The cestode E. multilocularis causes the disease alveolar echinococcosis (AE) in humans. The continuously proliferating metacestode (larval stage) of the parasite infects mostly the liver and exhibits tumor-like growth. Current chemotherapeutical treatment options rely on benzimidazoles, which are rarely curative and have to be applied daily and life-long. This can result in considerable hepatotoxicity and thus treatment discontinuation. Therefore, novel drugs against AE are urgently needed. The anti-malarial mefloquine was previously shown to be active against E. multilocularis metacestodes in vitro, and in mice infected by intraperitoneal inoculation of metacestodes when administered at 100 mg/kg by oral gavage twice a week for 12 weeks. In the present study, the same dosage regime was applied in mice infected via oral uptake of eggs representing the natural route of infection. After 12 weeks of treatment, the presence of parasite lesions was assessed in a liver squeeze chamber and by PCR, and a significantly reduced parasite load was found in mefloquine-treated animals. Assessment of mefloquine plasma concentrations by HPLC and modeling using a two-compartment pharmacokinetic model with first-order absorption showed that >90% of the expected steady-state levels (Cmin 1.15 mg/L, Cmax 2.63 mg/L) were reached. These levels are close to concentrations achieved in humans during long-term weekly dosage of 250 mg (dose applied for malaria prophylaxis). In vitro structure-activity relationship analysis of mefloquine and ten derivatives revealed that none of the derivatives exhibited stronger activities than mefloquine. Activity was only observed, when the 2-piperidylmethanol group of mefloquine was replaced by an amino group-containing residue and when the trifluoromethyl residue on position 8 of the quinoline structure was present. This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against malaria.
Both sonochemical and classical methodologies have been employed to convert camphor, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, C9H16C=O, into a number of derivatives including hydrazones, C9H16C=N-NHAr 3, imines, C9H16C=N-R 7, and the key intermediate nitroimine, C9H16C=N-NO2
6. Reactions of nitroamine 6 with nucleophiles by classical methods provided the desired compounds in a range of yields. In evaluations of activity against Mycobacterium tuberculosis, compound 7j exhibited the best activity (minimal inhibitory concentration (MIC) = 3.12 µg/mL), comparable to that of the antitubercular drug ethambutol. The other derivatives displayed modest antimycobacterial activities at 25–50 µg/mL. In in vitro tests against cancer cell lines, none of the synthesized camphor compounds exhibited cytotoxic activities.
Background and Introduction:
Mefloquine, a drug used to prevent and treat malaria is described
possessing activity against the Mycobacterium tuberculosis (Mtb) as well as against multidrugresistant
tuberculosis (MDR) and other types of bacteria. Despite their importance, few compounds
based on the Mefloquine nucleus have been synthesized and evaluated against TB.
Materials and Methods:
For the synthesis of all the compounds based on the Mefloquine nucleus we
used a synthetic route which utilized the key derivative 4-methoxy-2,8-bis(trifluoromethyl)quinoline 2
as starting material. The compounds 3 (a-c), 4 (a-b) were synthesized after one step by reaction of 2 with
appropriate amines substituted. The chloro derivatives 5 and 6 were obtained from compounds 4b and
4a by treatment with SOCl2 in CH2Cl2 at reflux in 75 and 80% yield, respectively. The analogue 6 was
converted to 7 after treatment with ethanolamine under heating at 90oC in 64% yield and to the azido
derivative 8 in 56% after reaction with sodium azide in MeOH at reflux for 2 h. The analogue 9 was obtained
after reaction of 5 with ethanolamine at 90oC for 1 h in 90% yield. All the new compounds were
identified by detailed spectral data, including 1H NMR, 13C NMR and high resolution mass spectra. All
the compound were evaluated for their in vitro antibacterial activity against sensitive Mycobacterium
tuberculosis ATCC 27294, using the microplate Alamar Blue assay (MABA). The more active compounds
3c, 7, and 9 were also evaluated against resistant strain SR 2571/0215 (resistant to Rifampicin
and Isoniazid) by above method. All compounds were tested against three cancer cell lines: SF-295
(glioblastoma), HCT-116 (colon) and PC-3 (prostate) using the MTT assay.
Results:
All the planned ten compounds were synthetically obtained in good global yield, displaying
activity against sensitive Mycobacterium tuberculosis in vitro, with exception of one, with MIC values
between 37.2 and 154.8 µM. The compounds 3c (37.2 µM), 7 (68.1 µM) and 9 (65.6 µM) showed the
highest activity in this series with MIC values similar when compare to the standard Mefloquine (30 –
60 µM), being 3c the most potent. The more active compounds 3c, 7, and 9 were also evaluated against
resistant strain, displaying MIC of 37.2, 136.2 and 65.6 µM, respectively. All compounds were tested
against three cancer cell lines and showed low cytotoxicity.
Conclusion:
All synthesized compounds, with the exception of 5, exhibited activity against the Mtb.
Compound 3c was the most potent against resistant and sensitive Mtb in this series, with MIC value of
37.2 µM. All compounds showed low cytotoxicity. These findings could be considered a good model to
develop possible lead compounds in the fight against TB based on Mefloquine nucleus.
This study describes a simple multigram-scale procedure for the preparation of (E)-N-(1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ylidene)nitramide, nitro-imine 2, by using both classical methods and
ultrasound irradiation from 1 utilizing Camphor, a natural product, as starting material. This key intermediate
2, a good building block, is useful to prepare various substances such as terpenoids, reagents
for large-scale hydroxylation and amination of organic substrates, and derivatives with anticonvulsant,
hypoglycemic, anti-inflammatory, antimicrobial and antiviral activities. It can be transformed into a
wide range of other derivatives which can then also be employed in inorganic chemistry. In this work,
another useful derivative (E)-2-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)ethanol 3 has
been prepared from nitro-imine 2 on multigram-scale which also allows access to a variety of products
of biological interest after suitable chemical transformations.
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