Structure-based bioisosteric design,synthesis and biological evaluation of novel pyrimidines as antiplasmodial antifolate agents |
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Institution: | 1. Egyptian Petroleum Research Institute, Nasr City, P.O. 11727, Cairo, Egypt;2. Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK;3. Department of Chemistry, Xi’an Jiaotong Liverpool University, Suzhou 215123, PR China |
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Abstract: | The efficacy of most marketed antimalarial drugs has been compromised by the development of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. This article describes the synthesis and the in vitro antimalarial profiling of antifolate P218 analogues, by exploring a bioisosteric replacement of the carboxylic group by a phosphinic moiety as well as structural isomerization of P218. The detailed synthetic route employed to access the title compounds is described. The listed compounds exhibited low antimalarial activity against drug-resistant strains of P. falciparum including chloroquine-resistant W2. |
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Keywords: | Antimalarial 2 4-Diaminopyrimidines Phosphinic acid P218 Bioisosterism Malarial dihydrofolate reductase |
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