Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Abstract

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.

Association of Aminoacyl-tRNA Synthetases with Cancer

“…Recent studies have suggested that targeting human ARSs may provide new strategies for developing therapies for human diseases. Halofuginone is a derivative of febrifugine, the active principal of the Chinese herb changshan (Dichroafebrifuga) which is used as an anti-malarial treatment in Chinese traditional medicine [142]. Halofuginone targets prolyl-tRNA synthetase (PRS) in EPRS and is in clinical trials for the treatment of cancer and fibrosis [111,143].…”

In vitro Biotransformation, in vivo Efficacy and Pharmacokinetics of Antimalarial Chalcones

“…The spectroscopic and analytical data recorded, consistent with the structure targeted, included 1 4 -n -Butoxy-4-hydroxy-2-methoxy-chalcone (compound 4) was prepared as above, but using the isomeric aldehyde 4-hydroxy-2-methoxybenzaldehyde (304 mg, 2.00 mmol), in a reaction run for 5 days at room temperature. In vitro Efficacy against P. falciparum The chloroquine-sensitive D6 strain and the chloroquine-resistant W2 strain of P. falciparum were used in a modified version of Desjardins' semiautomated microdilution technique using a reported protocol [17] . A test compound was dissolved in dimethylsulfoxide, then diluted 400-fold in RPMI 1640 culture medium that was supplemented with 25 mmol/l HEPES, 32 mmol/l NaHCO 3 and 10% Albumax I.…”

Design, Synthesis and Preliminary Pharmacological Screening (antimicrobial, analgesic and anti-inflammatory activity) of Some Novel Quinazoline Derivatives

“…In the literature, it has been reported that the quinazoline and its derivatives possesses a wide range of biological activities such as anti-convulsant (Adel S et al, 2012;Srivastava and Kumar, 2004;Sarvanan et al, 2012), Central nervous system (CNS) depressant (Kashaw et al, 2009;Kashaw et al, 2008), anti-cancer , anti-tubercular (Mosaad et al, 2004) and anti-malarial activity (Jiang et al, 2005). By analyzing the structural activity relationship (SAR) of synthesized quinazoline derivatives from literature survey, it revealed that substitution of different heterocyclic moieties at 2 nd or 3 rd position of quinazoline nucleus alters the biological activity (Patel and Patel, 2011).…”