The intracellular parasite Toxoplasma gondii is estimated to infect up to 30% of the world population, leading to lifelong chronic infection of the brain and muscle tissue. Although most latent T. gondii infections in humans have traditionally been considered asymptomatic, studies in rodents suggest phenotypic neurological changes are possible. Consequently, several studies have examined the link between T. gondii infection and diseases such as schizophrenia, epilepsy, depression, bipolar disorder, dysphoria, Alzheimer’s disease, Parkinson’s disease, and obsessive-compulsive disorder (OCD). To date, there is varying evidence of the relationship of T. gondii to these human neurological or neurobehavioral disorders. A thorough review of T. gondii literature was conducted to highlight and summarize current findings. We found that schizophrenia was most frequently linked to T. gondii infection, while sleep disruption showed no linkage to T. gondii infection, and other conditions having mixed support for a link to T. gondii. However, infection as a cause of human neurobehavioral disease has yet to be firmly established.
We now describe the physicochemical profiling, in vitro ADME, and antiparasitic activity of eight N,N′-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD7.4 values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no N,N′-diarylurea had submicromolar potency against Trypanosoma cruzi, two had submicromolar potencies against Toxoplasma gondii and Trypanosoma brucei rhodesiense, and five had submicromolar potencies against Leishmania donovani. Plasmodium falciparum appeared to be the most susceptible to growth inhibition by this compound series. Most of the N,N′-diarylureas had antiprotozoal selectivities ≥10. One N,N′-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.
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