- Evaluation of a series of 9,10-anthraquinones as antiplasmodial agents
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Background: A phytochemical study on medicinal plants used for the treatment of fever and malaria in Africa yielded metabolites with potential antiplasmodial activity, many of which are Anthraquinones (AQ). AQs have similar sub-structure as naphthoquinones and xanthones, which were previously reported as novel antiplasmodial agents. Objective: The present study aimed to investigate the structural requirements of 9,10-anthraquinones with hydroxy, methoxy and methyl substituents to exert strong antiplasmodial activity and to investigate their possible mode of action. Methods: Thirty-one AQs were synthesized through Friedel-Crafts reaction and assayed for antiplasmodial activity in vitro against Plasmodium falciparum (3D7). The selected compounds were tested for toxicity and probed for their mode of action against β-hematin dimerization through HRP2 and lipid catalyses. The most active compounds were subjected to a docking study using AutoDock 4.2. Results: The active AQs have similar common structural characteristics. However, it is difficult to establish a structure-activity relationship as certain compounds are active despite the absence of the structural features exhibited by other active AQs. They have either ortho- or meta-arranged substituents and one free hydroxyl and/or carbonyl groups. When C-6 is substituted with a methyl group, the activity of AQs generally increased. 1,3-DihydroxyAQ (15) showed good antiplasmodial activity with an IC50 value of 1.08 μM, and when C-6 was substituted with a methyl group, 1,3-dihydroxy-6-methylAQ (24) showed stronger antiplasmodial activity with an IC50 value of 0.02μM, with better selectivity index. Compounds 15 and 24 showed strong HRP2 activity and mild toxicity against hepatocyte cells. Molecular docking studies showed that the hydroxyl groups at the ortho (23) and meta (24) positions are able to form hydrogen bonds with heme, of 3.49 A and 3.02 A, respectively. Conclusion: The activity of 1,3-dihydroxy-6-methylAQ (24) could be due to their inhibition against the free heme dimerization by inhibiting the HRP2 protein. It was further observed that the anthraquinone moiety of compound 24 bind in parallel to the heme ring through hydrophobic interactions, thus preventing crystallization of heme into hemozoin.
- Osman, Che Puteh,Ismail, Nor Hadiani,Widyawaruyanti, Aty,Imran, Syahrul,Tumewu, Lidya,Choo, Chee Yan,Ideris, Sharinah
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p. 353 - 363
(2019/06/20)
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- Short-lived 1,5-biradicals formed from triplet 1-alkoxy- and 1-(benzyloxy)-9,10-anthraquinones
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The cyclopropylmethyl and (trans-2-phenylcyclopropyl)methyl radical clocks were used to estimate the lifetimes of triplet state biradicals formed from substituted 1-alkoxy-9,10-anthraquinones by photoexcitation and subsequent 1,5-hydrogen atom transfer. Irradiation (350 nm) of 1-(cyclopropylmethoxy)-2-methyl-9,10-anthraquinone (1cp) in argon-purged methanol generated the primary anthrahydroquinone product (2). Upon exposure to air, 2 was rapidly converted to cyclopropanecarboxaldehyde and 1-hydroxy-2-X-9,10-anthraquinone (3). In contrast, irradiation of 1-{(trans-2-phenylcyclopropyl)methoxy}-2-benzyl-9,10-anthraquinone (1pcp) under similar conditions produced only small amounts of 3 and the corresponding aldehyde, trans-(2-phenylcyclopropyl)carboxaldehyde. In addition, products resulting from rearrangement of the 1,5-biradical to a homoallylic 1,8-biradical were also obtained. Using the known rate constant for the rearrangement of the phenylcyclopropylmethyl radical to the homoallylic radical and the observed product ratio, lifetimes of approximately 1-2 ns were estimated for 1,5-biradicals from these anthraquinones which are about an order of magnitude shorter than those reported for triplet state biradicals derived from structurally related benzophenones and acetophenones. The short lifetimes of these biradicals are attributed to the facile formation of a zwitterion which results from an intramolecular electron transfer from one radical site, which serves as electron donor, to the other radical site, which is a semianthraquinone and therefore serves as a good electron acceptor. If either the electron-donating or electron-accepting site is absent in the biradical, zwitterion formation is not observed and coupling of the biradical occurs resulting in a longer lifetime.
- Smart, Robert P.,Peelen, Timothy J.,Blankespoor, Ronald L.,Ward, Donald L.
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p. 461 - 465
(2007/10/03)
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- Photochemistry of 1-Alkoxy- and 1-(Benzyloxy)-9,10-anthraquinones in Methanol: A Facile Process for the Preparation of Aldehydes and Ketones
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The facile production of acid sensitive aldehydes and ketones via photochemical intramolecular δ-hydrogen atom transfer in 1-alkoxy- and 1-(benzyloxy)-9,10-anthraquinones (1) was investigated.Irradiation of 1 in argon purged methanol generates the primary photoproducts, 1-(RCH(OMe)O)- and 1-(ArCH(OMe)O)-9,10-anthrahydroquinones (2), respectively.Upon exposure to air, the intermediate anthrahydroquinone is rapidly converted to the corresponding aldehyde and 1-hydroxy-9,10-anthraquinone (3), which can be recycled.Aldehydes containing an acetal or ketal were prepared in high yields using this photoprocess.Apparent rate constants for the photodemethylation of 1-methoxy-2-X-9,10-anthraquinones (X = H, Me, Et, Pr, i-Bu, and benzyl) were measured and found to vary by a factor of 10 separating the slowest anthraquinone (X = H) and the fastest (X = benzyl), indicating a strong dependency upon the size of the substituent at the 2-position.These rate constants are ascribed to equilibrium populations of conformers in the geometry required for the reaction in the n,?* triplet state.
- Blankespoor, Ronald L.,Smart, Robert P.,Batts, Eric D.,Kiste, Alan A.,Lew, Rebecca E.,Vliet, Marc E. Vander
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p. 6852 - 6859
(2007/10/03)
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- Synthesis of anthraquinone derivatives by palladium-catalyzed coupling of triflates with stannanes
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The palladium-catalyzed coupling of hydroxyanthraquinone triflates with stannanes provides an efficient entry into substituted anthraquinones under neutral conditions.
- Tamayo, Nuria,Echavarren, Antonio M.,Paredes, M. Carmen,Farina, Francisco,Noheda, Pedro
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p. 5189 - 5192
(2007/10/02)
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- Photodemethylation of Methoxy-Substituted 9,10-Anthraquinones in Methanol
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Irradiation of methoxy-substituted 9,10-anthraquinones with visible or ultraviolet light results in a demethylation reaction involving free radical intermediates.
- Blankespoor, Ronald L.,Hsung, Richard,Schutt, David L.
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p. 2877 - 2878
(2007/10/02)
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