Medicinal Chemistry
Design, Synthesis & Evaluation of New diamino-pyrimidine Anti-Malarial Inhibitors
Malaria is tropical infectious disease of humans and other animals caused by mosquito-borne parasites that include Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). The former causes the greatest percentage of deaths due to its more severe symptoms. The disease is prevalent in tropical climates in the African and Asian sub-continents, affecting countries with less developed economies
In this work a series of 2,4 diamino-pyrimidines have been identified from an analysis of open access high throughput anti-malarial screening data reported by GlaxoSmithKline at the 3D7 and resistant Dd2 strains. We have developed new inhibitors using structural knowledge of the most plausible parasite target. Seventeen new analogs have been synthesized and tested against the resistant K1 strain of Plasmodium falciparum (Pf). The cytotoxicity of the compounds was assessed in Vero and A549 cells and their selectivity towards human kinases including JAK2 and EGFR were undertaken. We identified compound 5n and 5m as sub-micromolar inhibitors, with equivalent anti-malarial activity to Chloroquine (CQ). Compounds 5d and 5k, mM inhibitors of Pf, displayed improved cytotoxicity with weak inhibition of the human kinases.
In this work a series of 2,4 diamino-pyrimidines have been identified from an analysis of open access high throughput anti-malarial screening data reported by GlaxoSmithKline at the 3D7 and resistant Dd2 strains. We have developed new inhibitors using structural knowledge of the most plausible parasite target. Seventeen new analogs have been synthesized and tested against the resistant K1 strain of Plasmodium falciparum (Pf). The cytotoxicity of the compounds was assessed in Vero and A549 cells and their selectivity towards human kinases including JAK2 and EGFR were undertaken. We identified compound 5n and 5m as sub-micromolar inhibitors, with equivalent anti-malarial activity to Chloroquine (CQ). Compounds 5d and 5k, mM inhibitors of Pf, displayed improved cytotoxicity with weak inhibition of the human kinases.
Article weblink: https://doi.org/10.1016/j.ejmech.2016.08.055
| 2016_phuangsawai_eurj.medchem_malaria-diamino-pyrimidine.pdf |
