Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry: potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase

Abstract

Efficient routes to 3-(1,2,3-triazol-1-yl)-and 3-(1,2,3-triazol-4-yl)pyrazolo [3,4-d]pyrimidin-4-amines using a one-pot two-step reaction are presented. The two routes give easy access to two different isomers of 1,4-disubstituted triazoles and the target compounds are obtained from a variety of readily available aromatic and aliphatic halides without isolation of potentially unstable organic azide intermediates. Two compounds show activity towards the PfPK7 kinase (IC 50 10-20 mM) of P. falciparum, the organism responsible for the most virulent form of malaria, and can be regarded as hits useful for further development into lead compounds.

Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia

“…8 In path a, Suzuki coupling between 3 and a boronic acid provided 4 which was subsequently alkylated at the N1 position of the pyrazole ring to yield 5 . 9 3-Chlorobenzoperoxoic acid ( m CPBA) oxidation followed by the displacement of the methyl sulfinyl/sulfonyl group by amines then provided the final pyrazolopyrimidine analogue 6 . 10 This sequence of reactions (path a) is ideal for exploration of structure-activity relationships (SAR) at the R 2 and R 3 positions.…”

A secreted Plasmodium falciparum kinase reveals a signature motif for classification of tyrosine kinase-like kinases

“…This suggests that this tyrosine residue might be exploited in the design of antimalarial drugs that target tyrosine gatekeeper-containing P. falciparum kinases. Structure-based inhibitor design using the crystal structure of PfPK7 has indeed started (Klein et al, 2009). Highly potent inhibitors targeting IRAK4 have been developed (Buckley et al, 2008a, b, c) and their potential for the treatment of inflammatory diseases is being evaluated (reviewed by Cohen, 2009;Wang et al, 2009).…”

Leveraging Cell Cycle Analysis in Anticancer Drug Discovery to Identify Novel Plasmodial Drug Targets

“…If not, it is likely that many compounds may be discarded because they do not show activity within 48 hours of culture. Several PfPK7 inhibitors show limited efficacy in 48 hour growth assays and it is tempting to speculate that these compounds would demonstrate better efficacy after prolonged parasite exposure (>48 hrs) [163,164].…”