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 (t_1/2 = 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.