Antimalarial Activity of Novel Arylene Bis(methylketone) Compounds
Identifieur interne : 002A08 ( Main/Exploration ); précédent : 002A07; suivant : 002A09Antimalarial Activity of Novel Arylene Bis(methylketone) Compounds
Auteurs : Bradley J. Berger [États-Unis] ; Alex Paciorkowski [États-Unis] ; Matthew Suskin [États-Unis] ; Wei Wei Dai [États-Unis] ; Anthony Cerami [États-Unis] ; Peter Ulrich [États-Unis]Source :
- Journal of Infectious Diseases [ 0022-1899 ] ; 1996.
Abstract
Because of the spread of drug-resistant Plasmodium species, there is an urgent need for novel effective antimalarial agents. A series of arylene bis(methylketone) compounds were screened in vitro against a number of Plasmodium falciparum clones and in vivo against Plasmodium berghei. 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium chloride (Cytokine Network Inc. [CNI]-H0294) was the most effective of the compounds in vitro, with an IC50 of 1.5–4.0 µ/M against parasite clones with a wide range of sensitivities to chloroquine and pyrimethamine. Other compounds in the series had in vitro IC50 values of 20–25 µ/M. In a 4-day test for suppression of P. berghei parasitemia in vivo, 50 mg/kg/day CNI-H0294 significantly decreased parasitemia by >90%. The compound was found to have low toxicity in mice, with an LD50 of 590 ± 66 mg/kg intraperitoneally, and rapid plasma kinetics. These results show that CNI-H0294 has considerable antimalarial activity and merits further study.
Url:
DOI: 10.1093/infdis/174.3.659
Affiliations:
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Berger</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Picower Institute for Medical Research, Manhasset</wicri:cityArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Reprints or correspondence: Dr. Bradley J. Berger, Picower Institute for Medical Research, 350 Community Dr., Manhasset</wicri:cityArea></affiliation></author><author><name sortKey="Paciorkowski, Alex" sort="Paciorkowski, Alex" uniqKey="Paciorkowski A" first="Alex" last="Paciorkowski">Alex Paciorkowski</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Picower Institute for Medical Research, Manhasset</wicri:cityArea></affiliation></author><author><name sortKey="Suskin, Matthew" sort="Suskin, Matthew" uniqKey="Suskin M" first="Matthew" last="Suskin">Matthew Suskin</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Picower Institute for Medical Research, Manhasset</wicri:cityArea></affiliation></author><author><name sortKey="Dai, Wei Wei" sort="Dai, Wei Wei" uniqKey="Dai W" first="Wei Wei" last="Dai">Wei Wei Dai</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Picower Institute for Medical Research, Manhasset</wicri:cityArea></affiliation></author><author><name sortKey="Cerami, Anthony" sort="Cerami, Anthony" uniqKey="Cerami A" first="Anthony" last="Cerami">Anthony Cerami</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Picower Institute for Medical Research, Manhasset</wicri:cityArea></affiliation></author><author><name sortKey="Ulrich, Peter" sort="Ulrich, Peter" uniqKey="Ulrich P" first="Peter" last="Ulrich">Peter Ulrich</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Picower Institute for Medical Research, Manhasset</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Infectious Diseases</title><title level="j" type="abbrev">J Infect Dis.</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date when="1996-09">1996</date><biblScope unit="vol">174</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="659">659</biblScope><biblScope unit="page" to="662">662</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Because of the spread of drug-resistant Plasmodium species, there is an urgent need for novel effective antimalarial agents. A series of arylene bis(methylketone) compounds were screened in vitro against a number of Plasmodium falciparum clones and in vivo against Plasmodium berghei. 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium chloride (Cytokine Network Inc. [CNI]-H0294) was the most effective of the compounds in vitro, with an IC50 of 1.5–4.0 µ/M against parasite clones with a wide range of sensitivities to chloroquine and pyrimethamine. Other compounds in the series had in vitro IC50 values of 20–25 µ/M. In a 4-day test for suppression of P. berghei parasitemia in vivo, 50 mg/kg/day CNI-H0294 significantly decreased parasitemia by >90%. The compound was found to have low toxicity in mice, with an LD50 of 590 ± 66 mg/kg intraperitoneally, and rapid plasma kinetics. These results show that CNI-H0294 has considerable antimalarial activity and merits further study.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>État de New York</li></region></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Berger, Bradley J" sort="Berger, Bradley J" uniqKey="Berger B" first="Bradley J." last="Berger">Bradley J. Berger</name></region><name sortKey="Berger, Bradley J" sort="Berger, Bradley J" uniqKey="Berger B" first="Bradley J." last="Berger">Bradley J. Berger</name><name sortKey="Cerami, Anthony" sort="Cerami, Anthony" uniqKey="Cerami A" first="Anthony" last="Cerami">Anthony Cerami</name><name sortKey="Dai, Wei Wei" sort="Dai, Wei Wei" uniqKey="Dai W" first="Wei Wei" last="Dai">Wei Wei Dai</name><name sortKey="Paciorkowski, Alex" sort="Paciorkowski, Alex" uniqKey="Paciorkowski A" first="Alex" last="Paciorkowski">Alex Paciorkowski</name><name sortKey="Suskin, Matthew" sort="Suskin, Matthew" uniqKey="Suskin M" first="Matthew" last="Suskin">Matthew Suskin</name><name sortKey="Ulrich, Peter" sort="Ulrich, Peter" uniqKey="Ulrich P" first="Peter" last="Ulrich">Peter Ulrich</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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