title: Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines.
abstract: Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmodium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl group at R(2) significantly affecting activity. A subsequent series addressed high LogD values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R(1)/R(2). A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF(3), however antiplasmodial activity decreased without any improvement in clearance. The C6-CF(3) group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4.
authors.affiliation: Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Martyn
authors.forename: Amarjit
authors.initials: A
authors.lastname: Nijjar
authors.forename: Cassandra A
authors.initials: CA
authors.lastname: Celatka
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Erin
authors.initials: E
authors.lastname: Tyndall
authors.forename: Hanlan
authors.initials: H
authors.lastname: Liu
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fitzgerald
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Shea
authors.forename: Sanjay
authors.initials: S
authors.lastname: Danthi
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine