Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

A. G. Sanford, T. T. Schulze, L. P. Potluri, G. F. Watson, E. B. Darner, S. J. Zach, R. M. Hemsley, A. I. Wallick, R. C. Warner, S. A. Charman, X. Wang, J. L. Vennerstrom, P. H. Davis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

Original languageEnglish
Pages (from-to)488-492
Number of pages5
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume8
Issue number3
DOIs
Publication statusPublished - 1 Dec 2018

Keywords

  • Anti-parasitics
  • Drug discovery
  • Lead compounds
  • Toxoplasma gondii

Cite this

Sanford, A. G., Schulze, T. T., Potluri, L. P., Watson, G. F., Darner, E. B., Zach, S. J., ... Davis, P. H. (2018). Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii. International Journal for Parasitology: Drugs and Drug Resistance, 8(3), 488-492. https://doi.org/10.1016/j.ijpddr.2018.11.001
Sanford, A. G. ; Schulze, T. T. ; Potluri, L. P. ; Watson, G. F. ; Darner, E. B. ; Zach, S. J. ; Hemsley, R. M. ; Wallick, A. I. ; Warner, R. C. ; Charman, S. A. ; Wang, X. ; Vennerstrom, J. L. ; Davis, P. H. / Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii. In: International Journal for Parasitology: Drugs and Drug Resistance. 2018 ; Vol. 8, No. 3. pp. 488-492.
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abstract = "Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.",
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Sanford, AG, Schulze, TT, Potluri, LP, Watson, GF, Darner, EB, Zach, SJ, Hemsley, RM, Wallick, AI, Warner, RC, Charman, SA, Wang, X, Vennerstrom, JL & Davis, PH 2018, 'Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii' International Journal for Parasitology: Drugs and Drug Resistance, vol. 8, no. 3, pp. 488-492. https://doi.org/10.1016/j.ijpddr.2018.11.001

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii. / Sanford, A. G.; Schulze, T. T.; Potluri, L. P.; Watson, G. F.; Darner, E. B.; Zach, S. J.; Hemsley, R. M.; Wallick, A. I.; Warner, R. C.; Charman, S. A.; Wang, X.; Vennerstrom, J. L.; Davis, P. H.

In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 8, No. 3, 01.12.2018, p. 488-492.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

AU - Sanford, A. G.

AU - Schulze, T. T.

AU - Potluri, L. P.

AU - Watson, G. F.

AU - Darner, E. B.

AU - Zach, S. J.

AU - Hemsley, R. M.

AU - Wallick, A. I.

AU - Warner, R. C.

AU - Charman, S. A.

AU - Wang, X.

AU - Vennerstrom, J. L.

AU - Davis, P. H.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

AB - Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

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DO - 10.1016/j.ijpddr.2018.11.001

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EP - 492

JO - International Journal for Parasitology: Drugs and Drug Resistance

JF - International Journal for Parasitology: Drugs and Drug Resistance

SN - 2211-3207

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