Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 2. Effect of Heteroatom Substitution at O-11: Synthesis and Bioassay of N-Alkyl-11-aza-9-desmethylartemisinins

Avery, Mitchell A.; Bonk, Jason D.; Chong, Wesley K. M.; Mehrotra, Sanjiv; Miller, Robert E.; Milhous, Wilbur K.; Goins, D K; Sathesh, Venkatesan; Wyandt, Christy M.; Khan, Inshad Ali

doi:10.1021/jm00026a011

Cited by 62 publications

(32 citation statements)

References 20 publications

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“…ART is a lipophilic molecule with a logP value of 2.65 ± 0.3. The toluene-water partition coefficient obtained in this experiment was in good agreement with the literature logP (octanol-water) value (2.90) [23] and clogP value (2.40). Tables 2-4 describe the solubility of ART in the presence of different concentrations of PVP in the three solvent systems examined in this work.…”

Section: Discussionsupporting

confidence: 90%

Effects of drug-polymer dispersions on solubility and in vitro diffusion of artemisinin across a polydimethylsiloxane membrane

et al. 2012

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Artemisinin (ART) is a sesquiterpene lactone with an endo-peroxide bridge that is thought to be responsible for its antimalarial activity. It has low oral bioavailability because of aqueous insolubility, which leads to local toxicity at the site of aggregation. The present work focused on increasing its solubility and evaluating its permeation across a model membrane to mimic transdermal delivery that bypasses the hepatic metabolism. For this purpose, physical mixtures (PM), solid dispersions (SD) and lyophilized dispersions (LD) with different drug-polymer ratios (1 : 0.5, 1 : 1, 1 : 2, 1 : 4 and 1 : 9) were prepared using the hydrophilic polymer polyvinylpyrrolidone (PVP). Drug-polymer dispersions were characterized using X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Solubility was measured in three solvents: de-ionized water, phosphate buffered saline (PBS) and methanol. The toluene-water partition coefficient was evaluated and compared with the literature and calculated logP values. In vitro diffusion of ART was studied across a polydimethylsiloxane membrane from a saturated solution of drug-polymer dispersions. XRD patterns showed a gradual decrease in crystallinity of ART with increasing polymer concentration, while FTIR confirmed no interactions between ART and PVP. Solubility was increased up to 4-, 5-and 8-fold for LD in water, PBS and methanol, respectively. The logP for toluene-water was 2.65 ± 0.3, which is in good agreement with literature and calculated logP values. Permeation was enhanced, which is attributed to the decrease in crystallinity and increase in wettability of the drug. The ART flux was significantly higher than that of pure ART (0.12 ± 0.01) with increasing PVP concentration for SD and LD formulations. In conclusion, drug-polymer dispersions with PVP improve the pharmaceutical properties of ART in the order LD>SD>PM.

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Section: Discussionsupporting

confidence: 90%

Effects of drug-polymer dispersions on solubility and in vitro diffusion of artemisinin across a polydimethylsiloxane membrane

et al. 2012

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“…The group of Avery synthesized a number of aza-desmethylartemisinins 38, 17 as a late synthetic precursor 39 was readily available from their artemisinin total synthesis project (Scheme 12). 4 Carboxylic acid 39 was converted to the corresponding mixed anhydride with ethyl chloroformate.…”

Section: -Aza-9-desmethylartemisininsmentioning

confidence: 99%

Synthesis, reactions and biological activity of 11-azaartemisinin and derivatives

Alen¹,

Truong²,

Nguyễn³

et al. 2011

Arkivoc

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In this review, we will give an overview of the synthesis and reactions of 11-azaartemisinins and their derivatives, from the first report in 1995 till now. The desoxo as well as the 9-desmethyl analogues are included. The biological activity of the azaartemisinins is also briefly discussed, with an emphasis on their potency as antimalarials. Computational studies on this type of compounds are beyond the scope of this review and will not be discussed, nor referenced.

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“…We have already demonstrated that certain azaartemisinin derivatives possess greatly enhanced thermal stabilities 19 and several have good antimalarial activities. 17,20 We describe here the preparation of selected N-alkane-and arenesulfonyl-11azaartemisinins that are screened against asexual and sexual blood stages of P. falciparum. The antimalarial activities are compared with cytotoxicities of the azaartemisinins against a non-proliferating mammalian cell line.…”

Section: Introductionmentioning

confidence: 99%

Activities of 11‐Azaartemisinin and N‐Sulfonyl Derivatives against Asexual and Transmissible Malaria Parasites

et al. 2017

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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 IC values <10.5 nm. The p-trifluoromethylbenzenesulfonyl-11-azaartemisinin derivative 11 [(4'-trifluoromethyl)benzenesulfonylazaartemisinin] was the most active, with IC values between 2 and 3 nm. The compounds were screened against Pf NF54 early and transmissible late intraerythrocytic-stage gametocytes using luciferase and parasite lactate dehydrogenase (pLDH) assays. The 2'-thienylsulfonyl derivative 16 (2'-thiophenesulfonylazaartemisinin) was notably active against late-stage (IV-V) gametocytes with an IC value of 8.7 nm. All compounds were relatively nontoxic to human fetal lung WI-38 fibroblasts, showing selectivity indices of >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.

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Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 2. Effect of Heteroatom Substitution at O-11: Synthesis and Bioassay of N-Alkyl-11-aza-9-desmethylartemisinins

Cited by 62 publications

References 20 publications

Effects of drug-polymer dispersions on solubility and in vitro diffusion of artemisinin across a polydimethylsiloxane membrane

Effects of drug-polymer dispersions on solubility and in vitro diffusion of artemisinin across a polydimethylsiloxane membrane

Synthesis, reactions and biological activity of 11-azaartemisinin and derivatives

Activities of 11‐Azaartemisinin and N‐Sulfonyl Derivatives against Asexual and Transmissible Malaria Parasites

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