Naphthoquinone Antimalarials. XIV. 2-Hydroxy-3-aryl-1,4-naphthoquinones

Zaugg, Harold E.; Rapala, Richard T.; Leffler, Marlin T.

doi:10.1021/ja01190a007

Cited by 11 publications

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“…The synthesis of the derivatives in the second group (8)(9)(10)(11)(12)(13)(14)(15)(16) with the pyridinylamino or dibenzylamino groups on their side chains is shown in Chart 2. Specifically, 4-methyl-2-aminopyridine and dibenzylamine were used as aromatic amines in the Mannich reaction.…”

Section: Chemical and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

“…During the last 50 years, various naphthoquinones and especially lawsone derivatives have been designed and extensively synthesized for the development of novel antiparasitics. [11][12][13][14] Within these studies, the 1,4-naphthoquinone analogues have been found to possess not only antimalarial activity but also a diverse range of biological activities, such as antioxidant, antibacterial, antitumor, antituberculosis activities. [14][15][16][17][18] Aminonaphthoquinone belongs to the quinone family which possesses an interesting scaffold conveying potential for a range of pharmacological applications.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of 2-Hydroxy-1,4-naphthoquinone Derivatives as Potent Antimalarial Agents

Paengsri

Promsawan

Baramee

2021

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 3-substituted-2-hydroxy-1,4-naphthoquinone derivatives with a variety of side chains were successfully synthesized by Mannich reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with selected amines and aldehydes. All substances (1-16) were evaluated for in-vitro antimalarial activity against strains of Plasmodium falciparum by microculture radioisotope technique. Bioassay data revealed that ten derivatives (1-8,11 and 13) displayed significantly good activity with values of IC 50 ranging from 0.77 to 4.05 g/mL. The best biological profile (IC 50 = 0.77 g/mL) was observed in compound 1, possessing a n-butyl substituted aminomethyl group. Experimental results support the potential use of our active Mannich components as promising antimalarial agents in the fight against malaria infections and multidrug resistance problems.

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Section: Chemical and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of 2-Hydroxy-1,4-naphthoquinone Derivatives as Potent Antimalarial Agents

Paengsri

Promsawan

Baramee

2021

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…With regard to the base of choice, potassium carbonate was selected for several reasons, including cost-effectiveness and safety in large-scale reactions. Moreover, most 2-hydroxynaphthoquinones (for example, phthiocol: pK a 5.08 17 and lawsone: pK a 3.98 18 ) are weak acids that can be easily deprotonated in the presence of mild carbonate salts. We also assumed that ion pairing with potassium cations would be effectively suppressed by the 18-crown-6 ether, impeding formation of metal complexes such as 1.…”

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confidence: 99%

“…Other 2-hydroxynaphthoquinones were evaluated to assess the effects of substituents on the O-alkylation reaction ( Table 1, entries 14-21). Moderate yields (44-59%) were obtained for the benzyl-, anisyl-, and chloro-substituted quinones 3l-p (entries [16][17][18][19][20]. However, when an electron-donating substituent (cyclohexyl) was present, the isolated yields rose to 72-82% (entries 14 and 15).…”

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confidence: 99%

“…13 C NMR (125 MHz, CDCl 3 ): δ = 186.0, 181.5, 158.0, 134.0, 133.4, 132.2, 132.0, 131.7, 126.4, 126.3, 61.3, 9.5. MS (EI, 70 eV): m/z (%) = 202 (100) [M + ], 187 (11), 172(15), 159(18), 144(16), 131(15).2-Methyl-3-propoxynaphthoquinone (3b)Yellow oil; yield: 10 mg (37%); R f = 0.46 (hexanes-EtOAc, 5:1). IR (neat): 1674, 1590, 1563, 1250, 1211, 1044, 1015 cm -1 1.…”

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Phase-Transfer Catalysts in the O-Alkylation of 2-Hydroxynaphthoquinones

et al. 2012

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A mild procedure has been developed for the O-alkylation of 2-hydroxynaphthoquinones by using phase-transfer catalysts. Optimal yields were obtained when 18-crown-6 (10 mol%) and tetrabutylammonium iodide (10 mol% ) were used as cocatalysts in refluxing tetrahydrofuran containing potassium carbonate. Variability in the product yields (0-82%) was attributed to differences in the reactivity of the alkylating agent and to resonance stabilization of the 2-hydroxynaphthoquinone anion. Comparisons of the UV-visible spectra suggest that the degree of electron delocalization has a marked effect on the outcome of the reaction. Quinoid π-electrons were more delocalized in the absence of a stabilizing counteraction, resulting in lower yields. In the presence of tetrabutylammonium iodide, reduced levels of electron delocalization were detected, possibly as a result of ion pairing between the tetrabutylammonium cation and the C-2 oxygen anion. Enhanced reactivity correlates to a lower level of delocalization, and a combination of both catalysts is necessary to facilitate the O-alkylation.Natural and synthetic 1,4-naphthoquinones 1 are important modulators of cellular function, serving as agonists or antagonists of various biological processes, depending on the type of cell. Natural phylloquinones (for example, vitamin K 1 ) and menaquinones (for example, vitamin K 2 ) are redox-active catalysts that participate in the enzymatic conversion of glutamate into γ-carboxyglutamate in mammalian blood clotting. 2 Bacterial menaquinones are cofactors that undergo redox cycling in facilitating the biosynthesis of ATP under anaerobic conditions. 3 Many synthetic 1,4-naphthoquinones are important antioxidants, ubiquinone antagonists, or competitive inhibitors of DNA topoisomerases. Potential clinical applications of this heterogeneous class of compounds include the treatment of cardiovascular diseases, 4 skeletal diseases, 5 inflammation, 6 cancer, 7 or microbial infections. 8The 2-hydroxynaphthoquinones are a prominent family of biologically active quinones, 9 among which the antiparasitic agent atovaquone 10 is the most established in medicinal use. Alkoxy analogues of 2-hydroxynaphthoquinones are also being studied for a variety of potential applications. 11 With the exception of procedures that employ an excess of silver(I) oxide, 11b the preparation of 2-alkoxynaphthoquinones by direct S N 2 alkylation of the C-2 hydroxyl group typically produces low yields of the required products. This poor reactivity of the quinones is partly the result of suppression of the nucleophilicity of the oxygen anion as a result of electron delocalization. 12 Further complications are encountered when bases containing mono-or divalent metals are used in the reaction, as 2-hydroxynaphthoquinones are efficient chelators of cationic metals, forming complexes that are highly insoluble in most organic solvents (for example, complex 1; Scheme 1). 13 Scheme 1 O-Alkylation of 2-hydroxy-3-methyl-1,4-naphthoquinone (phthiocol) in the presence and absence of 18...

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Intramolecular reactions of 1,5‐diaryl‐1,5‐pentadiyl radicals

1988

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Photochemical decomposition of 2,6-diarylcyclohexanones 1 a -d yields 1,2-diarylcyclopentannes 4 and 1,5-diaryl-l -pentenes 5 by intramolecular reaction of the intermediate 1,5-diaryl-1,5-pentadiyls 3. The two stereoisomers cis4 and trans-4 are formed in equal amounts. There hence exists a 1 : 1 equilibrium between the two conformers of 3 which lead to cis-and trms-4, respectively; the intramolecular combination step itself is not stereoselective. However, the product ratios of 4:5, i. e. combination: disproportionation, depend on the substituents. This regioselectivity is strongly dected by solvent and temperature.The chemistry of 1,5-diradicals 3 has been the subject of increasing attention during the last few years I-'). These radicals can be readily generated from the cyclohexanones 1 by a Norrish-type I photoreaction followed by loss of carbon monoxide from the ketyl-alkyl diradical 2 (Scheme 1). Special interest was given to the lifetimes of the two reactive intermediates, the ketyl-alkyl diradicals 2 and the corresponding 1,5-diradicals 3. It was shown that the diradicals 3 (R' = R2 = Phenyl, R' = Phenyl, R2 = H) have surprisingly long lifetimes'*4) of about 900 ns, whereas the ketylalkyl diradicals 2 lose carbon monoxide very rapidly within a laser pulse4). The latter fact is certainly due to the stabilization of the resulting benzylic radical center 6.7), whereas the lifetimes of the diradicals 3 are mainly controlled by the rate of intersystem crossing'). If R' # R2, four products can be formed by intramolecular reactions: cis-and trans-cyclopentanes 4 by combination as well as cis-and trans-l-pentenes 5 by disproportionation. These diradicals seem to be very suitable for the study of the regioselectivity (combination/disproportionation) and the stereoselectivity (cisltrans-cyclopentane) of free radical termination reactions. The radicals are easily generated by photolysis and long lifetimes ensure that the conformational equilibrium of the diradical is reached before ring closure. Therefore no memory effect is expected on the configuration (or conformation) of the cyclohexanone. Furthermore, the two reacting radical centers are connected by a "carbon backbone" ') and consequently only a few restricted conformations have to be considered as transition states. This should facilitate the interpretation relative to structurally related mono radical^'^^).

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Naphthoquinone Antimalarials. XIV. 2-Hydroxy-3-aryl-1,4-naphthoquinones

Cited by 11 publications

References 0 publications

Synthesis and Evaluation of 2-Hydroxy-1,4-naphthoquinone Derivatives as Potent Antimalarial Agents

Synthesis and Evaluation of 2-Hydroxy-1,4-naphthoquinone Derivatives as Potent Antimalarial Agents

Phase-Transfer Catalysts in the O-Alkylation of 2-Hydroxynaphthoquinones

Intramolecular reactions of 1,5‐diaryl‐1,5‐pentadiyl radicals

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