Exploration of benzofuran-based compounds as potent and selective Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) inhibitors

Abstract

Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) has been identified as a potential target for the development of novel drugs against multi-drug resistant malaria. A series of benzofuran-based compounds was synthesised and evaluated as inhibitors of recombinantly expressed and purified PfGSK-3 and human glycogen synthase kinase-3 beta (HsGSK-3β). Of this series, five compounds (5k, 5m, 5p, 5r, 5s) preferentially inhibited PfGSK-3, with four of these compounds exhibiting IC₅₀ values in the sub-micromolar range (0.00048-0.440 µM). Evaluation of the structure-activity relationships required for PfGSK-3 selective inhibition indicated that a C6-OCH₃ substitution on ring A is preferred, while the effect of the ring B substituent on activity, in decreasing order is: C4'-CN > C4'-F > C3'-OCH₃ > C3',4'-diCl. To date, development of PfGSK-3 inhibitors has been limited to the 4-phenylthieno[2,3-b]pyridine class. Chalcone-based scaffolds, such as the benzofurans described herein, are promising new hits which can be explored for future design of PfGSK-3 selective inhibitors.

Keywords: Benzofurans; Glycogen synthase kinase-3; Malaria; PfGSK-3; Plasmodium falciparum; Protein kinase; Structure-activity relationship.