Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the lead identification of novel inhibitors based on β-lactam and imine templates. β-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC(50) values of 5.6 μM, 14.5 μM, and 22.1 μM, respectively. The binding affinity displayed by these compounds positions them as lead compounds for the design of future inhibitors of heat shock protein 90 based on the β-lactam and imine templates.