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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Preclinical evaluation of the antifolate QN254, 5-chloro-n′6′- (2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate
Antimicrobial Agents and Chemotherapy, Volume 54, No. 6, Year 2010
Notification
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Description
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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Nzila, Alexis M.
Kenya, Nairobi
Wellcome Trust Research Laboratories Nairobi
United Kingdom, Oxford
Nuffield Department of Medicine
Rottmann, Matthias
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Chitnumsub, Penchit
Thailand, Pathum Thani
Thailand National Center for Genetic Engineering and Biotechnology
Kiara, Steven M.
Kenya, Nairobi
Wellcome Trust Research Laboratories Nairobi
Kamchonwongpaisan, Sumalee
Thailand, Pathum Thani
Thailand National Center for Genetic Engineering and Biotechnology
Maneeruttanarungroj, Cherdsak
Thailand, Pathum Thani
Thailand National Center for Genetic Engineering and Biotechnology
Taweechai, Supannee
Thailand, Pathum Thani
Thailand National Center for Genetic Engineering and Biotechnology
Yeung, Bryan K.S.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Goh, Anne
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Lakshminarayana, Suresh B.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Zou, Bin
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Wong, Josephine
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Ma, Ngai Ling
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Weaver, Margaret
United States, Cambridge
Novartis Institutes for Biomedical Research, Inc.
Keller, Thomas H.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Dartois, Véronique A.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Wittlin, Sergio
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Brun, Reto
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Yuthavong, Yongyuth
Thailand, Pathum Thani
Thailand National Center for Genetic Engineering and Biotechnology
Diagana, Thierry T.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Statistics
Citations: 20
Authors: 20
Affiliations: 6
Identifiers
Doi:
10.1128/AAC.01526-09
ISSN:
00664804
e-ISSN:
10986596
Research Areas
Health System And Policy
Infectious Diseases
Study Design
Cross Sectional Study