The convenient synthesis of zinc chloride-free 3,7-bis(dialkylamino)phenoxazinium salts

Ge, Jian‐Feng; Arai, Chika; Ihara, Masataka

doi:10.1016/j.dyepig.2008.01.001

Cited by 26 publications

(23 citation statements)

References 9 publications

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“…Phenoxazinium derivatives, a type of DLC exemplified by 3 and 4, displayed potent in vitro activity and oral efficacy. [12][13][14][15] However, cytotoxicity was observed at low micromolar concentrations in several phenoxazinium derivatives. 12,14 Because the electrophilicity of the carbon atom at the 1 position in the phenoxazinium skeleton would be troublesome, we examined the addition of a benzene ring to the phenoxazinium framework.…”

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confidence: 99%

Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

Arai

Yang

et al. 2010

ACS Med. Chem. Lett.

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Malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. Even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. Novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. A search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. The derivative SSJ-183 (5), having a 4-aminopyridine group, showed an IC 50 value against Plasmodium falciparum of 7.6 nM and a selectivity index of >7300. Cure was achieved by three oral doses of 5 at 100 mg/kg to mice infected with the Plasmodium berghei ANKA strain. The safety of 5 was supported by acute toxicity testing in mice with single doses up to 2000 mg/kg po, chromosome aberration test, in vitro as well as in vivo micronucleus tests, and phototoxicity studies in mice. Thus, 5 is a promising candidate as a new antimalarial agent.

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confidence: 99%

Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

Arai

Yang

et al. 2010

ACS Med. Chem. Lett.

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“…Most difficult was heterocyclization of 1,4-butane-and 1,5-pentanediols with p-anisidine (the yields were 18% for 12 and 5% for 24), the basicity of which (рK а = 5.29) differs little from the basicity of ptoluidine (рK а = 5,12), which forms cyclic amines 4 and 16 in 75 and 61% yields, respectively (Scheme 1). (14), m-CH 3 (15), p-CH 3 (16),…”

Section: Resultsmentioning

confidence: 99%

Synthesis of N-aryl-substituted pyrrolidines and piperidines by reaction of anilines with α,ω-diols catalyzed by FeCl3.6H2O in carbon tetrachloride

Хуснутдинов¹,

Bayguzina²,

Asylbaeva³

et al. 2014

Arkivoc

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N-Arylpyrrolidines and N-arylpiperidines were synthesized in 20-88% yields by the reaction of aniline and aniline derivatives with 1,4-butane-and 1,5-pentanediols in the presence of Fecontaining catalysts and carbon tetrachloride. 1,4-Butane-and 1,5-pentanediols are partially chlorinated under the reaction conditions to give chlorohydrins, which subsequently undergo Nheterocyclization with anilines to give N-arylpyrrolidines and N-arylpiperidines.

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“…Previous studies reported novel antiprotozoal compounds based on the π-delocalized lipophilic cations (DLC) hypothesis [11–17], in which hydrophobic cations containing delocalized π-electrons accumulate in the parasite mitochondria and inhibit metabolic activity [18]. Among them, phenoxazinium salt (basic blue 3 in this study) displayed strong antiprotozoal activity with high selectivity [17].…”

Section: Introductionmentioning

confidence: 85%

“…Moreover, these compounds are unsuitable for clinical use because they are typically purified using zinc chloride [19]. Therefore, a new method was developed to obtain these compounds with high purity via zinc chloride-free chromatography followed by crystallization [11]. In addition, some of their derivatives in which nitrogen atoms are bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were modified and showed potent antiprotozoal activity against P. falciparum , Trypanosoma cruzi , Trypanosoma brucei rhodesiense , and Leishmania donovani parasites in vitro [20].…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo characterization of anti-malarial acylphenoxazine derivatives prepared from basic blue 3

Tougan

Takahashi

Ikegami-Kawai

et al. 2019

Malar J

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Background Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum , Trypanosoma cruzi , Trypanosoma brucei rhodesiense , and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated. Methods Six acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model. Results All the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain. Conclusions The six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound. Electronic supplementary material The online version of this article (10.1186/s12936-019-2873-0) contains supplementary material, which is available to authorized users.

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The convenient synthesis of zinc chloride-free 3,7-bis(dialkylamino)phenoxazinium salts

Cited by 26 publications

References 9 publications

Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

Synthesis of N-aryl-substituted pyrrolidines and piperidines by reaction of anilines with α,ω-diols catalyzed by FeCl3.6H2O in carbon tetrachloride

In vitro and in vivo characterization of anti-malarial acylphenoxazine derivatives prepared from basic blue 3

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