Shaping Antimalarials: A Geometry-First Approach to PfCLK3 Covalent Inhibitors

The emergence ofPlasmodium falciparumresistance to frontline therapies
highlights the urgent need for
new antimalarial agents. The essential, multistage kinase PfCLK3 is a validated target, and covalent kinase inhibitors
(CKIs) offer potential for durable inhibition. However, CKI design
has largely prioritised warhead reactivity over the geometric requirements
which govern covalent bond formation. Herein, we describe a geometry-first
approach to optimize covalent PfCLK3 inhibitors,
starting from the highly reactive chloroacetamide SB4–17 (2). Systematic variation of warhead and linker geometry revealed
that maintaining the α-reactive geometry of the chloroacetamide
scaffold enables covalent engagement of Cys368 with substantially
less reactive electrophiles. Notably, the methyl sulfamate analogue
SB5–171 (14) showed potent antiparasitic activity
(EC50 = 104 nM) and improved metabolic stability (t1/2 = 35 min in mouse hepatocytes). These findings
demonstrate that geometric optimization can decouple covalent engagement
from high intrinsic reactivity, providing a rational framework for
designing selective, drug-like CKIs.