Cryptosporidiosis is a diarrheal disease caused by the parasites C. parvum and C. hominis which can be life-threatening for children and immunocompromised patients. The only currently approved treatment for cryptosporidiosis, nitazoxanide, is only moderately effective in children and not effective in patients with immunodeficiencies. This study seeks to develop a novel treatment for cryptosporidiosis by exploring the role of core structure in the potency of a series of phosphodiesterase inhibitors in the Cryptosporidium parasites. By changing the heterocyclic core structure of an active compound (“core-hopping”), the structure activity relationship can be determined and used to optimize the structure of the potential drug molecule. Inhibition of the Cryptosporidium parasites by the synthesized analogs indicates that a pyrazole core structure may not be essential for activity and could be equally or more efficacious with an alternate core. This study may help lead to the development of a compound effective in the treatment of cryptosporidiosis in children and immunocompromised patients.