The evaluation of metal co-ordinating Bis-Thiosemicarbazones as potential anti-malarial Agents

Fady N. Akladios, Scott D. Andrew, Samantha J. Boog, Carmen de Kock, Richard K. Haynes, Christopher J. Parkinson

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

BACKGROUND: The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority.

OBJECTIVE: The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents.

METHODS: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line. RESULTS: The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 < 250 nM).

CONCLUSION: Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.

Original languageEnglish
Pages (from-to)51-58
Number of pages8
JournalMedicinal chemistry (Shariqah (United Arab Emirates))
Volume15
Issue number1
DOIs
Publication statusPublished - 01 Jan 2019

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Thiosemicarbazones
Antimalarials
Metals
Artemisinins
Plasmodium falciparum
Benzene
Inhibitory Concentration 50
Iron
Fibroblasts
Lung
Pharmaceutical Preparations
In Vitro Techniques

Cite this

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title = "The evaluation of metal co-ordinating Bis-Thiosemicarbazones as potential anti-malarial Agents",
abstract = "BACKGROUND: The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority. OBJECTIVE: The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents. METHODS: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line. RESULTS: The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 < 250 nM). CONCLUSION: Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.",
keywords = "copper, iron, Malaria, metal coordination, Plasmodium, reactive oxygen, thiosemicarbazone.",
author = "Akladios, {Fady N.} and Andrew, {Scott D.} and Boog, {Samantha J.} and {de Kock}, Carmen and Haynes, {Richard K.} and Parkinson, {Christopher J.}",
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The evaluation of metal co-ordinating Bis-Thiosemicarbazones as potential anti-malarial Agents. / Akladios, Fady N.; Andrew, Scott D.; Boog, Samantha J.; de Kock, Carmen; Haynes, Richard K.; Parkinson, Christopher J.

In: Medicinal chemistry (Shariqah (United Arab Emirates)), Vol. 15, No. 1, 01.01.2019, p. 51-58.

Research output: Contribution to journalArticle

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T1 - The evaluation of metal co-ordinating Bis-Thiosemicarbazones as potential anti-malarial Agents

AU - Akladios, Fady N.

AU - Andrew, Scott D.

AU - Boog, Samantha J.

AU - de Kock, Carmen

AU - Haynes, Richard K.

AU - Parkinson, Christopher J.

PY - 2019/1/1

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AB - BACKGROUND: The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority. OBJECTIVE: The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents. METHODS: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line. RESULTS: The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 < 250 nM). CONCLUSION: Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.

KW - copper

KW - iron

KW - Malaria

KW - metal coordination

KW - Plasmodium

KW - reactive oxygen

KW - thiosemicarbazone.

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