Quantum chemical studies on antimalarial of artemisinin (qinghaosu) derivatives

In this paper theoretical studies were performed on artemisinin (qinghaosu) derivatives with semiempirical quantum chemical methods AMI and PM3. The antimalarial activity -logC has an obvious correlation with the net charge of C(16) and bond orders of bonds O(1)-C(10), O(2)-C(6), O(1)-O(2) and O(5)-C(16). According to the calculation results, we derived structure-activity relationship, presented the probable pharmacophore of qinghaosu derivatives and the interaction fashion between the drugs and the plasmodium receptor.     

Cleavage of Qinghaosu (Artemisinin) Induced by Non‐Iron Transition‐Metal Ions in the Presence of Excess Cysteine

In the presence of an excess of cysteine, a catalytic amount of a non‐iron transition‐metal ion (Co²⁺, Cu²⁺, Ni²⁺, Ti⁴⁺, and Mn²⁺) may also induce cleavage of qinghaosu (artemisinin; 1 ) to give those end products previously reported for Fe²⁺‐mediated degradation.     

The chemistry of drugs part IV,Configurations of antimalarials derived from qinghaosu: Dihydroqingyhaosu,artemether, and artesunic acid

The structures of the antimalarials dihydroqinghaosu (2) , artemether (3) , and artesunic acid (7a) derived from qinghaosu were elaborated by ¹ H-NMR spectroscopy, and supported with X-ray data obtained for 2 and 3 . Several new derivatives, useful for the chemical characterization of dihydroqinghaosu (2) and artesunic acid (7a) , were prepared.     

手征性5,5-二甲基-4,6一次甲基-2-甲基羰基-2-环己烯酮的选择性Diels-Alder反应在全合成青蒿素中的应用

报导了以(一)-β-蒎烯为原料有效地合成青蒿素.合成包括了用酮酯作为关键中间体,而这可应用我们实验室发展的Diels-Alder化学方便地制备.     

New Insights into the Degradation of Qinghaosu (Artemisinin) Mediated by Non‐Heme‐Iron Chelates,and Their Relevance to the Antimalarial Mechanism

Probing the degradation of qinghaosu ( 1 ) induced by cysteine‐iron chelates by varying the acidity of the reaction medium led to interesting insights into the cleavage of 1 , which help to elucidate the antimalarial action of the 1,2,4‐trioxanes.     

Simplified analogues of qinghaosu (artemisinin)

Three new simplified analogues of qinghaosu have been designed and synthesized through simple routes without recourse to the commonly employed photosensitized oxidation. The peroxy bonds in the target molecules were taken from UHP with the first peroxy-carbon bond formed through a hemiketal exchange reaction and the second by either an intramolecular Michael addition or a Hg(II)-mediated ring-closure reaction. All three peroxides possess a seven-membered peroxy ring fused to an all-carbon six-membered ring, a structural motif required for generating the carbon-centered substituted ethyl radicals.     

Interaction of Qinghaosu (Artemisinin) with Cysteine Sulfhydryl Mediated by Traces of Non-Heme Iron

The antimalarial action of 1,2,4-trioxanes such as qinghaosu (QHS) may take place through the mechanism shown schematically: In the presence of cysteine traces of non-heme iron (FeSO₄) may cleave the peroxy bond of QHS rapidly, and the transient carbon-centered radical can attack the sulfur ligand to form a covalent bond.     

Potent Antimalarial 1,2,4‐Trioxanes through Perhydrolysis of Epoxides

Perhydrolysis of a sterically congested multifunctional epoxide was achieved in ethereal H₂O₂ with the aid of a recently developed Mo catalyst. The resulting hydroperoxide cyclized to give a 1,2,4‐trioxane, which could be readily elaborated into qinghaosu and a range of novel analogues. Some of the compounds with two such trioxane moieties showed in vitro antimalarial activity comparable to or even better than that of artesunate or chloroquine.     

Correlating the molecular electrostatic potentials of some organic peroxides with their antimalarial activities

The molecular electrostatic potentials (MEPs) of artemisinin (also known as qinghaosu), yingzhaosu A, and some synthetic analogues have been calculated and studied as a means of distinguishing between high and low antimalarial activity. To facilitate comparison, the dimensionality of the MEP was reduced by Kohonen Neural Network transforms. The reduction revealed that peroxides exhibiting high antimalarial activity are characterized by a continuous strip of negative electric potential surrounding the molecule, whereas peroxides of lesser activity show a broken strip.     

无C环青蒿素类似物的合成研究

以天然的(-)-香芹酮为原料,设计、合成了四种环状烯醇醚,它们是标题化合物的关键中间体,然而这些化合物出乎意料地与单线态氧不发生反应,仅为光氧化反应提供了有参考价值的经验积累,以(-)-薄荷醇为原料用同样方法则可合成得到化合物4的骨架化合物的混合物。     

Some Attempts to Employ the Singlet Oxygen Generated from H2O2

Some attempts to employ the singlet oxygen generated from molybdate-catalyzed decomposition of hydrogen peroxide are presented. Reduction of ascaridole with diimide is also described, along with the preliminary results of the cleavage study using Fe-cysteinate as a simple model for Fe-S type redox species. There were strong indications that S-alkylation occurred as observed in similar cleavage of the potent antimalarial qinghaosu.     

Analysis of dihydroartemisinin in plasma by liquid chromatography—Mass spectrometry

Summary Artemisinin (ART), or qinghaosu, a sesquiterpene lactone containing an endoperoxide bridge, is an efficient drug against chloroquine-resistant strains ofPlasmodium falciparum in the treatment of cerebral malaria. ART and its derivatives are rapidly metabolized into dihydroartemisinin (DHA), which is responsible for the antimalarial activity. After a simple liquid-liquid extraction (LLE), determination of DHA in plasma was conducted by liquid chromatography-mass spectrometry (LC-MS) with an electrospray ionization (ESI) interface. Addition of dodecylamine to the mobile phase and analysis in selected-ion monitoring (SIM) mode resulted in enhanced sensitivity and selectivity. Use of a primary amine, e.g. propylamine, pentylamine, hexylamine or dodecylamine, in the mobile phase can inhibit the formation of multimer clusters and ion adducts by forming one dominating species (analyte-primary amine adduct). Dodecylamine (DDA) was selected after several assays as a competitive agent for adduct formation. The procedure was validated and precision and accuracy were found to be good for the matrix studied. The method was applied to samples provided by patients receiving artesunate (ARS) for antimalarial treatment.     

Reversed-Phase High-Performance Liquid Chromatographic Determination of Artemisitene in Artemisinin

Abstract

A new, simple and selective reversed-phase HPLC assay is developed for the determination of the clinically undesirable artemisitene in the antimalarial agent artemisinin (qinghaosu). It involves the use of an internal standard (santonin) and the determination time is less than 5 minutes. Detection was accomplished using a UV detector set at 216 nm and limits were as low as 15ng for a 10μl injection. Being simple and selective this method is particularly useful for the routine analysis of artemisinin to check its purity. In addition, the method can be used for preparative scale purification of these compounds. It has been applied for the evaluation of crystalline samples of artemisinin without prior preparation.     

Stereolability of dihydroartemisinin, an antimalarial drug: a comprehensive kinetic investigation. Part 2

Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug-resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH(4) reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1α and 1β. In the solid state, the drug consists exclusively of the β-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the α/β equilibration. To this purpose, free energy activation barriers (ΔG(?)) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of ΔG(?) on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level.     

酪氨酸酶催化下以吡啰红为指示剂荧光测定青蒿素

Fluorescence decrease ratio （F0/F） was applied to determination of artemisinin （qinghaosu, QHS） based on the catalytic effect of tyrosinase using tetraethyldiaminoxanthenyl chloride （pyronine B, PB） as monitor. A catalyst used commonly in the decomposition of QHS, tyrosinase, exhibited higher binding activity than hemin, which was expressed as Michaelis-Menten parameters, km, Vmax, and kcat respectively. Interaction of QHS with tyrosinase was inhibited in the presence of deactivating agents at high temperature whereas enhanced by ethanol. Under optimal conditions, a concentration of 1.4×10^-7-8.4×10^-7 mol·L^-1of QHS could be determined on the basis of fluorescence decrease ratio of PB, with a detection limit 3tr of 2.6×10^-9 mol·L^-1. The proposed method was applied to detection of the concentration of QHS in the media of plasma and urine.     

Assembly of a dinuclear silver complex containing an Ag2S2 motif from a phosphorus-supported trishydrazone ligand. P=S→Ag(I) coordination

The reaction of the phosphorus trihydrazide, (S)P[N(Me)-NH(2)](3) (1) with quinoline-2-carboxaldehyde (C(9)H(6)N-2-CHO) in a 1:3 ratio afforded a trishydrazone, (S)P[N(Me)-N=CH-2-C(9)H(6)N](3) (2). Crystals of 2 were grown in three different solvent media affording an unsolvated (2, monoclinic, P2(1)/n) and two solvated (2·3H(2)O, trigonal, R3 and 2·2CH(3)OH, triclinic, P ?1) crystal forms. Each of these, while possessing an essentially similar molecular structure, adopt different crystal packing giving rise to supramolecular structures mediated by a variety of weak interactions: O-H-N, O-H-O, C-H-N, C-H-O, C-H-S, C-H-π, π-π, N-π and S-π. The reaction of 2 with Ag(ClO(4))(2)·6H(2)O in methanol afforded a dinuclear cationic cage [Ag{(S)P[N(Me)-N=CH-2-C(9)H(6)N](3)}·ClO(4)](2) (3). The molecular structure of 3 reveals a dimeric structure consisting of two Ag(I) ions that are held together by two ligands. Only two arms of the tris hydrazone ligand are involved in coordination while an unprecedented P=S→Ag(I) coordination is seen. This results in the formation of an Ag(2)S(2) dimer that is encapsulated by two trishydrazone ligands. Both compounds 2 and 3 are photoluminescent.     

Reaction of Ta(NMe2)5 with O2: formation of aminoxy and unusual (aminomethyl)amide oxo complexes and theoretical studies of the mechanistic pathways

Reaction of d0 Ta(NMe2)5 (1) with O2 yields two aminoxy complexes (Me2N)(n)Ta(eta2-ONMe2)(5-n) (n = 4, 2; 3, 3) as well as (Me2N)4Ta2[eta2-N(Me)CH2NMe2]2(mu-O)2 (4) and (Me2N)6Ta3[eta2-N(Me)CH2NMe2]2(eta2-ONMe2)(mu-O)3 (5) containing novel chelating (aminomethyl)amide-N(Me)CH2NMe2 ligands. The crystal structures of 2-5 have been determined by X-ray crystallography. (Me2N)4Ta(eta2-ONMe2) (2) converts to (Me2N)3Ta(eta2-ONMe2)2 (3) in its reaction with O2. In addition, the reaction of Ta(NMe2)5 with 3 gives 2 only at elevated temperatures. Density functional theory (DFT) calculations have been used to investigate the mechanistic pathways in the reactions of Ta(NMe2)5 (1) with triplet O2. Monomeric reaction pathways in the formation of 2-5 are proposed. A key step is the oxygen insertion into a Ta-N bond in 1 through an intersystem conversion from triplet to singlet energy surface to give an active peroxide complex (Me2N)4Ta(eta2-O-O-NMe2) (A4). The DFT studies indicate that the peroxide ligand plays an important role, including oxidizing an amide to an imine ligand through the abstraction of a hydride. Insertion of Me-N=CH2 into a Ta-amide bond yields the unusual -N(Me)CH2NMe2 ligands.     

Asymmetric alternating copolymerization of cyclohexene oxide and CO2 with dimeric zinc complexes

Dimeric zinc complex 2a [ = Et(2)Zn(2)(1a)(2)] has been synthesized by the reaction of Et(2)Zn and (S)-diphenyl(pyrrolidin-2-yl)methanol (1a-H). X-ray crystallography revealed that the alkoxide ligand replaced one of the two ethyl groups of Et(2)Zn and formed a five-membered chelate ring through a Zn-N dative bond. Two zinc centers were bridged by oxygen atoms to form a Zn(2)O(2) four-membered ring with a syn relationship between the two ethyl groups on the zinc centers. Dimeric zinc complex 2a was an active catalyst for asymmetric alternating copolymerization of cyclohexene oxide and CO(2). An MALDI-TOF mass spectrum of the obtained copolymer showed that the copolymerization was initiated by the insertion of CO(2) into Zn-alkoxide to give [(S)-diphenyl(pyrroridin-2-ly)methoxy]-[C(=O)O-(1,2-cyclohexylene)-O](n)-H (copolymer I), including chiral ligand 1a as an initiating group. Complex 3a-OEt ( = EtZn(1a)(2)ZnOEt), in which an ethoxy group replaced one of the two ethyl groups in 2a, also polymerized cyclohexene oxide and CO(2) with higher catalytic activity and enantioselectivity than 2a and afforded EtO-[C(=O)O-(1,2-cyclohexylene)-O](n)-H ( = copolymer III), including an ethoxy group as an initiating group. Throughout the studies, dimeric zinc species are indicated to be the active species for the copolymerization. It is also depicted that the substituent on the aryl moiety in diaryl(pyrrolidin-2-yl)methanol 2b-e influenced the polymerization activity.     

Site-selective and stereoselective intramolecular (2pi + 2pi) photocycloaddition of arylalkenes to pyrene and its photocycloreversion

Irradiation of a benzene solution containing methyl p-(1-pyrenylmethoxymethyl)cinnamate (1a) with a high-pressure Hg lamp through Pyrex filter stereoselectively gave an intramolecular (2pi + 2pi) photocycloadduct (2a) in an 83% yield in a site-selective manner at the 4,5-position of the pyrene ring. Similar irradiation of an ortho-substituted derivative (3) afforded the corresponding (2pi + 2pi) cycloadduct (4) as a sole product at the 9,10-position of pyrene. The site-selective photocycloaddition can be reasonably explained by the intramolecular sandwich-type singlet exciplexes between the pyrene and phenyl rings.     

The effects of axial ligands on electron distribution and spin states in iron complexes of octaethyloxophlorin, intermediates in heme degradation

The results presented here show that the nature of the axial ligand can alter the distribution of electrons between the metal and the porphyrin in complexes where there is an oxygen atom replacing one of the meso protons. The complexes (1-MeIm)(2)Fe(III)(OEPO) and (2,6-xylylNC)(2)Fe(II)(OEPO(*)) (where OEPO is the trianionic octaethyloxophlorin ligand and OEPO(*) is the dianionic octaethyloxophlorin radical) were prepared by addition of an excess of the appropriate axial ligand to a slurry of [Fe(III)(OEPO)](2) in chloroform under anaerobic conditions. The magnetic moment of (2,6-xylylNC)(2)Fe(II)(OEPO(*)) is temperature invariant and consistent with a simple S = (1)/(2) ground state. This complex with an EPR resonance at g = 2.004 may be considered as a model for the free-radical like EPR signal seen when the meso-hydroxylated heme/heme oxygenase complex is treated with carbon monoxide. In contrast, the magnetic moment of (1-MeIm)(2)Fe(III)(OEPO) drops with temperature and indicates a spin-state change from an S = (5)/(2) or an admixed S = (3)/(2),(5)/(2) state at high temperatures (near room temperature) to an S = (1)/(2) state at temperatures below 100 K. X-ray diffraction studies show that each complex crystallizes in centrosymmetric form with the expected six-coordinate geometry. The structure of (1-MeIm)(2)Fe(III)(OEPO) has been determined at 90, 129, and 296 K and shows a gradual and selective lengthening of the Fe-N(axial bond). This behavior is consistent with population of a higher spin state at elevated temperatures.