Linked Life Data

13678413

Source:http://linkedlifedata.com/resource/pubmed/id/13678413

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2003-9-18
pubmed:abstractText
Quinazolinone type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use for malaria. Because of their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from 1 and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and -B (4 and 5) were isolated as the major metabolites of 1. In addition to 4 and 5, feb-C and -D (6 and 7) were also purified from the metabolic mixture of 3. Compounds 4 and 5 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 6 and 7, derived from 3, also bear febrifugine type structures in which the 4' '- and 6' '-positions of the piperidine ring of 1 were oxidized. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 4-6 and enantiomerically pure 7 demonstrated that 4 and 6 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. The antimalarial activity of 5 and 7, however, was dramatically decreased in the test. The in vitro antimalarial activity of analogues 22 and 43, which are stereoisomers of 4 and 6, was also evaluated, showing that 22 is active. The results suggest that basicity of both the 1- and the 1' '-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 4 and 6 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially, no serious side effects were observed with 4. Thus, the metabolite 4 appears to be a promising lead compound for the development of new types of antimalarial drugs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4351-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:13678413-Administration, Oral, pubmed-meshheading:13678413-Animals, pubmed-meshheading:13678413-Antimalarials, pubmed-meshheading:13678413-Antineoplastic Agents, pubmed-meshheading:13678413-Dose-Response Relationship, Drug, pubmed-meshheading:13678413-Injections, Intraperitoneal, pubmed-meshheading:13678413-Liver, pubmed-meshheading:13678413-Mammary Neoplasms, Experimental, pubmed-meshheading:13678413-Mice, pubmed-meshheading:13678413-Nuclear Magnetic Resonance, Biomolecular, pubmed-meshheading:13678413-Piperidines, pubmed-meshheading:13678413-Plasmodium berghei, pubmed-meshheading:13678413-Plasmodium falciparum, pubmed-meshheading:13678413-Quinazolines, pubmed-meshheading:13678413-Stereoisomerism, pubmed-meshheading:13678413-Structure-Activity Relationship, pubmed-meshheading:13678413-Tumor Cells, Cultured
pubmed:year
2003
pubmed:articleTitle
Metabolites of febrifugine and its synthetic analogue by mouse liver S9 and their antimalarial activity against Plasmodium malaria parasite.
pubmed:affiliation
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't