Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore

• Published in: European journal of medicinal chemistry 2023-03, Vol.249, p.115043-115043, Article 115043
• Main Authors: Ong, Han Wee, Truong, Anna, Kwarcinski, Frank, de Silva, Chandi, Avalani, Krisha, Havener, Tammy M., Chirgwin, Michael, Galal, Kareem A., Willis, Caleb, Krämer, Andreas, Liu, Shubin, Knapp, Stefan, Derbyshire, Emily R., Zutshi, Reena, Drewry, David H.
• Format: Article
• Language: English
• Subjects: Antimalarials - pharmacology; Antimalarials - therapeutic use; Antiplasmodial; Group efficiency; Humans; Kinase inhibitor; Malaria; Malaria, Falciparum - drug therapy; Pharmacophore; Plasmodium berghei; Plasmodium falciparum; Plasmodium falciparum Protein kinase 6 (PfPK6); Protein Kinases; Structure-activity relationship study
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.115043

Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of action. We report the discovery of Ki8751 as an inhibitor of essential kinase PfPK6. 79 derivatives were designed, synthesized and evaluated for PfPK6 inhibition and antiplasmodial activity. Using group efficiency analyses, we established the importance of key groups on the scaffold consistent with a type II inhibitor pharmacophore. We highlight modifications on the tail group that contribute to antiplasmodial activity, cumulating in the discovery of compound 67, a PfPK6 inhibitor (IC50 = 13 nM) active against the P. falciparum blood stage (EC50 = 160 nM), and compound 79, a PfPK6 inhibitor (IC50