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2. Molecular modelling analysis of
the metabolism of nitroimidazoles
Fazlul Huq
School of Biomedical Sciences, Faculty
of Health Sciences, The University of Sydney, Australia,
f.huq@fhs.usyd.edu.au
(Received 26 November 2005; accepted
21 February 2006)
Abstract:
Metronidazole (MNZ) and some other derivatives of 5-nitroimidazole are
potent drugs that provide effective therapy against protozoa such as
trichomas vaginalis, ameliosis and giardosis, in addition to being
effective against anaerobic bacterial infections. Nitroimidazoles are
also used to treat coccidiosis and histomoniasis in poultry. Examples
of other nitroimidazoles include ronidazole (RNZ), dimetridazole (DMZ)
and ipronidazole (IPZ). Common side effects of MNZ include nausea,
vomiting, headache, insomnia, dizziness, drowsiness, dry mouth and
metallic taste; more serious ones are eosinophilia, leukopenia,
palpitation, confusion and peripheral neuropathy. Nitroimidazoles have
been suspected of possessing carcinogenic and mutagenic properties.
Nitroimidazoles are metabolized primarily in the liver by oxidation of
side chain and glucuronidation. Oxidative metabolism of MNZ produces
two main metabolites, 1-acetic acid-2-methyl-5-nitroimidazole (AAMNZ)
and 1-(2-hydroxyethyl)-2-hydroxy- methyl-5-nitroimidazole (MNZOH). The
latter can be further metabolized to 2-hydroxymethyl-5-nitroimidazole-1-acetic
acid (AAM). In anaerobic organisms, 5-nitro group of the imidazole
ring MNZ is reduced to reactive intermediates via one electron
reduction to nitro radical anion. DMZ and RNZ are metabolized to
hydroxydimetridazole (DMZOH) whereas ipronidazole is metabolized to
hydroxy- ipronidazole (IPZOH). Molecular modelling analyses based on
molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G*
level) calculations using the program Spartan ’02 show that MNZ, DMZ,
RNZ, IPZ and their metabolites differ to some extent in their
solvation energy, surface charge distribution, dipole moment,
thermodynamic stability and kinetic lability. AAMNZ appears to be most
labile kinetically and hence most toxic. Closeness or overlap of
regions of negative electrostatic potential and HOMOs having high
electron density at some positions e.g. oxygen atoms of the nitro
group, give further support to the idea that the positions may be
subject to electrophilic attack.
Keywords:
Metronidazole, nitroimidazole,
ipronidazole, trichomoniasis, anaerobic bacteria, molecular modelling
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