A single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice

Abstract

Four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally. Keywordsantimalarial chemotherapy; trioxane dimer orthoesters; single oral dose ACT cure Many standard antimalarial drugs like chloroquine are no longer effective due to widespread resistance. 1 A new non-alkaloid class of antimalarial artemisinin trioxanes 2-9 , based on ancient Chinese folk medicine, is now recommended by the World Health Organization (WHO) and is being adopted widely [10][11][12][13][14][15][16] ; artemisinin combination therapy (ACT) features the very rapid clearance of most of the parasites by the trioxane drug followed by the prolonged antimalarial action of the partner drug. Typically, fixed dose combinations are used 17 , with the most popular example being a curative 6 dose regimen of a 1:6 fixed combination of artemether (total 320 mg) and lumefantrine (total 1920 mg). Often, however, patient compliance with a repeated-dose regimen is problematic. Therefore, a single dose cure of malaria-infected humans is highly desirable. Toward this goal, we have developed some trioxane monomers 18 and dimers 19 able to cure malaria-infected mice using only a single low oral dose combined with mefloquine. We recently reported a new series of 5-Supplementary data Supplementary data (experimental details and spectroscopic data for 5 and 6a-d) associated with this article can be found in the online version.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2012 May 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript carbon-linked trioxane dimers 4 which, combined with mefloquine, cure malaria-infected mice 20 . We report here a new series of 5-carbon-linked trioxane dimer orthoesters 6a-d.C-10 Acetoxy artemisinin 2b, prepared in nearly quantitative yield by reducing and then acetylating artemisinin ((1 → 2a → 2b) 21 , reacted with silylated 5-carbon-linker 3 to form 10β,10β-dimer allylic alcohol 4 as the major product in 65% yield (Figure 1) 20 . Scale up is not expected to be problematic. Dithexylborane hydroboration of bis-allylic...

Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives

“…Strikingly, the compounds HEQ, HEAQ, and HEAQD demonstrated IC 50 s of approximately 100 M, compared to 42.2 M for quinine, while the compound HEAQD was seven times less inhibitory than quinidine, inhibiting 50% of the CHO hERG channels at 27 M, compared to 4 M quinidine. Both quinine and quinidine had a less steep slope, with the IC 25 and IC 75 being more apart than for the derivatives with a steeper slope.…”

“…Mice were kept in the Johns Hopkins Bloomberg School of Public Health mouse facility according to ACUC animal protocol number MO09H401. Mice were infected intraperitoneally with Plasmodium berghei ANKA (1 ϫ 10 7 infected erythrocytes), and drugs were administered orally twice a day by using sterile plastic feeding tubes (catalog number FTP 2038; Instech Solomon Scientific) for 5 days beginning at 24 h postinfection (25,26). All quinoline salts were dissolved in distilled water (8 mg/ml or 2 mg/ml), and artesunate was dissolved in 100% ethanol (100 mg/ml) and diluted 1:100 in distilled water.…”

Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities

“…Although none of these hybrids have reached clinical application yet, there are many examples available in literature with already very promising in vivo results demonstrating the great potential of the hybridization concept. [28,29,[31][32][33][34][35][36] In this study, four artemisinin-derived hybrids 4-7 ( Figure 2) were synthesized and investigated for their potency against the malaria parasites P. falciparum 3D7 strain, the leukemia cell lines CCRF-CEM and CEM/ADR5000 as well as against HCMV. Dimer 4 is known from literature, [37] but was prepared only by degradation of artesunic acid (3) and up to now not investigated for its potential against cancer cells and HCMV.…”

Malaria-Infected Mice Are Completely Cured by One 6 mg/kg Oral Dose of a New Monomeric Trioxane Sulfide Combined with Mefloquine

“…A recent report features a single dose oral cure of P. berghei malaria-infected mice using synthetic 1,2,4-trioxolane ozonide OZ439 ( 3 , Figure 2). 11 We have recently reported single dose oral cures of P. berghei -infected mice using trioxane dimer sulfone carbamate 5 (Figure 2), 12 using dimer orthoester sulfone 6 , 13 and using trioxane monomer 4-fluoroanilide 12a . 14 We report here a new series of trioxane monomer anilides carrying one or two sulfide, sulfoxide, or sulfone substituents on the anilide aromatic ring; one of these new trioxane sulfides ( 12d ) fully cured malaria-infected mice using only one 6 mg/kg oral dose combined with 18 mg/kg mefloquine hydrochloride.…”