Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines.
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.
Martyn
Derek C
DC
Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
Nijjar
Amarjit
A
Celatka
Cassandra A
CA
Mazitschek
Ralph
R
Cortese
Joseph F
JF
Tyndall
Erin
E
Liu
Hanlan
H
Fitzgerald
Maria M
MM
O'Shea
Thomas J
TJ
Danthi
Sanjay
S
Clardy
Jon
J
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
D000962:Antimalarials; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine