Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold.

1,2,4-Triazolo[4,3-a]pyrazines have previously been explored by the Open Source Malaria project as potent in vitro and in vivo antimalarial drug leads. With a view to generating a library of unique antimalarial 1,2,4-triazolo[4,3-a]pyrazines and exploring regiochemical preference for nucleophilic amines, we utilised the known synthetic 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (1) as a scaffold for aminations with 14 commercially available primary amines. Reacting scaffold 1 with excess primary amine at room temperature for 16 h generated the desired amine analogues in respectable yields (18-87%) and high purity (≥95%) following chromatography workup. The structures of the 14 previously undescribed amine analogues 2-15 were fully characterised following 1D/2D NMR, UV, and HRMS data analyses. X-ray crystallographic analysis of crystals obtained from the aminated products 2, 7, 10, and 15 are also reported here. The new library of amine-substituted triazolopyrazines was screened against the Plasmodium falciparum 3D7 strain. The tertiary alkylamine products 10-14 displayed antimalarial activity with IC(50) values ranging from 9.90 to 23.30 µM against P. falciparum 3D7, with compounds 10-12 demonstrating no toxicity at 80 µM against the human embryonic kidney cell line HEK293.