Synthetic peroxides as potent antimalarials. News and views.

The present review describes the development of synthetic cyclic peroxides, which are designed to surpass the antimalarial activity of the lead molecule, the natural product (+)-artemisinin and some of its C10 derivatives. To begin with, tricyclic and bicyclic 1,2,4-trioxanes are taken to show how the pharmacophore was identified and chirality proved to be irrelevant. The action of ferrous salts on trioxanes illustrates the structural elements that are needed so that reductive breaking of the peroxide bond leads to C-centered radicals, the alleged parasiticidal agents. Views are expressed on how heme, Plasmodium SERCA, and plain ferrous ions, either as targets or activators, could be implicated in the mode of action. Thereafter, news about 1,2,4-trioxolanes, 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, 1,2-dioxolanes, and 1,2-dioxanes is recounted, emphasizing aspects of design, mechanism, and the importance of the adamantane entity for buttressing activity. News about compounds made up of a trioxane covalently bound to aminoquinoline, so-called hybrid molecules, is reported together with a view that they might be better than mechanical mixtures. No new antimalarial can be considered without a word about the risk posed by the parasite developing resistance. The review is not intended to be exhaustive. Some gaps prior to 2009 are filled in, while the later literature up to the end of July 2011 has been covered. Artemisinin and its derivatives fall outside the scope of the review. Nevertheless, some mechanistic insights garnered from artemisinin, which are relevant to synthetic peroxides, are included.

New developments in synthetic peroxidic drugs as artemisinin mimics.

The present review describes the current status of synthetic cyclic peroxides, trioxanes and trioxolanes that show significant promise as antimalarial drugs because of their artemisinin-like activity. The literature from 1996 onwards is critically surveyed to provide an update on how an age-old, persistent, debilitating and frequently deadly disease could be treated by new, affordable and effective medicines possessing the peroxide pharmacophore. The review is not exhaustive and does not cover recent progress on the lead structure artemisinin and its derivatives. Nevertheless, some mechanistic aspects gleaned from artemisinin that have relevance to synthetic peroxides are discussed.

Synthetic peroxides as antimalarials.

This review describes the present status of purely synthetic peroxides and 1,2,4-trioxanes and how they perform in various preclinical tests as potential antimalarial drug candidates. The literature is reviewed from 1986 onwards, comprising mostly articles published in the last ten years. As several papers on antimalarial peroxides have already been published, this review focuses on more recent studies detailing the novelty and potential of synthetic peroxides.

Photochemical study of [3(3)](1,3,5)cyclophane and emission spectral properties of [3n]cyclophanes (n = 2-6).

Thephotochemical reaction of [3(3)](1,3,5)cyclophane 2, which is a photoprecursor for the formation of propella[3(3)]prismane 18, was studied using a sterilizing lamp (254 nm). Upon photolysis in dry and wet CH2Cl2 or MeOH in the presence of 2 mol/L aqueous HCl solution, the cyclophane 2 afforded novel cage compounds comprised of new skeletons, tetracyclo[6.3.1.0.(2,7)0(4,11)]dodeca-5,9-diene 43, hexacyclo[6.4.0.0.(2,6)0.(4,11)0.(5,10)0(9,12)]dodecane 44, and pentacyclo[6.4.0.0.(2,6)0.(4,11)0(5,10)]dodecane 45. All of these products were confirmed by the X-ray structural analyses. A possible mechanism for the formation of these photoproducts via the hexaprismane derivative 18 is proposed. The photophysical properties in the excited state of the [3n]cyclophanes ([3n]CP, n = 2-6) were investigated by measuring the emission spectra and determining the quantum yields and lifetimes of the fluorescence. All [3n]CPs show excimeric fluorescence without a monomeric one. The lifetime of the excimer fluorescence becomes gradually longer with the increasing number of the trimethylene bridges. The [3n]CPs also shows excimeric phosphorescence spectra without vibrational structures for n = 2, 4, and 5, while phosphorescence is absent for n = 3 and 6. With an increase in symmetry of the benzene skeleton in the [3(3)]- and [3(6)]CPs, the probability of the radiation (phosphorescence) process from the lowest triplet state may drastically decrease.

A concise synthesis of siphonodictidine.

Siphonodictidine (1) has been synthesized for the first time in a concise and regiocontrolled manner by using 2-(tert-butyldimethylsiloxy)-3-methylfuran (6) as the crucial building block. The silver trifluoroacetate-induced alkylation of 6 with omega-bromogeranyl acetate 7 gave the key gamma-lactone intermediate 8, which on subsequent reduction, conversion of the hydroxyl into the amino group, and amidination afforded siphonodictidine (1) in an overall yield of 25.7% from 6.