Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.
Drug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.
Nzila
Alexis
A
Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
Rottmann
Matthias
M
Chitnumsub
Penchit
P
Kiara
Stevens M
SM
Kamchonwongpaisan
Sumalee
S
Maneeruttanarungroj
Cherdsak
C
Taweechai
Supannee
S
Yeung
Bryan K S
BK
Goh
Anne
A
Lakshminarayana
Suresh B
SB
Zou
Bin
B
Wong
Josephine
J
Ma
Ngai Ling
NL
Weaver
Margaret
M
Keller
Thomas H
TH
Dartois
Veronique
V
Wittlin
Sergio
S
Brun
Reto
R
Yuthavong
Yongyuth
Y
Diagana
Thierry T
TT
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001682:Biological Availability; D004351:Drug Resistance; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics
C552048:5-chloro-N'6'-(2,5-dimethoxybenzyl)quinazoline-2,4,6-triamine; D000962:Antimalarials; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine