Conversion of antimalarial drug artemisinin to a new series of tricyclic 1,2,4-trioxanes1

A highly efficient route for the conversion of the antimalarial drug artemisinin to a novel hydroxy-functionalized tricyclic 1,2,4-trioxane 6 is reported. Neither the trioxane 6 nor its derivatives 14-16, all of which lack the hydrolytically unstable acetal-lactone linkage, show antimalarial activity comparable with that of artemisinin.     

Synthesis of antimalarial 1,2,4-trioxanes via photooxygenation of a chiral allylic alcohol

[reaction: see text] Photooxygenation of the chiral allylic alcohol 4-methyl-3-penten-2-ol (3) in nonpolar solvents and subsequent Lewis acid-catalyzed peroxyacetalization afforded a series of monocyclic and spirobicyclic 1,2,4-trioxanes (5, 6). Two products show significant anti-Malaria activity against Plasmodium falciparum when compared with chloroquine.     

Synthesis,molecular docking and dynamics study of novel epoxide derivatives of 1,2,4-trioxanes as antimalarial agents

Structural Chemistry - Malaria infection continues to pose a substantial threat to human health in the twenty-first century. The parasites’ resistance against conventional antimalarial drugs...     

A facile access to bridged 1,2,4-trioxanes

Bicyclo[3.2.1] type 1,2,4-trioxanes are readily synthesized from precursors that may form intramolecular hemiketals using UHP (H₂O₂-urea complex) as the source of the peroxy bond and p-TsOH or CSA as the catalyst. The ring closure through an intramolecular Michael addition occurred in a highly stereoselective way, giving only one diasteromer as shown by the NMR spectra.     

Photooxygenation of 3-aryl-2-cyclohexenols: synthesis of a new series of antimalarial 1,2,4-trioxanes

Using easily accessible 3-aryl-2-cyclohexenols, a photooxygenation route for the preparation of bicyclic 1,2,4-trioxanes is reported. Several of these trioxanes have shown significant antimalarial activity against multidrug resistant Plasmodium yoelii in mice by the oral route.     

Synthesis of aminopyrimidylindoles structurally related to meridianins

The synthesis of new meridianin derivatives substituted at the C-5′ position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. The 2-aminopyrimidine ring was obtained via a Bredereck synthesis. Aryl groups were introduced by Suzuki cross-coupling after bromination of the 2-aminopyrimidine ring at the C-5′ position.     

Synthesis of novel structurally simplified estrogen analogues

A library of 17 novel estrogen analogues 3 and 4 containing different substituents at rings A and D (steroid nomenclature) was prepared in a five- to seven-step synthesis. The key transformation is a Sonogashira-coupling of cyclic vinyl iodides of type 7 or 8 with phenylacetylenes of type 9. Reduction of the keto function in 3 led to the estradiol analogue 5.     

Synthesis of new ether glycerophospholipids structurally related to modulator

A series of new glycerophospholipids, bearing a short-chain carboxylic acid in position sn-1 and phosphocholine or phosphoserine in postion sn-3 of glycerol, have been prepared in good overall yields. Compound 11, 1-0-(6-carboxyhexyl)-sn-glycero-3-phosphoserine, a strict analog of the structure proposed for modulator, has been synthesized in a stereoselective way from (R)-1,2-isopropylideneglycerol 1.     

Synthesis,Structure, and Antimalarial Activity of Some Enantiomerically Pure,cis-fused cyclopenteno-1,2,4-trioxanes

Two pairs of enantiomerically pure cis-fused cyclopenteno-1,2,4-trioxanes ( 7 , ent- 7 and 8 , ent- 8 ) are prepared (Schemes 1–3). Their identities are established by dye-sensitized photo-oxygenation of ent- 7 and 8 , ent- 8 to the allylichydroperxides, reduction to the corresponding alcohols, and conversion to the (1S)-camphanates (Scheme 4), the structures of which are determined by X-ray analysis. The dynamic properties of ent- 7 are investigated by NMR spectroscopy and PM3 calculations. Evidence for an easily accessible twist-boat conformation is obtained. The in vitro and in vivo antimalarial activities of 7 , ent- 7,8 , and ent- 8 as well as those of the racemic mixtures are evaluated against Plasmodium falciparum, P. berghei, and P. yoelii. No correlation is observed between configuration and activity. Racemates and pure enantiomers have commensurate activities. The mode of action on the intraerythrocytic parasite is rationalized in terms of close docking by the twist-boat conformer of the trioxane on the surface of a molecule of heme, single-electron transfer to the O? O σ* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C-centered radical, the ultimate lethal agent (Scheme 5).     

Triple-layered QSAR studies on substituted 1,2,4-trioxanes as potential antimalarial agents: superiority of the quantitative pharmacophore-based alignment over common substructure-based alignment

This study reports the utilization of three approaches – pharmacophore, CoMFA/CoMSIA and HQSAR studies – to identify the essential structural requirements in 3D chemical space for the modulation of the antimalarial activity of substituted 1,2,4-trioxanes. The superiority of quantitative pharmacophore-based alignment (QuantitativePBA) over global minima energy conformer-based alignment (GMCBA) has been reported in CoMFA and CoMSIA studies. The developed models showed good statistical significance in internal validation (q ², group cross-validation and bootstrapping) and performed very well in predicting the antimalarial activity of test set compounds. Structural features in terms of their steric, electrostatic and hydrophobic interactions in 3D space have been found to be important for the antimalarial activity of substituted 1,2,4-trioxanes. Further, the HQSAR studies based on the same training and test set acted as an additional tool to find the sub-structural fingerprints of substituted 1,2,4-trioxanes for their antimalarial activity. Together, these studies may facilitate the design and discovery of new substituted 1,2,4-trioxanes with potent antimalarial activity.     

Alkylation of heme by the antimalarial drug artemisinin

The peroxide function of artemisinin has been activated by iron(II)-heme generated in situ from iron(III)-protoporphyrin-IX and glutathione, a biologically relevant reductant. In mild conditions, this reaction produced a high yield (85%) of heme derivatives alkylated at alpha-, beta-, and delta-meso positions by a C4-centered radical derived from artemisinin.     

Synthesis and in vitro cytotoxic evaluation of aminoquinones structurally related to marine isoquinolinequinones

The synthesis of 4-methoxycarbonyl-3-methylisoquinolinequinone (1) and a variety of its substitution products with amino-, alkylamino and halogen groups on the quinone nucleus is reported. The series of 6-, 7- and 6,7-subtituted isoquinolinequinones were evaluated in vitro for their cytotoxic activity using the MTT colorimetric method. All the newly synthesized compounds showed moderate to high potency against MRC-5 healthy lung fibroblasts and four human tumor cell lines: AGS gastric adenocarcinoma, SK-MES-1 lung, J82 bladder carcinoma, and HL-60 leukemia cells. Among the series, compounds 4b, 12 and 13 exhibited interesting antitumor activity against human gastric adenocarcinoma, human lung and human bladder carcinoma cancer cells. 7-Amino-6-bromoisoquinoline-5,8-quinone (13) was found to be the most promising active compound against the tested cancer cell lines, with IC?? values in the 0.21-0.49 μM range, lower than the anti-cancer agent etoposide used as reference.     

Synthesis and antimicrobial activities of some novel 1,2,4-triazole derivatives

In the present investigation, a series of new Schiff bases 4a–f were synthesized by the condensation of N-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-4-substituted-benzamides 3a–b with various substituted aromatic aldehydes in ethanol–dioxane mixture using catalytic amount of sulfuric acid. The starting materials 3a–b were in turn synthesized by the fusion of benzoyl glycine/substituted benzoylglycine with thiocarbohydrazide. Newly synthesized compounds were characterized by IR, NMR, mass spectra and elemental analyses. All the compounds were evaluated for their antibacterial and antifungal activity using the Minimum Inhibition Concentration (MIC) method by serial dilution technique. Few of the compounds were found to be biologically active.     

Synthesis and properties of water-soluble 5,8-dihydroxy-1,4-naphthoquinone thioglucosides structurally related to echinochrome

Acetylated hydroxynaphthazarin di- and trithioglucosides structurally related to echinochrome were synthesized. Their deacetylation by the action of sodium methoxide in methanol and the effect of hydroxy groups on this process were studied. Water-soluble echinochrome thioglucosides were synthesized for the first time.     

Hydroxyl mechanism of the antimalarial effect of artemisinin and its analogs

Kinetic schemes for the intramolecular oxidation of four artemisinin analogs, which are used as drugs against malaria, were developed. Each stage of the kinetic scheme is characterized by the enthalpy, activation energy, and rate constant calculated using the model of intersecting parabolas. The competition of mono- and bimolecular radical reactions was taken into account when developing the schemes. The hydroperoxide groups are formed as a result of the intramolecular oxidation of these compounds and generate free radicals in the reaction with Fe^II. Among these free radicals, hydroxyl radicals play the key role, since their yield (n _OH) correlates with the antimalarial activity of the peroxide compound. The efficiency of the drug (index IC₅₀) exponentially depends on n _OH and is expressed by the formula IC₅₀(Artemisinin)/IC₅₀(Compound) = 1.54·10⁻⁶exp(3.9n _OH). The elementary reactions resulting in the generation of hydroxyl radicals are considered. It is supposed that DNA of a malaria parasite is the main biological target for hydroxyl radicals.     

Synthesis of biotinylated pentasaccharide structurally related to a fragment of glucomannan from Candida utilis

Russian Chemical Bulletin - The polysaccharide mannan is the main surface antigen of the cell wall of Candida fungi, playing an important role in the pathogenesis of diseases caused by these...     

Synthesis of novel heteroaromatics structurally related to ellipticine alkaloids via thermolysis of pyridannulated enyne-carbodiimides

New synthetic pathways to the 5H-pyrido[3',4':4,5]pyrrolo[2,3-b]quinolines 6, the 6H-pyrido[3',4':4,5]pyrrolo[2,3-b][1,6]naphthyridines 7, and the 11H-pyrido[4',3':4,5]pyrrolo[2,3-b]quinolines 8 via thermolysis of the pyridannulated enyne-carbodiimides 14, 19, and 23 were established. These novel heteroaromatic systems are structurally related to ellipticine alkaloids and could serve as DNA-intercalating agents.     

青蒿素及其衍生物抗疟活性的密度泛函理论研究

为了深入研究青蒿素及其衍生物的抗疟活性和分子结构之间的关系,运用密度泛函理论B3LYP方法,以6-31G*为基组对青蒿素及其衍生物二氢青蒿素、蒿甲醚和青蒿琥酯进行了优化计算.从分子的几何构型、NBO电荷及前线轨道能等方面分析了青蒿素及其衍生物的抗疟活性与结构之间的关系.青蒿素及其衍生物结构中的过氧桥键是其抗疟作用的活性位,O17和O_20带负电荷越多、ΔE_(LUMO-HOMO)越低、E_(HOMO)能级越高,分子的抗疟活性越强.结果表明,4种化合物的抗疟活性顺序为:青蒿素二氢青蒿素蒿甲醚青蒿琥酯,与临床实验结果相吻合.