Versatile Imidazole Scaffold with Potent Activity against Multiple Apicomplexan Parasites

• DOI: 10.1021/acsinfecdis.5c00049
• Publication Date: 2025-05-08T18:07:53Z
• Authors: Monique Khim; Jemma Montgomery; Mariana Laureano ...; Melvin Delvillar; Lyssa J. Weible; Mayuri Prabakaran; Matthew A. Hulverson; Tyler Eck; Rammohan Y. Bheem...; P. Holland Alday; David P. Rotella; J. Stone Doggett; Bart L. Staker; Kayode K. Ojo; Purnima Bhanot

Malaria, toxoplasmosis, and cryptosporidiosis are caused by apicomplexan parasites Plasmodium spp., Toxoplasma gondii, Cryptosporidium parvum, respectively, pose major health challenges. Their therapies inadequate, ineffective or threatened drug resistance. The development of novel drugs against them requires innovative resource-efficient strategies. We exploited the kinome conservation these to determine cellular targets effects two falciparum inhibitors in T. gondii C. parvum. imidazoles, (R)-RY-1-165 (R)-RY-1-185, were developed target cGMP dependent protein kinase P. (PfPKG), orthologs which present Using structural modeling approaches we determined that molecules bind stereospecifically interact with PfPKG a manner unique among described inhibitors. used enzymatic assays mutant expressing substituted "gatekeeper" residue activity is mediated through additional PfPKG. These likely include calcium 1 4 (PfCDPK-1, -4), kinases that, like PfPKG, have small amino acids at position. active tachyzoites being particularly sensitive. parasites, enzyme studies demonstrate TgPKG, TgCDPK1, TgCDPK4 mitogen activated kinase-like (MAPKL-1). Our results suggest this scaffold holds promise for new toxoplasmosis drugs.