Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines

The classical anti-microbial antifolates trimethoprim, pyrimethamine, and cycloguanil are poor inhibitors of purified dihydrofolate reductase (DHFR) from Leishmania major. They show no selectivity for Leishmania DHFR relative to the human enzyme, and it is not surprising that they are ineffectual as...

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Veröffentlicht in:Molecular and biochemical parasitology 1988-10, Vol.31 (1), p.79-85
Hauptverfasser: Sirawaraporn, Worachart, Sertsrivanich, Rachada, Booth, Raymond G., Hansch, Corwin, Neal, R.A., Santi, Daniel V.
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Sprache:eng
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Zusammenfassung:The classical anti-microbial antifolates trimethoprim, pyrimethamine, and cycloguanil are poor inhibitors of purified dihydrofolate reductase (DHFR) from Leishmania major. They show no selectivity for Leishmania DHFR relative to the human enzyme, and it is not surprising that they are ineffectual as anti-leishmanial agents. Several 5-(substituted-benzyl)-2,4-diaminopyrimidines have been screened as inhibitors for purified L. major and human DHFRs. These compounds inhibit Leishmania DHFR with I 50 values ranging from 0.2 to 11 μM, and show about 5 to 100-fold greater selectivity for the parasite DHFR than the human enzyme. These pyrimidine analogs are more potent inhibitors of Leishmania promastigote and amastigote growth than the classical anti-microbial antifolates, and serve as lead compounds for the development of new selective antileishmanial agents.
ISSN:0166-6851
1872-9428
DOI:10.1016/0166-6851(88)90147-8