N-Hydroxyhomophthalimide is an inhibitor of viral and bacterial nucleases, and is thought to act by binding two closely-positioned divalent metal ions in the nuclease catalytic sites. This inhibitor has potential applications in inhibiting E. coli RNase III and Group I intron ribozymes that are present in opportunistic fungal pathogens, but not in humans. We are exploring the structure-activity relationships for this small molecule inhibitor. A simple, efficient method for preparing substituted homophthalic acids, beginning with readily available benzaldehydes, will be described.