Anti-malarial activities of acylated bruceolide derivatives

Murakami, Nobutoshi; Umezome, Takashi; Mahmud, Taifo; Sugimoto, Masako; Kobayashi, Mariko; Wataya, Yusuke; Kim, Hyesook

doi:10.1016/s0960-894x(98)00045-6

Cited by 17 publications

(15 citation statements)

References 6 publications

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“…The downfield shift of C-4 (d 136.2) confirmed that the hydroxyl group at C-3 was selectively protected. Acetylation of compound 7 leads to the formation of its diacetyl derivative (8). In its 1 H NMR spectrum, compound 8 showed downfield shifts in H-11 (d 5.20) and H-12 (d 5.27); however, H-2 0 (d 6.02) remains intact with respect to that of 7; in the case of 4 0 -O-Ac derivatives, H-2 0 appears to be shifted upfield, as in compound 4.…”

Section: Resultsmentioning

confidence: 99%

“…However, it was very important to check the effect of the acetylation of each of the hydroxyl groups at positions C-3, C-11, C-12, and C-4 0 on the activity. Therefore; taking bruceine C (2) as an example, and noting the differences in the reactivities of the four hydroxyl groups [8], its mono and diacetyl derivatives at different positions were synthesized, and their activities were compared with each other and with that of bruceine C. 3-O-acetyl bruceine C (5) showed greater activity than 3,12-di-O-acetyl bruceine C (6) and 3, 11,12,4 0 -tetra-Oacetyl bruceine C (4), respectively, indicating that as the number of free hydroxyl groups increases the activity increases. Comparing the activities of bruceine C (2), bruceantinol (4 0 -O-acetyl bruceine C, 3), 3-O-acetyl-bruceine C (5), and 3-O-acetyl bruceantinol (10) confirmed that the effect of the free hydroxyl group at C-4 0 of the ester side chain at C-15 on the activity is insignificant.…”

Section: Resultsmentioning

confidence: 99%

“…H] ? (calcd for C 34 H 51 O 12 Si, 679.3150).3-O-t-Butyl dimethylsilyl-11,12-di-O-acetyl bruceine C(8) …”

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Antitrypanosomal activities of acetylated bruceines A and C; a structure–activity relationship study

et al. 2011

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The crude extract of Brucea javanica showed strong in vitro inhibitory activity against Trypanosoma evansi. Among the isolated quassinoids, bruceines A, C, and bruceantinol were found to be the most potent compounds against T. evansi. To gain a deeper understanding of the relationship between the free hydroxyl groups and the activity, several O-acetylated derivatives of bruceines A and C were synthesized and their in vitro antitrypanosomal activities against trypomastigotes of T. evansi were examined and compared with those of the original compounds. The following structure-activity relationships were observed: (1) the free hydroxyl groups at positions C-3, C-11, and C-12 are essential for antitrypanosomal activity; (2) the C-11 and C-12 hydroxyl groups are more important for the activity than the enolic hydroxyl group at C-3, and; (3) the free hydroxyl group at C-4' of bruceine C does not have any significant effect on the activity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Antitrypanosomal activities of acetylated bruceines A and C; a structure–activity relationship study

et al. 2011

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“…Several Brucea quassinoids, especially bruceolide ( 12 ) and brusatol ( 16 ), were subjected to synthesis, and analog preparation by Lee et al [37] , Murakami et al [38] and [39] and Kim et al [14] for SAR studies. The synthesis of a brusatol analog with a modified C-15 side chain and the antimalarial activity of brusatol related compounds indicated that the requirement of a C-15 ester moiety is quite specific for enhanced activity among brusatol related quassinoids [37] .…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

“…The synthesis of a brusatol analog with a modified C-15 side chain and the antimalarial activity of brusatol related compounds indicated that the requirement of a C-15 ester moiety is quite specific for enhanced activity among brusatol related quassinoids [37] . of bruceolide (( 57 -63 ), Figure 4 ) were prepared, and their in vitro and in vivo activities against Plasmodium strains were evaluated by Murakami et al [38,39] . Methyl, ethyl and isopropyl carbonates of bruceolide ( 59 -61 ) showed strong in vitro activity against P. falciparum CQ-sensitive FCR-3 strains, whereas both dimethylcarbonate ( 59 ) and diethylcarbonate ( 60 ) significantly increased the lifespan of mice as compared with 3,15-di-O -acetylbruceolide ( 13 ) and CQ.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

Antimalarial quassinoids: past, present and future

Muhammad

Samoylenko

2007

Expert Opinion on Drug Discovery

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This review is a compilation of the investigations reported to date on the sources, isolation, chemistry and antimalarial activities of natural quassinoids and their synthetic and semisynthetic analogs. It also provides an analysis of the in vitro structure-activity relationship of quassinoids for further evaluation in animal models. The introduction of non-nitrogenous antimalarial drugs has created a new era of malaria chemotherapy to treat Plasmodium falciparum strains that are resistant to existing nitrogenous drugs and the rising incidence of the deadly cerebral malaria. Many antimalarial quassinoids are discovered from simaroubaceous plants that are used traditionally to treat fever and malaria, thereby reiterating the critical role of ethnopharmacology as a rich source of novel drug discovery.

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Antimalarial Agents

Casteel¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Malaria continues to be a major global health problem and seems to be increasing in some parts of the world. By way of an introduction, relevant aspects of the disease, including incidence and resistance, and of the parasite and its biochemistry and genetics are presented. The chemotherapeutic agents now available to prevent and treat malaria are discussed individually. Some of these drugs have been in use for decades or even centuries, such as quinine, chloroquine, and primaquine. Other agents are of more recent origin including mefloquine, halofantrine, atovaquone, and the artemisinins. Chloroquine had been the drug of first resort for many years. It is inexpensive, well‐tolerated, and extremely effective where parasites remain sensitive. But the development of resistance to chloroquine has emphasized the need for new agents and strategies to treat malaria. New information on the genetic basis of chloroquine resistance and on the overall mechanism of action of chloroquine holds promise for advances in therapy. Another important tactic in dealing with infection by resistant parasites is the use of drug combinations. The combination of pyrimethamine and sulfadoxine has been very successful, but resistance is developing. Newer, highly effective combinations include atovaquone with proguanil, lumefantrine with artemether, and chlorproguanil with dapsone. The artemisinin group of compounds has made a powerful positive impact on malaria chemotherapy although their use in monotherapy is not recommended. Details of the mechanism of action of these drugs are becoming clearer. Knowledge about action should assist in addressing issues of possible toxicity. Great progress has been made in sequencing the genome of Plasmodium falciparum . New molecular targets have been identified as a result and efforts are underway to develop antimalarial agents based on these targets. Researchers around the world are also exploring natural products for yet another lead in antimalarial chemotherapy. “If we take as our standard of importance the greatest harm to the greatest number, then there is no question that malaria is the most important of all infectious diseases 1 .” “Ah, poor heart! he is so shaked of a burning quotidian tertian, that it is most lamentable to behold [2].”

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Anti-malarial activities of acylated bruceolide derivatives

Cited by 17 publications

References 6 publications

Antitrypanosomal activities of acetylated bruceines A and C; a structure–activity relationship study

Antitrypanosomal activities of acetylated bruceines A and C; a structure–activity relationship study

Antimalarial quassinoids: past, present and future

Antimalarial Agents

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