title: Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines.
abstract: 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 I50 values ranging from 0.2 to 11 microM, and show about 5 to greater than 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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
authors.forename: W
authors.initials: W
authors.lastname: Sirawaraporn
authors.forename: R
authors.initials: R
authors.lastname: Sertsrivanich
authors.forename: R G
authors.initials: RG
authors.lastname: Booth
authors.forename: C
authors.initials: C
authors.lastname: Hansch
authors.forename: R A
authors.initials: RA
authors.lastname: Neal
authors.forename: D V
authors.initials: DV
authors.lastname: Santi
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005493:Folic Acid Antagonists; D007895:Leishmania tropica / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D002727:Proguanil; D011739:Pyrimethamine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D014227:Triazines; C026009:cycloguanil; D014295:Trimethoprim; D002727:Proguanil; D011739:Pyrimethamine