# Versatile Imidazole Scaffold with Potent Activity against Multiple Apicomplexan Parasites

## TL;DR

Researchers developed imidazole compounds that show strong activity against multiple apicomplexan parasites, offering a potential new approach for treating diseases like malaria and toxoplasmosis.

## Contribution

The study introduces a novel imidazole scaffold with potent and broad-spectrum antiparasitic activity targeting multiple conserved kinases in apicomplexan parasites.

## Key findings

- The imidazoles (R)-RY-1-165 and (R)-RY-1-185 show potent activity against Plasmodium falciparum and Toxoplasma gondii.
- The compounds target PfPKG and additional kinases like PfCDPK-1 and PfCDPK-4 due to conserved gatekeeper residues.
- The scaffold is effective against TgPKG, TgCDPK1, TgCDPK4, and MAPKL-1 in Toxoplasma gondii.

## Abstract

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