title: Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis.
abstract: The search for effective therapeutics for cryptosporidiosis and toxoplasmosis has led to the discovery of novel inhibitors of dihydrofolate reductase (DHFR) that possess high ligand efficiency: compounds with high potency and low molecular weight. Detailed analysis of the crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis and a homology model of DHFR from Toxoplasma gondii inspired the synthesis of a new series of compounds with a propargyl-based linker between a substituted 2,4-diaminopyrimidine and a trimethoxyphenyl ring. An enantiomerically pure compound in this series exhibits IC50 values of 38 and 1 nM against C. hominis and T. gondii DHFR, respectively. Improvements of 368-fold or 5714-fold (C. hominis and T. gondii) relative to trimethoprim were generated by synthesizing just 14 new analogues and by adding only a total of 52 Da to the mass of the parent compound, creating an efficient ligand as an excellent candidate for further study.
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Pelphrey
authors.forename: Veljko M
authors.initials: VM
authors.lastname: Popov
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Joska
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Beierlein
authors.forename: Erin S D
authors.initials: ES
authors.lastname: Bolstad
authors.forename: Yale A
authors.initials: YA
authors.lastname: Fillingham
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.forename: Amy C
authors.initials: AC
authors.lastname: Anderson
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry; D003458:Cryptosporidium / Q000201:enzymology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014122:Toxoplasma / Q000201:enzymology*
chemical_list: D000480:Alkynes; D000981:Antiprotozoal Agents; D001555:Benzene Derivatives; D005493:Folic Acid Antagonists; D008024:Ligands; D023303:Oxazolidinones; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase