Synthesis of New 1,2,4-Trioxanes and their Antimalarial Activity

The three dihydronaphtho[1,2,4]trioxines 9 – 11 have been synthesized and two of them converted to the five carbamate and ester derivatives 12 – 16 (Schemes 1 and 2). The resulting new trioxanes together with two already known and ascaridole ( 7 ) were tested for antimalarial activity against the sensitive N strain of Plasmodium berghei in mice. On comparison with artemisinin ( 1 ) and dihydroartemisinin ( 2 ), modest activity was found. The four most active compounds were some 12–18 times less potent than 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).     

Total Synthesis and Biological Investigation of (−)‐Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific

Here, we describe an efficient and diversity‐oriented entry to both (?)‐artemisinin ( 1 ) and its natural antipode (+)‐artemisinin, starting from commercially and readily available S‐(+)‐ and R‐(?)‐citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug‐sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin.     

Versatile Synthesis of Fused Tricyclic 1,2,4-Triazole Derivatives

ABSTRACT

A rapid and general method for the synthesis of symmetrical disulfides involves reaction of sulfur with sodium hydroxide under PTC-microwave irradiation condition to give sodium disulfide, which reacts with alkyl halides to afford the disulfides in good to excellent isolated yields.     

A New Approach to 1,2,4-Trioxanes form Cyclic Allylic Hydroperoxides

Summary The reaction of 4,5-dimethyl-4-hydroperoxy-1(4H)-nephthalenone ( 9 ) with acetaldehyde, pivalaldehyde, benzaldehyde, and p-chlorobenzaldehyde in CH₂Cl₂ in the presence of Amberlyst-15 as catalyst gave the corresponding cis-3-methyl, t -butyl, phenyl and p -chlorophenyl derivatives of 10,10b-dimethylnaphtono[2,1-e][1,2,4]trioxin-6(5)H-one in 80-95% yields. Acetone reacted similarly with 9 to give the 3,3′ -dimethyl derivative. Configurations of all trioxinones were assigned by comparison of their spectral properties with that of the p -chloro derivative whose structure was determined by X-ray. 2,5-Diphenyl-2-hydroperoxypyrrole was less efficient that 9 , but it condensed with acetaldehyde and pivaladehyde under the same conditions giving the cis - 3-methyl and cis - 3-(t -butyl) derivatives of 6,7a-diphenyl-4a, 7a-dihydro-3H, 5H -[1,2,4]trio-xino[3,2-e]pyrrole in 24 and 20% yield, respectively.     

A Vibrational Study of Some 1,2,4-Trioxanes

The vibrational spectra of some 1,2,4-trioxanes present two characteristic bands at 790 and 880 cm^?1. On the basis of ¹⁸O-isotopic substitution and comparison with analogous compounds, these bands have been assigned to coupled C? O and O? O stretching modes of the C? O? O element.     

Synthesis,Structure, and In Vitro Anti-HIV Activity of New Pyrazole, 1,2,4-Thiadiazole,and 1,2,4-Triazole Derivatives

α,α′-Dichloroazo compounds 6 react with Lewis acid to furnish 1-(chloroalkyl)-1-aza-2-azoniaallene salts 4. The cations 4 react with acetylenes, isothiocyanates, isocyanates, and carbodiimides under [3+2]-cycloaddition. The cycloadducts undergo consecutive reactions, e.g., [1,2]-shifts of alkyl groups. The newly synthesized products were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.     

Mechanistic and Synthetic Studies on the Formation of 1,2,4-Trioxanes Related to Arteannuin. Photooxygenation of a bicyclic dihydropyran

The photooxygenation of (4R,4aS,7R)-4,4a,5,6,7,8-hexahydro-4,7-dimethyl-3H-2-benzopyran ( 16 ) was performed in (i) MeOH, (ii) acetaldehyde, and (iii) acetone at ?78°. The products obtained respectively were (i) (2R)-2-[(1S,4R)-4-methyl-2-oxocyclohexyl]propyl formate ( 17 ; 72% yield), (ii) 17 (54.5%), (1R,4R,4aS,7R)-3,4,4a,5,6,7-hexahydro-4,7-dimethyl-1H-2-benzopyran-2-yl hydroperoxide ( 19 ; 16.7%), a 12:1 ratio of (3R,4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,7,10-trimethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4-trioxane ( 20 ) and its C(3)-epimer 21 (17%), together with evidence for the 1,2-dioxetane ( 22 ) originating from the addition of dioxygen to the re-re face of the double bond of 16 , and iii) unidentified products and traces of 22 . Addition of trimethylsilyl trifluoromethanesulfonate (Me₃SiOTf) to the acetone solution of 16 after photooxygenation afforded (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4,-trioxane ( 23 , 40%). The photooxygenation of 16 in CH₂Cl₂ at ?78° followed by addition of acetone and Me₃SiOTf afforded 17 (11%), 23 (59%), and (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[8a,1-e]-1,2,4-trioxane ( 24 ; 5%. Repetition of the last experiment, but replacing acetone by cyclopentanone, gave 17 (16%), (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[1,8a-e]-1,2,4-trixane] ( 25 ; 61%), and (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[8a,1-e]-1,2,4-trixane] ( 26 , 4%). The X-ray analysis of 23 was performed, which together with the NMR data, established the structure of the trioxanes 20, 21, 24, 25 , and 26 . Mechanistic and synthesis aspects of these reactions were discussed in relation to the construction of the 1,2,4-trioxane ring in arteannuin and similar molecules.     

Synthesis, Crystal Structure and Biological Activity of a New 1,2,4-Triazole Derivative

A new 1,2,4-triazole containing cyclopropane moiety was synthesized and characte- rized by 1H NMR, MS and elemental analyses. The crystal structure of the title compound (C13H14FN3S, Mr = 263.33) has been determined by single-crystal X-ray diffraction. The crystal is of monoclinic, space group P21/c with a = 12.614(3), b = 7.0202(14), c = 15.556(3), β = 110.92(3)°, V = 1286.7(4)3 , Z = 4, F(000) = 552, Dc = 1.359 g/cm 3 , μ = 0.25 mm-1 , the final R = 0.0336 and wR = 0.0898 for 2568 observed reflections with Ⅰ > 2σ(Ⅰ). A total of 10093 reflections were collected, of which 3045 were independent (Rint = 0.0268). The herbicidal activity of the title compound was determined, and this compound displays excellent herbicidal activity against Brassica campestris.     

Design,Synthesis and Anticancer Activity of 1,2,4-Thiadiazole Derivatives Bearing 1,2,4-Oxadiazole

Russian Journal of General Chemistry - A series of novel 1,2,4-thiadiazole derivatives bearing 1,2,4-oxadiazole is synthesized. Structures of the synthesized compounds are confirmed by 1H and 13C...     

Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action

An efficient synthesis of rac-6-desmethyl-5β–hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (−)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(−)-2a. Several new compounds 9–16, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.     

The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity in Plasmodium falciparum

The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or hemoglobin digestion, were tried to boost intracellular heme levels, and under several scenarios, free heme levels were significantly augmented. Interestingly, all results arrived at the same conclusion, i.e., elevating heme acted in a strongly negative way, impacting the antimalarial action of artemisinin, but exerted no effect on several other antimalarial drugs. Suppression of the elevated free heme level by introducing heme oxygenase expression effectively restored artemisinin potency. Consistently, zinc protoporphyrin IX/zinc mesoporphyrin, as analogues of heme, drastically increased free heme levels and, concomitantly, the EC₅₀ values of artemisinin. We were unable to effectively mitigate free heme levels, possibly due to an unknown compensating heme uptake pathway, as evidenced by our observation of efficient uptake of a fluorescent heme homologue by the parasite. Our results thus indicate the existence of an effective and mutually compensating heme homeostasis network in the parasites, including an uncharacterized heme uptake pathway, to maintain a certain level of free heme and that augmentation of the free heme level negatively impacts the antimalarial action of artemisinin. Importance: It is commonly believed that heme is critical in activating the antimalarial action of artemisinins. In this work, we show that elevating free heme levels in the malarial parasites surprisingly negatively impacts the action of artemisinin. We tried to boost free heme levels with various means, such as by modulating heme synthesis, heme polymerization, hemoglobin degradation and using heme analogues. Whenever we saw elevation of free heme levels, reduction in artemisinin potency was also observed. The homeostasis of heme appears to be complex, as there exists an unidentified heme uptake pathway in the parasites, nullifying our attempts to effectively reduce intraparasitic free heme levels. Our results thus indicate that too much heme is not good for the antimalarial action of artemisinins. This research can help us better understand the biological properties of this mysterious drug.     

The Deoxygenation and Isomerization of Artemisinin and Artemether and Their Relevance to Antimalarial Action

The treatment of artemisinin ( 1 ) and β-artemether ( 6 ) with Zn dissolving in AcOH for a few hours results in mono-deoxygenation giving deoxyartemisinin ( 5 ) and deoxy-β-artemether ( 7 ), respectively, as the sole product. In contrast, submission of 1 to FeCl₂ · 4 H₂O in MeCN at room temperature for 15 min causes only isomerization, (3aS,4R,6aS,7R,10S,10aR)-octahydro-4,7-dimethyl-8-oxo-2H-10H-furo[3,2-i] benzopyran-10-yl acetate ( 8 ) and (3R)-3-hydroxydeoxyartemisinin ( 9 ) being produced in 78 and 17% yield, respectively. The action of FeCl₂ · 4 H₂O in MeCN on 6 is similar. Under the same conditions, 6 gives products analogous to 8 and 9 accompanied by an epimeric mixture of 2-[4-methyl-2-oxo-3-(3-oxobutyl)cyclohexyl]propanaldehyde in yields of 32, 23, and 16%, respectively. No epoxide is formed on repeating the last two experiments in the presence of cyclohexene. The deoxygenation of 1 and 6 by Zn is rationalized in terms of its oxophilic nature. The catalyzed isomerization of 1 and 6 by Fe²⁺ is attributed to the redox properties of the Fe²⁺/Fe³⁺ system.     

New Tricyclic Amides. Synthesis,Structure, and Oxidation with Peroxyphthalic Acid

4-Azatricyclo[5.2.1.0^2,6]dec-8-ene was synthesized and brought into reactions with benzoyl, o-chlorobenzoyl, p-bromobenzoyl, p-, m-, and o-nitrobenzoyl, and bicyclo[2.2.1]hept-2-ene-endo-5,endo-6-dicarboximidoacetyl chlorides in chloroform in the presence of pyridine. The tricyclic amides thus obtained were epoxidated with peroxyphthalic acid prepared in situ by reaction of phthalic anhydride with a 35% aqueous solution of hydrogen peroxide. The structure of newly synthesized compounds was confirmed by IR and ¹H and ¹³C NMR spectroscopy and mass spectrometry. Their NMR spectra were compared with those of previously synthesized N-arylsulfonyl-4-azatricyclo[5.2.1.0^2,6]dec-8-enes on the basis of conformational composition of the corresponding p-nitrophenyl-substituted derivatives, which was determined by PM3 semi-empirical quantum-chemical calculations.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005, pp. 837–845.Original Russian Text Copyright © 2005 by L. Kas’yan, Okovityi, Tarabara, A. Kas’yan, Bondarenko.     

Synthesis,Antiviral, and Antimicrobial Activity of 1,2,4-Triazole Thioglycoside Derivatives

Abstract

The reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol with glucosyl, galactosyl, lactosyl bromide, and peracetylated ribose under the conventional and microwave irradiation methods afforded the corresponding S-glycosides. Deacetylation of S-glycosides gave the corresponding deacetylated derivatives. Reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol with 4-acetoxybutyl bromide, 2-acetoxyethoxymethyl bromide, 3-chloropropanol, 1,3-dichloroopropan-2-ol, epichlorohydrin, allyl bromide, and propargayl bromide gave the corresponding S-acyclonucleosides, which were deacetylated to give the corresponding deacetylated compounds. All the newly synthesized compounds were characterized by the IR, ¹H, ¹³C NMR, and elemental analyses. Some of these compounds were screened for their antiviral and antimicrobial activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the related elements to view the free supplemental file.     

Synthesis,Structure, and Alkylation of 4-Nitroamino-1,2,4-triazole

Nitration of 4-amino-1,2,4-triazole with nitric acid in acetic anhydride gives the corresponding N-nitroamino derivative which has an inner salt structure. Its alkylation with alkyl halides, as well as with oxiranes, occurs only at the endocyclic nitrogen atom, while the exocyclic reaction center is not involved. All the 1-substituted products have the structure of 1-alkyl-1,2,4-triazol-1-io-4-N-nitroimides.