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Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diamino-pyrimidine-based kinase inhibitors

Phuangsawai, Oraphan, Beswick, Paul, Ratanabunyong, Siriluk, Tabtimmai, Lueacha, Suphakun, Praphasri, Obounchoey, Phongphat, Srisook, Pimonwan, Horata, Natharinee, Chuckowree, Irina, Hannongbua, Supa, Ward, Simon, Choowongkomon, Kiattawee and Gleeson, M. Paul 2016. Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diamino-pyrimidine-based kinase inhibitors. European Journal of Medicinal Chemistry 124 , pp. 896-905. 10.1016/j.ejmech.2016.08.055

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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. SAR expansion has been performed 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: 2,4-Diaminopyrimidine, Plasmodium falciparum, Antimalarials, Drug design, Tyrosine kinase inhibitors, K1 strain, JAK2 kinase
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 8 October 2018
Date of Acceptance: 24 August 2016
Last Modified: 09 Oct 2018 21:46

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