Development of pyridyl thiosemicarbazones as highly potent agents for the treatment of malaria after oral administration.

Abstract

OBJECTIVES:

Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead.

METHODS:

Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse-Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis.

RESULTS:

TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice.

CONCLUSIONS:

TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted.

• Authors: Christopher J Parkinson, Geoffrey W Birrell, Marina Chavchich, Donna Mackenzie, Richard K Haynes, Carmen de Kock, Des R Richardson, Michael D Edstein
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 74 Issue 10 Pg. 2965-2973 (10 01 2019) ISSN: 1460-2091 [Electronic] England
• PMID: 31325302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Antimalarials
• Thiosemicarbazones

Topics

• Administration, Oral
• Animals
• Antimalarials (administration & dosage, chemical synthesis, pharmacokinetics, pharmacology)
• Blood Chemical Analysis
• Cell Line
• Cell Survival (drug effects)
• Chromatography, Liquid
• Disease Models, Animal
• Female
• Humans
• Malaria (drug therapy)
• Mass Spectrometry
• Mice
• Parasitic Sensitivity Tests
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Thiosemicarbazones (administration & dosage, chemical synthesis, pharmacokinetics, pharmacology)
• Treatment Outcome