2003 Fiscal Year Final Research Report Summary
Synthesis and evaluation of the anti-malarial activity of the quaternary ammonium salt dimer as the new anti-malarial candidate
| Project/Area Number |
14572092
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
SASAKI Kenji Okayama University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (20116461)
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| Project Period (FY) |
2002 – 2003
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| Keywords | quaternary ammonium salt dimer / anti-malarial / Plasmodium falciparum / drug resistance / chemotherapeutic reagent / anti-malarial activity / selective toxicity / counter-anion |
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| Research Abstract |
Malaria is one of the most deadly diseases for humans worldwide and more than 2.5 million people die from it each year. Due to the emergence and ongoing spread of the chloroquine-resistent strains of Plasmodium falciparum, including multi-drug resistant strains to conventional anti-malarial drugs, development of the entirely new anti-malarial drug is focused. Recently we have found that one of the quaternary ammonium salt dimers that had developed as the new antibacterial agent has the anti-malarial activity. In this research many derivatives of the quaternary ammonium salt dimer were prepared and evaluated for their anti-malarial activity. The structure-activity relationship of these quaternary ammonium salt dimers for their anti-malarial activity was also performed. It was found that the strongest anti-malarial agent was S,S'-tetramethylenebis(1-hexyl-4-thiopyridinium iodide) in which a carbon number of the methylenes of the linker moiety was three and its selective toxicity was 667.
… More
In this series of the compounds of S,S'-tetramethylenebis(1-hexyl-4-thiopyridinium iodide}, it has the tendency that IC_<50> was lower when the carbon number of the methylene part of the linker moiety is smaller. In the series of N,N'-tetramethylenebis(4-carbamoyl-1-hexylpyridinium bromide) in which alkyl chain is sandwiched in two amide groups, the highest selective toxicity was 580 when the carbon number of the methylene part of the linker moiety is six and the canon number of the N-alkyl chain moiety is eight. A carbon number of the N-alkyl chain and IC_<50> for malarial parasite showed a good correlation in this series, that is, IC_<50> became lower when the carbon number of the N-alkyl chain is smaller. About the carbon number of the methylene part in the linker moiety, an optimal value is not clear at present.
The molecular structures of the compounds in this research are completely different from the conventional anti-malarial drugs. Therefore our new anti-malarial agents are expected as the new candidate which is active against drug-sensitive and drug resistant strains of P. falciparum. Less
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