title: Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum.
abstract: The reduced binding of pyrimethamine to Ser108Asn (S108N) mutants of parasite dihydrofolate reductase (DHFR), which forms the basis of resistance of Plasmodium falciparum to pyrimethamine, is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5-p-Cl-phenyl group. This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil. Less effect on binding to some bulky mutants was observed for trimethoprim, with greater flexibility for the 5-substituent. S108N DHFR also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p-Cl, and the binding was generally progressively poorer for the double (C59R+S108N) mutant. Removal of the p-Cl or replacement with m-Cl led to better binding with the mutant DHFRs. Pyrimethamine analogues with unbranched hydrophobic 6-substituents showed generally good binding with the mutant DHFRs. A number of compounds were identified with high affinities for both wild-type and mutant DHFRs, with very low to no affinity to human DHFR. Some of these compounds show good antimalarial activities against pyrimethamine-resistant P. falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines.
authors.affiliation: National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Rama 6 Road, Bangkok 10400, Thailand.
authors.forename: Bongkoch
authors.initials: B
authors.lastname: Tarnchompoo
authors.forename: Chawanee
authors.initials: C
authors.lastname: Sirichaiwat
authors.forename: Worrapong
authors.initials: W
authors.lastname: Phupong
authors.forename: Chakapong
authors.initials: C
authors.lastname: Intaraudom
authors.forename: Worachart
authors.initials: W
authors.lastname: Sirawaraporn
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.forename: Jarunee
authors.initials: J
authors.lastname: Vanichtanankul
authors.forename: Yodhathai
authors.initials: Y
authors.lastname: Thebtaranonth
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002522:Chlorocebus aethiops; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D011739:Pyrimethamine / Q000031:analogs & derivatives*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine