergo further in vivo and in vitro testing.

The palmarumycins are a structurally related and diverse class of biologically active natural products which contain a unique spiro-acetal moiety, formally derived from 1, 8-dihydroxynaphthalene, linked to a second naphthalene ring at rich and varied levels of oxidation. Palmarumycin CP , structurally the least complex, was selected as a suitable synthetic target for both a synthetic and biological investigation.

A novel series of palmarumycin analogues were prepared, either by the direct oxidative cyclisation of aminonaphthyloxynaphthols, or by the cycloaddition of 3- oxo-2-pyrones to a novel series of quinone monoacetals. Thermal conditions gave poor to moderate yields, but high pressure led to quantitative conversion. Spectral data indicated that the cycloaddition reactions occurred with a high degree of site-, regio-, and stereo-selectivity which was dependant upon the substitution pattern of the quinone monoacetals. An account of this study has been published (Tetrahedron Letters, 2000, 41, 9105).

In general the quinone monoacetals and cycloaddition products that possessed an unsubstituted enone system showed significant activity against methicillin resistant Staphylococcus aureus (MRSA), with MIC values less than 10ppm. In contrast substituted cycloaddition products were inactive, which suggests that the biological activity of the compounds is reflected by their ability to act as Michael acceptors, and they are therefore unlikely to act as lead compounds for clinically useful antimicrobial agents.

Item Type:

Thesis

Creators:

Allcock, R.W.

Date:

2000

ISBN:

9781369325607

Identifiers: