title: Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.
abstract: 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.
authors.affiliation: Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Penchit
authors.initials: P
authors.lastname: Chitnumsub
authors.forename: Stevens M
authors.initials: SM
authors.lastname: Kiara
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.forename: Cherdsak
authors.initials: C
authors.lastname: Maneeruttanarungroj
authors.forename: Supannee
authors.initials: S
authors.lastname: Taweechai
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.forename: Josephine
authors.initials: J
authors.lastname: Wong
authors.forename: Ngai Ling
authors.initials: NL
authors.lastname: Ma
authors.forename: Margaret
authors.initials: M
authors.lastname: Weaver
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
mesh_terms: 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
chemical_list: 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