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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, January 1999, p. 73-76, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Efficacy of New 5-Nitroimidazoles against
Metronidazole-Susceptible and -Resistant Giardia,
Trichomonas, and Entamoeba spp.
Jacqueline A.
Upcroft,1,*
Raymond W.
Campbell,1
Kamel
Benakli,2
Peter
Upcroft,1 and
Patrice
Vanelle2
The Queensland Institute of Medical Research,
Brisbane, Queensland 4029, Australia,1 and
Laboratoire de Chimie Organique, Université de la
Méditerranée, Faculté de Pharmacie, 13385 Marseille
Cedex 05, France2
Received 17 February 1998/Returned for modification 19 June
1998/Accepted 12 October 1998
 |
ABSTRACT |
The efficacies of 12 5-nitroimidazole compounds and 1 previously
described lactam-substituted nitroimidazole with antiparasitic activity, synthesized via SRN1 and subsequent reactions,
were assayed against the protozoan parasites Giardia
duodenalis, Trichomonas vaginalis, and
Entamoeba histolytica. Two metronidazole-sensitive lines and two metronidazole-resistant lines of Giardia and
one line each of metronidazole-sensitive and -resistant
Trichomonas were tested. All except one of the compounds
were as effective or more effective than metronidazole against
Giardia and Trichomonas, but none was as
effective overall as the previously described 2-lactam-substituted
5-nitroimidazole. None of the compounds was markedly more effective
than metronidazole against Entamoeba. Significant
cross-resistance between most of the drugs tested and metronidazole was
evident among metronidazole-resistant lines of Giardia and
Trichomonas. However, some drugs were lethal to metronidazole-resistant Giardia and had minimum lethal
concentrations similar to that of metronidazole for drug-susceptible
parasites. This study emphasizes the potential in developing new
nitroimidazole drugs which are more effective than metronidazole and
which may prove to be useful clinical alternatives to metronidazole.
| |
INTRODUCTION |
The introduction of
nitroheterocyclic drugs in the late 1950s and the 1960s heralded a new
era in the treatment of infections caused by gram-negative and
-positive bacteria and a range of pathogenic protozoan parasites. The
antibiotic azomycin (a 2-nitroimidazole), isolated in Japan from a
streptomycete, was the first active nitroimidazole to be discovered
(15) and acted as the main impetus for the systematic search
for drugs with activity against anaerobic protozoa. This led to
the synthesis of the 5-nitroimidazole metronidazole (1-
-hydroxyethyl-2-methyl-5-nitroimidazole) and the
demonstration of its activity against Trichomonas vaginalis
by Cosar and Julou (6). Subsequently, metronidazole was
shown to cure giardiasis (21), amoebiasis
(18), and Balantidium infections (7). Metronidazole is the drug now most widely used in the treatment of
anaerobic protozoan parasitic infections caused by T. vaginalis, Giardia duodenalis, and
Entamoeba histolytica (22). It is
remarkably safe compared with the toxic amoebicide emetine
(12) and is the recommended alternative for the treatment of
amoebiasis. Although failures of the treatment of liver abscess and
dysentery with metronidazole have been reported (12), no
clinical resistance has been reported in E. histolytica.
Metronidazole and the related nitroimidazole tinidazole (which is not
available in some countries) are also the only drugs effective for the
treatment of trichomoniasis and are the drugs of choice for the
treatment of giardiasis (26). In the latter cases clinical
resistance to these drugs has been documented (9, 26, 31).
In the event of overt clinical resistance to metronidazole in the
anaerobic protozoa, there is no alternative treatment for either
trichomoniasis or invasive amoebiasis, keeping in mind the documented
cross-resistance between currently used nitroimidazole drugs
(22) and worldwide availability. On the positive side, a
great deal of flexibility is offered by the side chains attached to the
imidazole ring structure bearing the all-important nitro group. Since
the discovery in 1966 (13, 13a, 19) that alkylation of
ambident anions by p-nitrobenzyl chloride is an
electron-transfer chain process termed SRN1
(11), the extensions at the sp3 carbons attached to
heterocyclic systems have been studied extensively (3). A
most attractive feature of SRN1 reactions is that they proceed under very mild conditions and produce excellent yields of pure
products. As a consequence, they are especially valuable for the
synthesis of a large number of complex and highly branched compounds.
Recently, 5-nitroimidazole derivatives including the lactam-substituted
nitroimidazole have been shown to be significantly more effective
antiprotozoal agents than metronidazole (8, 30). In the
study described here we examined the activities of other new
5-nitroimidazole compounds against metronidazole-sensitive and
-resistant G. duodenalis (synonymous with Giardia
lamblia and Giardia intestinalis) and T. vaginalis and against E. histolytica, the three most
medically important anaerobic protozoa.
| |
MATERIALS AND METHODS |
Drugs.
All compounds used in this study were identified by
spectral data, purified by chromatography on silica gel columns, and
recrystallized from appropriate solvents. Their purity was checked with
appropriate controls by thin-layer chromatography and elemental
analysis (C, H, N). The purity was always over 99.6%. The synthesis,
structural identification, and purity of compounds 1, 2, 3, 4, 5, 6, 7, 8, and 13 have been reported previously (8, 27, 28). Data for products 9, 10, 11, and 12 were presented at 33rd International Meeting on Medicinal Chemistry (28a).
Briefly, the
3-chloro-2-chloromethyl-1-(1-methyl-5-nitroimidazol-2-yl)prop-1-ene
compound (compound 1) reacted with the 2-nitropropane anion and led to
products 2, 3, and 4 formed by an initial SRN1 mechanism
followed by an SN2 or SN2' and Michael
reactions or another SRN1 reaction, respectively
(28) (Fig. 1). The extension of the bis-SRN1 reaction to
2,2-dimethyl-5-nitro-1,3-dioxane salt led to compound 5 (27). Base-promoted nitrous acid elimination from
bis-C-alkylation products gave mono- or diunsaturated compounds 6, 7, and 8 (Fig. 1).
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FIG. 1.
Structures of new 5-nitroimidazoles. The formula and
molecular weight (MW) of the compounds used in this study are
presented. MZ, metronidazole.
|
|
Compounds 9 and 10 were synthesized by the reaction of the bis-chloride
(compound 1) with p-toluenesulfinic salt in dimethyl sulfoxide. The E and Z isomers (compounds 11 and
12, respectively) were obtained by the LD-SRN1 mechanism
after subjecting compound 9 to 2-nitropropane anion (Fig. 1).
Compound 13 was prepared by reacting
1-methyl-2-chloromethyl-5-nitroimidazole with
1-methyl-3-nitro-2-pyrrolidinone anion under phase-transfer catalysis
(8) (Fig. 1).
Metronidazole (Fig. 1) was from Sigma. All drugs were dissolved in
chromatography-grade dimethylformamide (DMF) (Sigma) at 100 mM and were
diluted into medium as required.
Cultures.
All strains used in this work are described in
Table 1.
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TABLE 1.
MLC of metronidazole for metronidazole-sensitive and
metronidazole-resistant G. duodenalis,
T. vaginalis, and E. histolytica
|
|
Growth Conditions.
Giardia and Trichomonas
parasites were grown in TYI-S-33 medium supplemented with bile (1 mg/ml; Sigma) (17). The same medium without bile was used
for Entamoeba. Parasites were grown at 37°C (35.5°C for Entamoeba) in filled 5-ml plastic
tubes and were maintained upright. Giardia and
Trichomonas trophozoites were subcultured every 2 to 3 days,
and Entamoeba trophozoites were subcultured every 3 to 4 days.
Metronidazole-resistant lines of protozoa were maintained in culture in
the presence of metronidazole (Table 1).
Drug assays.
Trophozoites for drug assays were
harvested in the mid-logarithmic phase of growth and were distributed
identically among 5-ml tubes; 2 × 105 to 9 × 105 Giardia trophozoites, 2 × 106 to 7 × 106 trichomonads, and 3 × 104 Entamoeba parasites were seeded
per ml. On the following day different concentrations (0.5, 1, 5, 10, 50, 100, and 500 µM) of drugs in a maximum volume of 25 µl of DMF
were added to the tubes, and the parasites were allowed to grow for 3 days in the presence of drug. Twenty-five microliters of DMF alone did
not affect the parasites. For assays of antigiardial activity, all the
medium including unattached trophozoites was removed after 3 days and
was replaced with fresh medium without drug. Medium and unattached
Entamoeba parasites were also removed after 3 days. For drug assays with trichomonads, the tubes were centrifuged, the
medium containing drug was removed but the trophozoites and debris were
left in place, and fresh medium was added. After a further 4 days the
assay was terminated.
Metronidazole-resistant Giardia and Trichomonas
parasites were allowed to grow without metronidazole for 2 days prior
to the commencement of the drug assays.
Parasite viability was evaluated on each day and was finally scored on
the basis of a viable or nonviable culture. The viability score did not
depend on the numbers of parasites present but depended on the presence
of live (motile) parasites. It was important to score the cultures on a
daily basis because the organisms in some cultures, particularly those
containing the Trichomonas strain that we used, grew very
rapidly. In some assays, untreated controls and cultures with low
levels of drug reached maximum growth prior to the change of medium
or soon afterward and were in decline by the end of the assay.
These cultures were scored as viable. The data presented in Table 2 do
not indicate whether confluent cultures versus only a few live
parasites were obtained at the end of the assay.
The antiprotozoal activities of all of the drugs were compared with
that of metronidazole within the same experiment. The minimum lethal
concentration (MLC) of metronidazole was estimated as the lowest
concentration of drug with which no viable organisms were observed at
the termination of the assay.
| |
RESULTS |
Drug assays.
In the assays described here the MLCs of
metronidazole for susceptible strains were 50 to 100 µM, which are
consistent with those in previous reports (10, 16) but
higher than the previously reported doses of metronidazole inhibitory
for Giardia which have relied on a variety of criteria
(26). The MLC of about 10 µM metronidazole for
Entamoeba and the MLC of 100 µM (16 µg/ml)
metronidazole for Trichomonas grown under anaerobic
conditions are similar to previously reported MLCs (see reference
20 and references therein; 14).
The high levels of metronidazole resistance that developed in
Giardia lines WB1B-M3 and BRIS/83/HEPU/106-2ID10
and the Trichomonas line BRIS/92/STDL/F1623-M1 are described
in Table 1.
The activities of the 12 new 5-nitroimidazole compounds tested and 1 previously tested compound were compared with that of metronidazole
against the test organisms (Table 2). The
aim of this study was to identify those compounds which were
consistently and significantly more effective than metronidazole
against Giardia, Trichomonas, and
Entamoeba. All compounds except compound 3 were as
effective or more effective than metronidazole, and none was as
effective as compound 13 against all three parasite species tested.
Compounds 4, 6, 7, 10, 11, 12, and 13 demonstrated increased activity
over that of metronidazole against Giardia and
Trichomonas. Compounds 1, 2, and 13 maintained similar
levels of activity against metronidazole-sensitive and -resistant
Giardia parasites. When we assayed parasites of
Giardia sp. strain BRIS/83/HEPU/106 against several of the
most effective drugs (compounds 4, 6, 10, 12, and 13) on three
occasions, the MLCs ranged between <1 and 5 µM on all
occasions.
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TABLE 2.
Antiprotozoal activity of nitroimidazole derivatives
against metronidazole-sensitive and metronidazole-resistant strains
of G. duodenalis, T. vaginalis, and
E. histolyticaa
|
|
Metronidazole-resistant Trichomonas was generally resistant
to the same concentrations of all of the nitroimidazole compounds tested.
| |
DISCUSSION |
The observations that important antibacterial and antiprotozoal
activities of nitroimidazoles are associated with reductive metabolism
have led to considerable interest in nitroimidazole reduction chemistry
and the synthesis of new, highly effective drugs. Recently, we
demonstrated that 1-methyl-2-chloromethyl-5-nitroimidazole reacted by
the SRN1 mechanism with various aliphatic, cyclic, or
heterocyclic nitronate anions led to a new class of 5-nitroimidazoles bearing a trisubstituted double bond at the 2 position (8, 29). The subsequent structure-activity relationships
revealed that the most antimicrobial and antiparasitic compounds
showed a greater resonance conjugation in the molecular
structure. In order to increase the conjugate system and in connection
with mechanistic studies, we have synthesized new mono- and
bis-alkylating agents and explored their reactivities with nitronate
anions. The structures and antiprotozoal activities of these compounds are described here.
A great deal of variation in the antiprotozoal efficacies of the 13 compounds tested was revealed. Only one compound was less effective than metronidazole against all three species of protozoa examined. All other compounds were as effective or more effective than
metronidazole against some or all organisms tested. The
lactam-substituted compound (compound 13) was significantly more
effective than metronidazole against Giardia (50 to 100 times more effective) and Trichomonas (50 times more
effective), but against the Entamoeba strain that we
used the compound was not as effective as it was previously (30). Compound 3 was uniformly less effective than
metronidazole on every occasion in which it was tested, showing that
the substitution on the imidazole ring by an acyl group resulted in a
loss of antiprotozoal activity. The influence of the substitution
by one or two alkylnitromethyl groups (compounds 4 and 6) was also
noted, and the highly conjugated imidazoles (compounds 7 and
8) were generally less active than the corresponding
bis-C-alkylation product (compound 4) or the monounsaturated product
(compound 6). However, only compound 13 remained very effective
against the metronidazole-resistant Giardia lines
BRIS/83/HEPU/106-2ID10 and WB1B-M3.
The new compounds tested have side chains that are more hydrophobic
than those of metronidazole, and in some cases this may reflect the
increased activities of the new compounds because the site of
metronidazole activation in the anaerobic protozoa is the
membrane-localized electron transport pathway (4, 22, 24).
Whether the increased hydrophobicity would be detrimental or otherwise
to the activities of these drugs in vivo remains to be tested.
With the clinical nitroimidazole resistance in Trichomonas
being well documented, there is clearly a great need for the
development of new antiparasitic drugs. However, cross-resistance
among the nitroimidazole drugs in Giardia and
Trichomonas has been documented previously (2,
26) and was again demonstrated in this study. Except for compound
13 (which was effective against metronidazole-resistant Giardia), no drug is likely to be uniformly more
effective than metronidazole in vivo against highly
metronidazole-resistant parasites.
The mechanism of action of metronidazole in anaerobes requires
reduction of the critical nitro group to toxic radicals by ferredoxin,
which itself is reduced by the membrane-localized enzyme
pyruvate:ferredoxin oxidoreductase (PFOR) (22). In highly metronidazole-resistant Trichomonas, which we have used in
these studies, there is no PFOR or ferredoxin (4), and
metronidazole and the other 5-nitroimidazoles tested here were not
activated in these organisms. In metronidazole-resistant
Giardia, although PFOR activity is decreased
(24), it is still detectable and is thus able to activate
5-nitroimidazole drugs, as we have seen in this study. In both these
parasites we have reported alternative oxoacid oxidoreductases which do
not apparently reduce the characterized ferredoxins and which are at
least as active or more active in metronidazole-resistant lines than in
their drug-sensitive parent strain (4, 24). These
alternative pathways in the anaerobic protozoa are poorly understood
and may well be the targets of highly active 5-nitroimidazoles or
related compounds. For this reason and with the encouraging results
obtained with compounds such as the lactam-substituted nitroimidazole
(compound 13), continued assessment of new 5-nitroimidazole drugs is
extremely worthwhile.
| |
ACKNOWLEDGMENT |
This work was supported by grants from the National Health and
Medical Research Council of Australia.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: The Queensland
Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. Phone: 61 7 3362 0369. Fax: 61 7 3362 0105. E-mail: jacquiU{at}qimr.edu.au.
| |
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Antimicrobial Agents and Chemotherapy, January 1999, p. 73-76, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
