Novel Toxoplasma gondii inhibitor chemotypes

Abstract

We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC values ranging from 0.3 to 2μM, comparable to that of 0.25 to 1.5μM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization.

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

“… Derivatives of KG8 ( Sanford et al, 2018 1 ) that were identified as effective in the preliminary screen ( Table 1 ) were further screened for possible cell viability inhibition in NR-9456, U2OS, and HEK293. Potential point mutagenicity was also screened for with the use of a bacterial reversion assay (Ames Assay).…”

“… Derivatives of KG8 ( Sanford et al, 2018 1 ) that were identified as effective in the preliminary screen ( Table 1 ) were further screened for possible cell viability inhibition in NR-9456, U2OS, and HEK293. …”

“… Derivatives of KG8 ( Sanford et al, 2018 1 ) were screened against both RH-dTom and Pru-dTom T. gondii . …”

“…A high-throughput phenotypic screen (HTS) of a chemical library produced a small collection of drug-like compounds with demonstrated efficacy against both Plasmodium falciparum and T. gondii in vitro ( Guiguemde et al, 2010 ). The three compounds with the highest potency against T. gondii were further characterized as potential leads for further optimization and development ( Sanford et al, 2018 ). The most promising of these was KG8 ( Fig.…”

“…KG8 and closely related analogues have been previously shown to inhibit cyclooxgenase-2 and 5-lipoxygenase ( Misra et al, 2013 ) in the host, and potentiate nerve growth factor ( Eguchi et al, 2000 ). KG8 is also an acyl hydrazone derivative of the antibiotic isoniazid; however, the latter was inactive against T. gondii in vitro ( Sanford et al, 2018 ). These data may suggest a host target of KG8, or potentially a parasite homolog target.…”