Orally active esters of dihydroartemisinin: Synthesis and antimalarial activity against multidrug-resistant Plasmodium yoelii in mice

Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 03/2008; 18(4):1436-41. DOI: 10.1016/j.bmcl.2007.12.074
Source: PubMed


A series of artemisinin derived esters 7a-j, incorporating pharmacologically privileged substructure, such as biphenyl, adamantane and fluorene, have been prepared and evaluated for antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis by oral route. Several of these compounds were found to be more active than the antimalarial drugs beta-arteether 4 and artesunic acid 5. Ester 7i, the most active compound of the series, provided 100% and 80% protection to the infected mice at 24 mg/kg x 4 days and 12 mg/kg x 4 days, respectively. In this model beta-arteether provided 100% and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively.

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    • "e l s e v i e r . c o m / l o c a t e / i j p h a r m However, because of its high lipophilicity (Singh et al., 2008), poor water solubility and low stability in gastric medium (Bayomi et al., 1998; Drew et al., 2006), it results in poor and mercurial absorption upon oral administration and also it has short half-life and is subjected to high first pass metabolism (Titulaer et al., 1990). ART is only available as an oily intramuscular injection, which demands sterile dosage forms and a skilled health workforce. "
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    ABSTRACT: Arteether (ART), an artemisinin derivative, is a life saving drug for multiple drug resistant malaria. It has a deliverance effect in Falciparum malaria and cerebral malaria. We have prepared solid lipid nanoparticles (SLN) by high pressure homogenization (HPH) technique. ART-loaded SLN (ART-SLN) has been produced reproducibly with homogeneous particle size. ART-SLN was characterized for their size measured by Zetasizer Nano-ZS, Malvern, UK and by high resolution transmission electron microscopy (HR-TEM) and which was found to be 100±11.2nm. The maximum percentage entrapment efficiency (%EE) determined with the high-performance liquid chromatography (HPLC) has been found to be 69±4.2% in ART-SLN-3. The release pattern from ART-SLN revealed that the release of ART is slow but time-dependent manner, which is desirable as it will help to protect the acid degradation of ART in stomach. The percentage cytotoxicity of blank SLN has been found within the acceptable range. The pharmacokinetics results indicated that ART-SLN-3 absorption has been significantly enhanced in comparison to ART in aqueous suspension and ART in ground nut oil (GNO) in rats. The % relative bioavailability (RB%) of ART-SLN to the ART in GNO and ART in aqueous suspension in rats was 169.99% and 7461%, respectively which was found to be significantly high in both the cases. From the results, it can be concluded that ART-SLN offers a new approach to improve the oral bioavailability of ART.
    International Journal of Pharmaceutics 03/2014; 466(1-2). DOI:10.1016/j.ijpharm.2014.03.036 · 3.65 Impact Factor
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    • "In vivo experimental animals and parasite P. yoelii nigeriensis (procured from Central Drug Research Institute, CSIR India), which gives high parasitaemia and is multidrug resistant (Singh et al. 2008), was used to access the in vivo intrinsic antimalarial activity. To confirm the resistance level, a pilot experiment was taken up by treating infected mice with chloroquine ranging from 25 to 150 mg/kg. "
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    ABSTRACT: In an effort to evaluate novel derivatives from artemisinin, possessing potential antimalarial activity, a new derivative artecyclopentyl mether (CPM-1) was derivatized and evaluated for its dose-dependent efficacy in Plasmodium yoelii nigeriensis infected mice. The survivability of mice at 7.5 mg/kg was >28 days with negligible parasitaemia and recovered anemia (66.16-72.62%). Artecyclopentyl mether was also found to modulate the pro- and anti-inflammatory cytokines (IFN-γ, 39.64-56.92%; TNF, 49.10-74.31%; IL-4, 11.53-43.22%; IL-10, 37.60-53.52%) favourably besides optimizing the oxidative stress to the infected subjects as evident by the nitric oxide (88.76-95.43%), lipid peroxidation (59.30-76.05%) and glycaemic data (62.70-76.66%). The results indicate the potentiality of the new derivative as an antimalarial against asexual stages of the parasite.
    Parasitology Research 05/2011; 109(4):1003-8. DOI:10.1007/s00436-011-2344-1 · 2.10 Impact Factor
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    ABSTRACT: The problem of endemic malaria continues unabated globally. Malaria affects 40 % of the global population, causing an estimated annual mortality of 1.5–2.7 million people. The World Health Organization (WHO) estimates that 90 % of these deaths occur in sub-Saharan Africa among infants under the age of five. While a vaccine against malaria continues to be elusive, chemotherapy remains the most viable alternative towards treatment of the disease. During last years, the situation has become urgent in many ways, but mainly because of the development of chloroquine-resistant (CQR) strains of Plasmodium falciparum (Pf). The discovery that artemisinin (ART, 1), an active principle of Artemisia annua L., expresses a significant antimalarial activity, especially against CQR strains, opened new approaches for combating malaria. Since the early 1980s, hundreds of semisynthetic and synthetic peroxides have been developed and tested for their antimalarial activity, the results of which were extensively reviewed. In addition, in therapeutic practice, there is no reported case of drug resistance to these antimalarial peroxides. This review summarizes recent achievements in the area of peroxide drug development for malaria chemotherapy.
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