More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-<i>a</i>]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.

ABSTRACT: The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stabilit

SUBMITTER: Ong HW 

PROVIDER: S-EPMC11284802 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature