Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Abstract

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

Inhibition of Toxoplasma gondii Growth by Dihydroquinine and Its Mechanisms of Action

“…Remarkably, our studies showed that DHQ does not affect host cells’ mitochondrial membrane potential as shown in Figure 4C . A similar result was reported for other mitochondrial membrane potential inhibitors of T. gondii ( Zhang et al., 2019a ; Zhang et al., 2019b ; McPhillie et al., 2020 ). Thus, the DHQ mechanism of action was solely on the parasite mitochondria and not due to the influence of the hTERT cells.…”

The Apicomplexan Parasite Toxoplasma gondii

“…Therapeutic options available at present fail to eliminate tissue cysts that may reactivate at a later stage, usually when the immune system is compromised, leading to manifestations of acute toxoplasmosis. A new compound, the tetrahydroquinolone JAG21, has recently been reported as a promising treatment for acute and chronic toxoplasmosis [51].…”

A fresh look at the role of spiramycin in preventing a neglected disease: meta-analyses of observational studies

“…Since pyrimethamine and sulfadiazine can lead to negative PCR results [ 22 ], interpretation of amniocentesis and decisions about subsequent medical care may be complicated when a pregnant woman has received a pyrimethamine sulfadiazine regimen beforehand. While developing new medicines [ 38 – 40 ] may have less teratogenicity in the first trimester than pyrimethamine, and vaccination [ 41 ] may be another cost-effective preventative approach, at present gestational screening and spiramycin-based treatment for seroconverting women in the first 14 weeks of gestation protect against congenital toxoplasmosis.…”