Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum.
A Plasmodium falciparum dihydroorotate dehydrogenase ( PfDHODH) inhibitor that is potent ( KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).
Phillips
Margaret A
MA
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA. margaret.phillips@UTSouthwestern.edu
Gujjar
Ramesh
R
Malmquist
Nicholas A
NA
White
John
J
El Mazouni
Farah
F
Baldwin
Jeffrey
J
Rathod
Pradipsinh K
PK
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D006801:Humans; D007700:Kinetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D011743:Pyrimidines; D013844:Thiazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors