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Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (<b>3y</b>, IC₅₀ = 23.1 µM) enabled determination of a K_i value of 10.2 +/− 0.26 µM and observed two separate T_m values for <i>H. influenzae</i> DapE (<i>Hi</i>DapE).