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

• Published in: Bioorganic chemistry 2021-07, Vol.112, p.104839-104839, Article 104839
• Main Authors: Moolman, Chantalle, van der Sluis, Rencia, Beteck, Richard M., Legoabe, Lesetja J.
• Format: Article
• Language: English
• Subjects: Benzofurans; Glycogen synthase kinase-3; Malaria; PfGSK-3; Plasmodium falciparum; Protein kinase; Structure-activity relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104839

[Display omitted] •Benzofurans screened against recombinant P. falciparum glycogen synthase kinase-3.•Five compounds demonstrated selectivity for PfGSK-3 vs the human orthologue.•Most potent PfGSK-3 inhibitors (5p and 5m) exhibit sub-micromolar IC50 values.•Evaluated structure-activity relationships responsible for PfGSK-3 selectivity. 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.