Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diamino-pyrimidine-based kinase inhibitors.
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, μM inhibitors of Pf, displayed improved cytotoxicity with weak inhibition of the human kinases.
Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Oraphan
O
Phuangsawai
School of Life Sciences, University of Sussex, Brighton BN1 9QJ, United Kingdom.
Paul
P
Beswick
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Siriluk
S
Ratanabunyong
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Lueacha
L
Tabtimmai
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Praphasri
P
Suphakun
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand; Interdisciplinary Program in Genetic Engineering, Graduate School, Kasetsart University, Chatuchak, Bangkok 10900, Thailand.
Phongphat
P
Obounchoey
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Pimonwan
P
Srisook
Faculty of Medicinal Technology, Huachiew Chalermprakiet University, Samut Prakarn 10540, Thailand.
Natharinee
N
Horata
School of Life Sciences, University of Sussex, Brighton BN1 9QJ, United Kingdom.
Irina
I
Chuckowree
Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Supa
S
Hannongbua
School of Life Sciences, University of Sussex, Brighton BN1 9QJ, United Kingdom. Electronic address: simon.ward@sussex.co.uk.
Simon E
SE
Ward
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
Kiattawee
K
Choowongkomon
Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand. Electronic address: paul.gleeson@ku.ac.th.
M Paul
MP
Gleeson
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity*; D014709:Vero Cells
D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011743:Pyrimidines; D011494:Protein Kinases; C531238:calcium-dependent protein kinase-1, Plasmodium falciparum
2,4-Diaminopyrimidine; Antimalarials; Drug design; JAK2 kinase; K1 strain; Plasmodium falciparum; Tyrosine kinase inhibitors