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

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-3 beta). 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 mu M). Evaluation of the structure-activity relationships required for PfGSK-3 selective inhibition indicated that a C6OCH3 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.

Automated summary

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 were synthesized and evaluated as inhibitors of PfGSK-3 and human glycogen synthase kinase-3 beta (HsGSK-3 beta). Among these compounds, five preferentially inhibited PfGSK-3, with four exhibiting IC50 values in the sub-micromolar range. Evaluation of the structure-activity relationships revealed potential for future design of PfGSK-3 selective inhibitors using chalcone-based scaffolds like benzofurans.