title: Design, synthesis and biological evaluation of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines as antiplasmodial antifolates.
abstract: The design, synthesis and biological evaluation of a series of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines is described. These compounds exhibited in vitro antiplasmodial activity in the low nanomolar range against both drug sensitive and drug resistant strains of P. falciparum, with 1-(3-(2,4-dichlorophenoxy)propyl)-6-phenyl-1,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride identified as the most potent compound from this series against the drug resistant FCR-3 strain (IC50 2.66 nM). The compounds were not toxic to mammalian cells at therapeutic concentrations and were shown to be inhibitors of parasitic DHFR in a biochemical enzyme assay.
authors.affiliation: CSIR Biosciences, Meiring Naude Road, Pretoria, 0001 Gauteng, South Africa. Amanda.Rousseau@wits.ac.za and Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
authors.forename: Anna C U
authors.initials: AC
authors.lastname: Lourens
authors.affiliation: CSIR Biosciences, Meiring Naude Road, Pretoria, 0001 Gauteng, South Africa. Amanda.Rousseau@wits.ac.za and Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gravestock
authors.affiliation: Pharmacology Division, Department of Pharmacy and Pharmacology, WITS Research Institute for Malaria (WRIM), Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: van Zyl
authors.affiliation: CSIR Biosciences, Meiring Naude Road, Pretoria, 0001 Gauteng, South Africa. Amanda.Rousseau@wits.ac.za and Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa.
authors.forename: Heinrich C
authors.initials: HC
authors.lastname: Hoppe
authors.affiliation: CSIR Biosciences, Meiring Naude Road, Pretoria, 0001 Gauteng, South Africa. Amanda.Rousseau@wits.ac.za.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kolesnikova
authors.affiliation: BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand.
authors.forename: Supannee
authors.initials: S
authors.lastname: Taweechai
authors.affiliation: BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand.
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
authors.affiliation: BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand.
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.affiliation: CSIR Biosciences, Meiring Naude Road, Pretoria, 0001 Gauteng, South Africa. Amanda.Rousseau@wits.ac.za and Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS, 2050, South Africa.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Rousseau
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D003959:Diamines; D005493:Folic Acid Antagonists; D014227:Triazines