Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids

BACKGROUND:Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. METHODS: In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 - 3 for four days at a dosage of 0.8mg/kg, 2.5mg/kg, 7.5mg/kg or 15mg/kg intraperitoneally (ip), or orally (per os) with 2.7mg/kg, 8.3mg/kg, 25mg/kg or 50mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. RESULTS: Hybrids 1 - 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8mg/kg by the ip route and 12, 16 and 13mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15mg/kg via ip route and at 50mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30mg/kg ip and 80mg/kg per os. CONCLUSIONS: These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated

1-Bromo-2-(10β-dihydro­artemisin­oxy)ethane

The title compound, C17H27BrO5, DEB, is a derivative of artemisinin which is used in malara therapy. The OR-group at C12 is cis to the CH3-group at C11 and axially oriented on ring D which has a chair conformation. The crystal packing is stabilized by several weak inter­molecular C—H⋯O inter­actions, which combine to form a C—H—O bonded network parallel to (001)

Activities of 11‐azaartemisinin and N‐sulfonyl derivatives against asexual and transmissible malaria parasites

Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use—artemether and artesunate—induces quiescence in ring‐stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11‐azaartemisinin 5 and selected N‐sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug‐sensitive Pf NF54 and drug‐resistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC50 values 2000 toward asexual parasites. Overall, the readily accessible 11‐azaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisinin‐resistant parasites.http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1860-71872018-12-19hj2018Biochemistr

Prodrug Strategies for Enhancing the Percutaneous Absorption of Drugs

The transdermal application of drugs has attracted increasing interest over the last decade or so, due to the advantages it offers, compared to other delivery methods. The development of an efficient means of transdermal delivery can increase drug concentrations, while reducing their systemic distribution, thereby avoiding certain limitations of oral administration. The efficient barrier function of the skin, however, limits the use of most drugs as transdermal agents. This limitation has led to the development of various strategies to enhance drug-skin permeation, including the use of penetration enhancers. This method unfortunately has certain proven disadvantages, such as the increased absorption of unwanted components, besides the drug, which may induce skin damage and irritancy. The prodrug approach to increase the skin’s permeability to drugs represents a very promising alternative to penetration enhancers. The concept involves the chemical modification of a drug into a bioreversible entity that changes both its pharmaceutical and pharmacokinetic characteristics to enhance its delivery through the skin. In this review; we report on the in vitro attempts and successes over the last decade by using the prodrug strategy for the percutaneous delivery of pharmacological molecules

Etude épidémiologique de la paragonimose dans trois foyers situés dans le sud-ouest de la Côte d'Ivoire

LIMOGES-BU Médecine pharmacie (870852108) / SudocSudocFranceF