Hit-to-Lead Studies of Pyrazinylpiperazines against Visceral Leishmaniasis: Pharmacokinetic Profile and Efficacy of Potent Compounds against .

As part of the hit-to-lead optimization of antileishmanial pyrazinylpiperazines, the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the initial hit and five candidates for studies were assessed . These candidates, which displayed improved potency against (IC < 5 μM), were selected from an earlier structure-activity relationship study. Such assessment revealed that, except for the catechol derivative , all derivatives exhibited an improved overall ADME profile in comparison to the initial hit. The -hydroxyl analog stood out as the most promising candidate, being the second most potent compound against the parasite and showing far superior metabolic stability (more than twice as stable as the initial hit) in mouse liver microsomes, together with a reasonable gastrointestinal absorption and a lack of blood-brain barrier permeation. assessment of the antileishmanial efficacy of in a BALB/c mice model of visceral leishmaniasis revealed a reduction in parasitemia by 91.1 and 90.0% in the spleen and liver, respectively, after a 10 day treatment of infected animals with a 100 mg/kg daily dose of , without any acute toxicity or death among mice treated with . Flow cytometry demonstrated that the antileishmanial activity of is linked to a cytostatic effect, marked by cell cycle arrest in the G0/G1 phase and enhanced production of reactive oxygen species. Subsequent studies suggested that the activity of the novel antileishmanial pyrazinylpiperazine lead could be due to the inhibition of a nonspecific serine/threonine protein kinase in ; however, inhibition assays failed to identify a target for among a set of kinases and other proteins.