The botulinum neurotoxin serotype A (BoNT/A) is the deadliest toxin known to man with a lethal dose of 1.3 ng/kg of body weight. This neurotoxin is composed of a heavy chain (HC) which aides in binding and passing through nerve cell membranes and a light chain (LC), a zinc metalloprotease, that translocates through the cytosol and irreversibly cleaves its target substrate, SNAP-25. Cleavage of SNAP-25 prevents the release of acetylcholine and causes severe paralysis that is long-lasting and potentially fatal. Due to its high potency and ease of production, the BoNT/A is a potential threat as a biological weapon, and therefore, therapeutic countermeasures are of great interest. A series of small molecule inhibitors were designed around an indole core that was functionalized at various positions to increase interactions within the active site of BoNT/A LC. The 3-position of the indole was equipped with an L-isoleucine linker containing a hydroxamic acid at the C-terminus, which is necessary for chelation of the catalytic zinc ion in the active site. Various groups were substituted at the indole N-position and a phenyl ring was found to provide the best inhibition of 29% at 30 µM. To understand how the inhibitors interacted with the BoNT/A LC active site, computational docking was performed and revealed the importance of incorporating an amino acid linker, aromatic substitutions, and eluded to hydrophobic interactions that could be made in future scaffolds.