We reported the first small molecule inhibitors of the interaction between the 
clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., 
clathrin inhibition1). Initial screening of a ∼17 000 small molecule ChemBioNet 
library identified 1. Screening of an existing in-house propriety library 
identified four substituted 1,8-napthalimides as ∼80-120 μM clathrin inhibitors. 
Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, 
potassium salt (18, IC50 ≈ 18 μM). A second library targeting the 4-aminobenzyl 
moiety was developed, and four analogues displayed comparable activity (26, 27, 
28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further 
four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 
10 μM, respectively. Docking studies rationalized the structure-activity 
relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, 
potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal 
domain-amphiphysin inhibitor reported to date.