The anti-malarial activity of bivalent imidazolium salts

Vlahakis, Jason Z.; Mitu, Simona; Roman, Gheorghe; Rodriguez, E. Patricia; Crandall, Ian; Szarek, Walter A.

doi:10.1016/j.bmc.2011.06.002

Cited by 41 publications

(35 citation statements)

References 34 publications

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“…A series of novel 4-anilinoquinoline Mannich base molecules were synthesized, and the in vivo inhibition of Plasmodium yoelii N67 in Swiss mice by compound BM-1 [4-(7-chloroquinolin-4-ylamino)-2-morpholin-4-ylmethylphenol] at a dosage of 500 mg/kg by the oral route was 100% (27). A series of compounds containing bivalent imidazolium rings and one triazolium analog were synthesized; parasitemia was reduced by ϳ50% in mice receiving the lower dose of compound 39 of 3.75 mg/kg and by ϳ75% in mice receiving the higher dose of 15 mg/kg (28). Ethanol and aqueous leaf extracts of Aloe sp.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Zhao

et al. 2014

Antimicrob Agents Chemother

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dArtemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activities of the lipid emulsions developed were tested in Plasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and the in vivo performance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation. Malaria is one of the most significant causes of morbidity and death worldwide. Every year, nearly one million deaths result from malaria infection, with about 85% occurring among children under 5 years of age. Indeed, one patient dies from malaria every 36 s (1).Artemisinin and its derivatives are the most important antimalarial drugs; the chemical structures of the four artemisinin compounds and lumefantrine (also known as benflumetol) are presented in Fig. 1. Artemisinin is an effective antimalarial drug isolated from the Chinese herbal medicine Artemisia annua L. It has a special sesquiterpene lactone with a peroxy group. In malaria parasites, artemisinin can be activated by intraparasitic heme iron, which catalyzes cleavage of the endoperoxide (2). Due to its unique structure and antimalarial mechanism, artemisinin has excellent antimalarial activity with low toxicity; therefore, artemisinin-based combination therapy (ACT) is recommended as the first-line strategy to treat malaria (3). After the introduction of ACT interventions, morbidity and mortality rates associated with malaria were decreased in several parts of the world (4). However, antimalarial resistance would probably be increased after longterm application of artemisinin alone. WHO reformed the malaria treatment policy in February 2004, proposing to stop the use of single antimalarial drugs (e.g., artemisinin and quinine) and promoting the use of ACTs. Recently, combination therapies such as artemether in co...

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Section: Discussionmentioning

confidence: 99%

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Zhao

et al. 2014

Antimicrob Agents Chemother

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“…In continuation of our interest in developing novel therapeutic candidates for the treatment of malaria, [10][11][12][13][14][15] a preliminary study aimed at exploring the relevance of astemizole as a starting point for further development was undertaken. The synthesis, characterization, and in vitro anti-Plasmodium activity of several compounds structurally related to astemizole are reported herein.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti‐Plasmodium Activity of Benzimidazole Analogues Structurally Related to Astemizole

2013

Self Cite

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A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti-Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4-fluorobenzyl and/or 4-methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4-fluorobenzyl group, and variation of the 4-aminopiperidine moiety, were explored. In vitro evaluation of the anti-Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.

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“…[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] The known carbenes 1a, 2d, 3c, 7 were used in an isolated state. Methods for their preparation are also given in the SI.…”

Section: Preparation Of Carbenes and Precarbenesmentioning

confidence: 99%

Highly efficient carbene and polycarbene catalysis of the transesterification reaction

Marichev¹,

Коротких²,

Cowley³

et al. 2017

Arkivoc

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Highly efficient carbene and polycarbene catalysis of the transesterification reaction of ethyl benzoate in methanol has been observed and results in values of TON as high as 4000-6150 at a molar ratio of ester to methanol of 1:18 at room temperature. The most effective catalysts were found to be the individual carbenes or in situ generated carbenes, namely adamantyl and aromatic substituted cyclic compounds and polymeric carbenes. None of the reactions requires the use of molecular sieves. The polymeric imidazol-2-ylidene catalyst was used for the efficient production of biodiesel fuel from sunflower oil.

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The anti-malarial activity of bivalent imidazolium salts

Cited by 41 publications

References 34 publications

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Synthesis and Anti‐Plasmodium Activity of Benzimidazole Analogues Structurally Related to Astemizole

Highly efficient carbene and polycarbene catalysis of the transesterification reaction

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