Expeditious synthesis and biological evaluation of novel 2,N-6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials

• Published in: European journal of medicinal chemistry Vol. 46; no. 6; pp. 2022 - 2030
• Main Authors: Gravestock, David, Rousseau, Amanda L., Lourens, Anna C. U., Moleele, Simon S., van Zyl, Robyn L., Steenkamp, Paul A.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier 01.06.2011
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ANTIFOLATE RESISTANCE; Antimalarial; 2,N-6-Disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamine; FALCIPARUM DIHYDROFOLATE-REDUCTASE; ANALOGS; 1,2-DIHYDRO-S-TRIAZINES; MALARIA PARASITES; Cycloguanil; STRUCTURAL BASIS; PLASMODIUM-FALCIPARUM; Biguanide; FCR-3 Plasmodium falciparum strain; WR99210
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.02.054

A small set of novel 2,N-6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal aryl ring. Three zones were varied in this series of compounds, namely the nature of the substituent(s) on C-2; the nature of the substituent(s) on the distal aryl ring; as well as the nature and length of the flexible tether between the rings. The compound showing the best antimalarial activity (cycloguanil-resistant FCR-3 Plasmodium falciparum IC50 = 0.99 mu M) was N-6-(3-(4-chlorophenoxy)propyl)-2-(furan-2-yl)-1,2-dihydro-1,3,5-triazine-4,6-diamine hydrochloride. (C) 2011 Elsevier Masson SAS. All rights reserved.