The three most likely intermediates in the mechanism of
action of 5-nitroimidazole antibiotics (the radical anions
of nitroimidazoles, imidazol-5-yl radicals and 5-nitroso
imidazoles) have been studied.
A range of 5-nitroimidazoles have been synthesised and
analysed by electron spin resonance spectroscopy, (e.s.r.)
and the electron spin density of their radical anions has
been determined. Under reducing conditions known to proceed
by a radical mechanism, a number of 5-nitroimidazoles did
not undergo intramolecular cyclisation, [e.g. 1-(but-3-en-1-
yl)-2-methyl-5-nitroimidazolel, form stable covalent adducts
with nucleotide bases, or dissociate to nitrite anions and
the corresponding imidazol-5-yl radicals. This disproves
the putative explanation for the generation of nitrite
anions in the antimicrobial mode of action of 5-
ni troimidazoles. A mechanism has been proposed to explain
the release of nitrite in the mechanism of action of 5-nitroimidazoles [continued]…
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.
The Boots Company Ltd. Bombay, the Boots Company p.l.c.
(Nottingham) and Science Engineering Research Council of Great Britain.