2,4-Diaminothienopyrimidines as orally active antimalarial agents.
A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.
Department of Chemistry and ■Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
Diego
D
González Cabrera
Claire
C
Le Manach
Frederic
F
Douelle
Yassir
Y
Younis
Tzu-Shean
TS
Feng
Tanya
T
Paquet
Aloysius T
AT
Nchinda
Leslie J
LJ
Street
Dale
D
Taylor
Carmen
C
de Kock
Lubbe
L
Wiesner
Sandra
S
Duffy
Karen L
KL
White
K Mohammed
KM
Zabiulla
Yuvaraj
Y
Sambandan
Sridevi
S
Bashyam
David
D
Waterson
Michael J
MJ
Witty
Susan A
SA
Charman
Vicky M
VM
Avery
Sergio
S
Wittlin
Kelly
K
Chibale
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D062126:Databases, Chemical; D018432:Drug Resistance, Multiple; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057166:High-Throughput Screening Assays; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011743:Pyrimidines; D013876:Thiophenes