Browsing by Author "Abbott, Belinda M."

A series of isoquinolines have been evaluated in a homology model of Plasmodium falciparum Protein Kinase A (PfPKA) using molecular dynamics. Synthesis of these compounds was then undertaken to investigate their structure–activity relationships. One compound was found to inhibit parasite growth in an in vitro assay and provides a lead to further develop 3-methylisoquinoline-4-carbonitriles as antimalarial compounds. Development of a potent and selective PfPKA inhibitor would provide a useful tool to shed further insight into the mechanisms enabling malaria parasites to establish infection.

An efficient and scalable route for a series of novel substituted 2-anilino-7H-pyrrolopyrimidine compounds as potential inhibitors of PDK1, an important regulator of the PI3K/Akt pathway that is dysregulated in many cancers, was developed and is described. The synthetic strategy was designed around Suzuki and BuchwaldeHartwig cross-couplings of a boronate fragment and various customised anilines sequentially with 2,4-dichloro-7-tosyl-7H-pyrrolopyrimidine. All fragments were constructed separately and cross-coupled to provide access to a range of novel compounds. Biological evaluation of these was undertaken, with modest inhibition observed.

PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed.

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki crosscoupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and SNAr/reductive cyclisation sequences, respectively.