Alkaloids of Dichroa Febrifuga Lour.

Kuehl, Frederick A.; Spencer, Claude F.; Folkers, Karl

doi:10.1021/ja01186a031

Cited by 70 publications

(28 citation statements)

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“…The medical use of chang shan was described in an ancient Chinese pharmacopoeia (17) for the treatment of malaria and stomach cancer and as an expectorant, emetic, and febrifuge, with side effects of nausea and vomiting (10). Febrifugine was extracted (7) and was later identified as a quinazoline derivative with the molecular structure C 16 H 21 O 3 N 3 (15). The purified febrifugine displayed potent antimalarial activity and was 100 times as active as quinine against P. lophurae in duck models and 50 times as active as quinine against P. cynomolgi infection in rhesus monkeys (12,13).…”

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confidence: 99%

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Jiang

Zeng

Gettayacamin

et al. 2005

Antimicrob Agents Chemother

125

102

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Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects. We report new findings on the effects of febrifugine analogs compared with those of febrifugine extracted from the dry roots of D. febrifuga. The properties of the extracted febrifugine were comparable to those obtained from the standard febrifugine provided by our collaborators. A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites. Neuronal (NG108) cells were even more insensitive to these drugs (selectivity indices, >1,000), indicating that a feasible therapeutic index for humans could be established. The analogs, particularly halofuginone, notably reduced parasitemias to undetectable levels and displayed curative effects in Plasmodium berghei-infected mice. Recrudescence of the parasites after treatment with the febrifugine analogs was the key factor that caused the death of most of the mice in groups receiving an effective dose. Subcutaneous treatments with the analogs did not cause irritation of the gastrointestinal tract when the animals were treated with doses within the antimalarial dose range. In summary, these analogs appear to be promising lead antimalarial compounds that require intensive study for optimization for further down-selection and development.

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mentioning

confidence: 99%

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Jiang

Zeng

Gettayacamin

et al. 2005

Antimicrob Agents Chemother

125

102

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“…The assay using febrifugine and isofebrifugine mixture from D. febrifuga roots also showed the activity in mice treated only at 1.0 mg/kg b.wt. It is reported that febrifugine showed approximately one hundred times the activity of quinine and isofebrifugine showed relatively slight activity against P. lophurae in ducks (Kuehl et al, 1948). It is possible that the properties or ratios of these alkaloids might be changed following fractionation.…”

Section: Discussionmentioning

confidence: 99%

“…Otaksa belongs to the family Saxifragaceae which includes Dichroa febrifuga Lour. from the roots of which the quinazolone alkaloid febrifugine has been isolated as a malariacidal constituent (Koepfli et al, 1947;Kuehl et al, 1948;Koepfli et al, 1949), and thus it was suggested that the active alkaloid of H. macrophylla var. Otaksa leaf extract might have the same principle as that of D. febrifuga.…”

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confidence: 99%

Comparison of antimalarial activity of the alkaloidal fraction of Hydrangea macrophylla var. Otaksa leaves with the hot‐water extract in ICR mice infected with Plasmodium yoelii 17 XL

Ishih

Miyase

Terada

2003

Phytotherapy Research

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The antimalarial activity of the fractions isolated from the leaves of Hydrangea macrophylla Seringe var. Otaksa Makino was evaluated against Plasmodium yoelii 17 XL in mice. Four different fractions were prepared in the usual manner to obtain an alkaloid fraction. All mice treated with the fraction containing febrifugine and isofebrifugine mixture at 1 mg/kg twice a day for 5 consecutive days survived during the experiment, and the change of mean parasitemia level showed almost the same pattern as that from mice treated with the hot-water extract of the same plant leaves. Activity of this fraction, however, was markedly reduced compared with the hot-water extract. Furthermore, no antimalarial activity was shown in the hotwater extract from H. macrophylla var. Otaksa roots or Dichroa febrifuga Lour. leaves.

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“…Oshima and co-workers [28] reported the isolation and structural elucidation of two primary metabolites of febrifugine after its incubation for 1 hour at 37°C with mouse liver S9. Febrifugine is a highly potent anti-malarial alkaloid isolated from the roots, stem and leaves of the plant Dichroa febrifuga , a Chinese herb locally referred to as Chang Shan [29]. One of the major metabolites designated feb-A (Figure 1) showed extremely potent in vitro anti-plasmodial activity.…”

Section: Metabolism and Metabolite Identification Studiesmentioning

confidence: 99%

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Guantai

Chibale

2011

Malar J

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Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds.

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Alkaloids of Dichroa Febrifuga Lour.

Cited by 70 publications

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Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Comparison of antimalarial activity of the alkaloidal fraction of Hydrangea macrophylla var. Otaksa leaves with the hot‐water extract in ICR mice infected with Plasmodium yoelii 17 XL

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

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