Synthesis of New Triazolopyrazine Antimalarial Compounds

Johnson, Daniel J. G.; Jenkins, Ian D.; Huxley, Cohan; Coster, Mark J.; Lum, Kah Yean; White, Jonathan M.; Avery, Vicky M.; Davis, Rohan A.

doi:10.3390/molecules26092421

Open AccessFeature PaperEditor’s ChoiceArticle

Synthesis of New Triazolopyrazine Antimalarial Compounds

by

Daniel J. G. Johnson

¹,

Ian D. Jenkins

¹,

Cohan Huxley

¹,

Mark J. Coster

¹,

Kah Yean Lum

^1,2

,

Jonathan M. White

³,

Vicky M. Avery

^1,4

and

Rohan A. Davis

^1,2,*

¹

Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia

²

NatureBank, Griffith University, Brisbane, QLD 4111, Australia

³

School of Chemistry and Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia

⁴

Discovery Biology, Griffith University, Brisbane, QLD 4111, Australia

^*

Author to whom correspondence should be addressed.

Molecules 2021, 26(9), 2421; https://doi.org/10.3390/molecules26092421

Submission received: 31 March 2021 / Revised: 15 April 2021 / Accepted: 15 April 2021 / Published: 21 April 2021

(This article belongs to the Special Issue Organic Synthesis in Drug Discovery)

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Abstract

A radical approach to late-stage functionalization using photoredox and Diversinate^™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC₅₀ values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.

Keywords: Open Source Malaria; drug discovery; synthesis; triazolopyrazine; late-stage functionalization; photoredox; Diversinate^™; methylation; difluoroethylation; antimalarial; X-ray; radical disproportionation; mechanism

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MDPI and ACS Style

Johnson, D.J.G.; Jenkins, I.D.; Huxley, C.; Coster, M.J.; Lum, K.Y.; White, J.M.; Avery, V.M.; Davis, R.A. Synthesis of New Triazolopyrazine Antimalarial Compounds. Molecules 2021, 26, 2421. https://doi.org/10.3390/molecules26092421

AMA Style

Johnson DJG, Jenkins ID, Huxley C, Coster MJ, Lum KY, White JM, Avery VM, Davis RA. Synthesis of New Triazolopyrazine Antimalarial Compounds. Molecules. 2021; 26(9):2421. https://doi.org/10.3390/molecules26092421

Chicago/Turabian Style

Johnson, Daniel J. G., Ian D. Jenkins, Cohan Huxley, Mark J. Coster, Kah Yean Lum, Jonathan M. White, Vicky M. Avery, and Rohan A. Davis. 2021. "Synthesis of New Triazolopyrazine Antimalarial Compounds" Molecules 26, no. 9: 2421. https://doi.org/10.3390/molecules26092421

APA Style

Johnson, D. J. G., Jenkins, I. D., Huxley, C., Coster, M. J., Lum, K. Y., White, J. M., Avery, V. M., & Davis, R. A. (2021). Synthesis of New Triazolopyrazine Antimalarial Compounds. Molecules, 26(9), 2421. https://doi.org/10.3390/molecules26092421

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Synthesis of New Triazolopyrazine Antimalarial Compounds

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